RNA and Life Threatening Diseases 1774695073, 9781774695074

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RNA and Life Threatening Diseases

RNA AND LIFE THREATENING DISEASES

Edited by: Esha Rami

www.delvepublishing.com

RNA and Life Threatening Diseases Esha Rami Delve Publishing 224 Shoreacres Road Burlington, ON L7L 2H2 Canada www.delvepublishing.com Email: [email protected] e-book Edition 2023 ISBN: 978-1-77469-657-6 (e-book)

This book contains information obtained from highly regarded resources. Reprinted material sources are indicated and copyright remains with the original owners. Copyright for images and other graphics remains with the original owners as indicated. A Wide variety of references are listed. Reasonable efforts have been made to publish reliable data. Authors or Editors or Publishers are not responsible for the accuracy of the information in the published chapters or consequences of their use. The publisher assumes no responsibility for any damage or grievance to the persons or property arising out of the use of any materials, instructions, methods or thoughts in the book. The authors or editors and the publisher have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission has not been obtained. If any copyright holder has not been acknowledged, please write to us so we may rectify.

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ABOUT THE EDITOR

Dr. Esha Rami is presently working as an Assistant Professor, in the Department of Life science, Parul Institute of Applied Science, Parul University, India. She Did her Post graduated from Ganpat University, Ph.D. in biotechnology from Hemchandracharya North Gujarat University, in the year 2015. She has authored a number of national and international publications in reputed journals.

TABLE OF CONTENTS



List of Figures.................................................................................................xi



List of Tables..................................................................................................xv

Abstract...................................................................................................... xvii Preface..................................................................................................... ....xix Chapter 1

Introduction to RNA and Life-Threatening Diseases.................................. 1 1.1 Introduction.......................................................................................... 2 1.2 Mutations that Cause Splicing Defects in Disease ................................ 8 1.3 Splicing as a Modifier of Disease Susceptibility................................... 15 1.4 Splicing Abnormalities in Cancer........................................................ 22 1.5 Disruption of Alternative Splicing ...................................................... 23 1.6 RNAs as Therapeutic Targets and Tools................................................ 28 1.7 RNA Interference................................................................................ 32 References................................................................................................ 36

Chapter 2

Myotonic Dystrophy Type 2 (DM2)......................................................... 49 2.1 Introduction........................................................................................ 50 2.2 Nomenclature..................................................................................... 51 2.3 History................................................................................................ 52 2.4 Aetiology............................................................................................ 53 2.5 Pathogenesis....................................................................................... 55 2.6 Frequency........................................................................................... 56 2.7 Clinical Presentation........................................................................... 56 2.8 Instrumental Findings.......................................................................... 58 2.9 Diagnosis............................................................................................ 59 2.10 Conclusion....................................................................................... 62 References................................................................................................ 63

Chapter 3

Fragile X- Associated Tremor/Ataxia Syndrome .................................... 67 3.1 Introduction........................................................................................ 68 3.2 Fragile X Syndrome and Associated Disorders..................................... 68 3.3 Epidemiology of FXTAS....................................................................... 70 3.4 Clinical Presentation of FXTAS............................................................ 71 3.5 Neuroradiological Findings................................................................. 76 3.6 Pathophysiology.................................................................................. 77 3.7 Diagnosis............................................................................................ 82 3.8 Management and Ongoing Research.................................................. 84 3.9 Conclusions........................................................................................ 85 References................................................................................................ 87

Chapter 4

Past, Present, and Future of Arenavirus Taxonomy ................................. 95 4.1 Introduction........................................................................................ 96 4.2 Past Advancements in Arenavirus Taxonomy....................................... 98 4.3 Current Arenavirus Taxonomy........................................................... 100 4.4 Nomenclature: Spelling of Arenavirus Species Names...................... 104 4.5 Solutions to the Present Taxonomic Problems with Arenaviruses....... 106 References.............................................................................................. 111

Chapter 5

Cardiovascular Disease ......................................................................... 117 5.1 Introduction...................................................................................... 118 5.2 Topology of Disease.......................................................................... 118 5.3 Disease Burden................................................................................. 121 5.4 Future of Disease.............................................................................. 129 5.5 Cardiovascular Research................................................................... 130 5.6 Typology of Research........................................................................ 133 5.7 High Profile Research....................................................................... 136 5.8 Future Research Agenda................................................................... 137 References.............................................................................................. 139

Chapter 6

Neurological Disorders.......................................................................... 147 6.1 Introduction...................................................................................... 148 6.2 A Disease of Alzheimer and Other Dementias.................................. 150

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6.3 Epilepsy............................................................................................ 155 References.............................................................................................. 160 Chapter 7

Diabetes and Cancer ............................................................................. 165 7.1 Introduction...................................................................................... 166 7.2 Cancer Risk is Increased in Diabetic Patients.................................... 167 7.3 Incidence of Liver and Pancreatic Cancer is Increased in Diabetes........................................................................................ 168 7.4 The Role of Hyperinsulinemia .......................................................... 178 7.5 Anti-Diabetic Drugs that May Influence Cancer Risk in Diabetic Patients........................................................................... 183 7.6 Other Factors that May Influence the Risk of Cancer in Diabetes...... 185 References.............................................................................................. 188

Chapter 8

Blood Diseases ...................................................................................... 195 8.1 Introduction...................................................................................... 196 8.2 Anemia............................................................................................. 196 8.3 Leukocytosis..................................................................................... 202 8.4 Polycythemia Vera............................................................................ 203 8.5 Sickle Cell Disease........................................................................... 206 8.6 Thalassemia...................................................................................... 208 8.7 Von Willebrand Disease.................................................................... 211 8.8 Effects of Blood Disorders................................................................. 213 8.9 Diagnosis and Tests........................................................................... 215 References.............................................................................................. 221

Index...................................................................................................... 229

ix

LIST OF FIGURES Figure 1.1. Providing dsRNA to C. elegans (A) C. elegans can take in dsRNA that is expressed in bacteria that it consumes. (B) C. elegans can take in dsRNA by swimming in a fluid that already contains the molecule. (C) If dsRNA is injected into an egg, the process of gene silencing in the growing worm will be initiated. Figure 1.2. Splicing illnesses are caused by mutations, and the effects of these mutations are unknown. Figure 1.3. Posttranscriptional Gene Regulation and the mRNA Biogenesis Pathway Figure 1.4. Splicing Defects and diseases are caused by mutations that disrupt the CisActing Splicing Code. Figure 1.5. The variety of mRNA is increased through alternative splicing sequences. Alternative splicing dramatically increases the variety of mRNA transcripts by using different exons, introns, promoters, and polyadenylation sites. Figure 1.6. Pre-mRNA splicing is shown in a diagram. Figure 1.7. Splicing of pre-mRNA Figure 1.8. Diversification by alternative splicing. A graphic illustrating the numerous sorts of alternative splicing events that might occur in cells. Figure 1.9. Gain of Function in RNA Figure 1.10. RNA-based or RNA-targeted therapeutic approaches Figure 2.1. Myotonic Dystrophy Type 2 (DM2) Figure 2.2. Myotonic Dystrophy Type 2 (DM2) Figure 3.1. Fragile X premutation with fragile X-associated tremor/ataxia syndrome (FXTAS) diagnostic manifestations across time. Figure 3.2. In FXTAS, repeat the corresponding non-AUG (RAN) translations. RAN translating results in the generation of RAN products, based on where the process of translation begins. In the +0 reading frame, initiation (black triangle) leads to the formation of FMRpolyR (greenish squares), +1 to FMRpolyG (brown squares), and +2, inside the CGG-repeat region, to FMRpolyA. (yellow squares) Figure 3.3. The protein sequester was triggered by FMR1 RNA. The FMR1 free mRNA’s enlarged CGG-repeat region may create higher-order nanostructures that sequester proteins, resulting in a protein shortfall inside the cell. Repeat molecules that bind such as heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1), DiGeorge syndromes critical region 8 (DGCR8) protein, and Pur-alpha ((Pur) protein attach directly to the CGG-repeat region. Through interactions with directly attached proteins,

the CGG-repeat region may also indirectly sequester additional proteins. Drosha and heterochromatin protein 1 are two proteins that may be indirectly sequestered (HP1). Figure 3.4. FXTAS is diagnosed using neuroradiological criteria. T2-FLAIR: white matter abnormalities in the corpus callosum splenium, T2-TSE: symmetric white matter abnormalities in the middle cerebellar peduncles (MCP sign), T2-FLAIR: cerebral white matter abnormalities and brain atrophy Figure 4.1. Arenavirus particles emerge from an infected cell in electron micrographs. Figure 4.2. Arenavirus particle schematic diagrams. Figure 4.3. Study of L section sequences using Pairwise Sequence Comparison (PASC) and analysis of NP section sequences by amino acid distance. Figure 5.1. In 2002, the main causes of death were the leading causes of death worldwide (millions) Figure 5.2. CVD was the leading cause of mortality worldwide in 2002. (millions) Figure 5.3. In 2002, the top four illnesses in terms of worldwide DALYs lost were: Disease-related DALYs account for % of worldwide DALYs lost. Figure 5.4. In certain nations, the number of DALYs lost per 1000 people has decreased (2003 or nearest data) Figure 5.5. CVD research timeline: 1860s to 1970s Figure 5.6. From the 1980s until the present, researchers have been studying the cardiovascular disease. Figure 5.7. The number of worldwide clinical studies in chosen biomedical topics that have been reported in Medline. Figure 6.1. METHODS and associations regarding the neurological disorders. Figure 6.2.Cataloging of neurological disorders Figure 6.3. Disease of Alzheimer Figure 6.4. Kinds of epilepsy Figure 7.1. Illustration of diabetes and cancer Figure 7.2. the defining characteristics of diabetes and cancer, as well as the impacted biological systems. Figure 7.3. Diabetes and disease risk in the traditional paradigm of how diabetes promotes cancer progression. Figure 7.4. (A) Mammary tumor development in four equal groups of mice fed whether a regular diet or a food supplemented with oral glucose, insulin injections, or both (big variations: *P0.05; **P0.01; ***P0.0005(Heuson et al, 1972). Figure 7.5. the distribution of endogenous insulin using a three-chamber model: Insulin is generated by pancreatic b-cells and travels to the liver, where it is mostly utilized and destroyed; hence, peripheral tissues get 1/3–1/10 of the quantity acquired by the liver.

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Exogenous insulin is dispersed using a single compartment approach, which means once that infused, all tissues get a similar dosage. Figure 7.6. Total IR concentration and IR isoform transcription in matched healthy and malignant human breast, lung, and colon tissues. Cancer, as well as healthy tissue samples, were taken from the same people, and IR concentration was measured by ELISA. Figure 7.7. The ‘paradox’ of insulin resistance is seen Figure 8.1. Red blood cell counts that are unusually low are known as anemia. Figure 8.2. A bleeding ailment called hemophilia impairs the blood coagulation mechanism. Figure 8.3. Blood leukocytes with and without leukocytosis Figure 8.4. Standard versus Polycythemia Vera Figure 8.5. Sickle cell anemia Figure 8.6. Analyzing the differences between thalassemia and normal blood Figure 8.7. Normal and von Willebrand Disease contrasted

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LIST OF TABLES Table 1.1. Trans-Acting Mutations Affecting RNA-Dependent Functions that Cause Disease Table 2.1. Myotonic diseases have genetic traits. Table 2.2. Myotonic dystrophy form 1 (DM1) then myotonic dystrophy form 2 (MD2) have different genetic features (DM2) Table 2.3. Myotonic dystrophy kind 1 (DM1) and myotonic dystrophy kind 2 (DM2) clinical features (MD2) Table 2.4. Contributory conclusions in myotonic dystrophy form 1 (DM1) and myotonic dystrophy type 2 (DM2) patients (MD2) Table 5.1. Worldwide CVD morbidity projections in the future Table 5.2. Prediction of main CVD risk variables Table 6.1. Disability-Accustomed Life Span by Region and Cause, 2001 Table 7.1. Meta-analyses on the relative risk (RR) of cancer in different organs of diabetic patients Table 7.2. Oral hypoglycemic medications for treating type 2 diabetes mellitus are listed

ABSTRACT

A huge number of messenger RNAs (mRNAs) and non-coding RNAs must be accurately expressed for cells to function normally. These RNAs take a role in transcription, RNA processing, and translation. An in-depth examination of RNA-mediated genome regulation at several levels has been provided in the book RNAbased Regulation in Human Health and Disease. Starting with the Introduction of RNA, RNA as a therapeutic target, a further section examines the various diseases and significant potential for RNAbased medicines and diagnostics in the future. The book helps researchers, students and clinicians across the world who will find this book very informative as well as practical.

PREFACE

Numerous RNAs that code for proteins as well as those that do not code for proteins and the RNA-binding proteins that are linked with them combine to create ribonucleoprotein complexes, which are required for cellular activity (RNPs). It is possible for a mutation to be harmful if it causes a disruption in the RNA or protein components of RNPs, as well as the factors necessary for their assembly. Because of alternative splicing, cells have the extraordinary ability to precisely adjust both their transcriptome and their proteome in response to various signals. Splicing is dependent on a complicated code, a large number of RNA-binding proteins, and an extremely extensive network of connections between all of these components. As a result, there is an increased risk of being exposed to mutations and improper regulation, both of which can lead to illness. Both the finding of disease-causing mutations in RNAs and the rising understanding of the biology and chemistry of RNA are generating a multitude of potential therapeutic targets, and the growing understanding of RNA biology and chemistry is offering new RNA-based tools for the development of therapies. The book contains a total of eight different chapters that are separated from one another. In the first chapter, the reader is given an introduction to RNA as well as disorders that are potentially life threatening. Chapter 2 devotes a significant amount of space and time to analyzing the Myotonic Dystrophy Type 2 (DM2) condition. The Fragile X-Associated Tremor/Ataxia Syndrome is discussed in great depth in Chapter 3, which may be found here. Readers of the book are given an overview of the past, present, and future of arenavirus taxonomy in Chapter 4 of the aforementioned book. In Chapter 5, a significant amount of emphasis is placed on the cardiovascular diseases. In Chapter 6, the neurological disorders are analyzed and presented in more detail. Diabetes and cancer are both topics that are covered in Chapter 7. Blood diseases are covered in great depth in the last chapter, “Chapter 8, Blood Diseases,” which may be found here. This book does an excellent job of presenting a summary of the many various features of life-threatening disorders in a comprehensive manner. The information is given in such a manner that even an unskilled reader should have no problem grasping the core notions underlying RNA and life-threatening illnesses if they read this book. This is because the content is presented in such a way.

CHAPTER

1

INTRODUCTION TO RNA AND LIFE-THREATENING DISEASES

CONTENTS 1.1 Introduction.......................................................................................... 2 1.2 Mutations that Cause Splicing Defects in Disease ................................ 8 1.3 Splicing as a Modifier of Disease Susceptibility................................... 15 1.4 Splicing Abnormalities in Cancer........................................................ 22 1.5 Disruption of Alternative Splicing ...................................................... 23 1.6 RNAs as Therapeutic Targets and Tools................................................ 28 1.7 RNA Interference................................................................................ 32 References................................................................................................ 36

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1.1 INTRODUCTION The proper production of a vast quantity of protein-coding RNAs (also known as messenger RNAs [mRNAs]) and non-protein-coding RNAs is necessary for cells to carry out their typical functions. These RNAs take part in processes of transcription (for example, the 7SK RNA), RNA production process (for example, the minor nuclear RNAs [snRNAs] as well as the microRNAs RNAs [snoRNAs]), and transformation (for example, the ribosomal RNAs [rRNAs], transmitting RNAs [tRNAs], 7SL/SRP RNA, and small interfering RNA [miRNAs]). There seem to be a lot of different RNAs that are involved in various processes, such as transcriptase, MRP, or RNAs P RNAs (Alter et al., 2006). There are other RNAs whose roles are not completely understood or have only been partially defined (e.g., cupola RNAs, Y RNAs, Piwi-interacting RNAs [piRNAs]). RNAs occur in tissues as ribonucleoprotein combinations (RNPs), which are made up of one or even more RNAs and often a large number of RNA-binding amino acids. RNPs may include anywhere from one to hundreds of RNAs The RNPs are also the operational versions of respective RNAs, as well as the following certain procedures of the RNPs is dependent not only on the particular composition of respective protein components but also on the exact arrangement of those constituents (Asparuhova et al., 2007). Because there are many RNAs and also a very huge number of complex proteins that may bind to RNA, the biosynthesis of RNPs has to be carefully managed to ensure high levels of accuracy. Errors that damage some of the other elements of RNPs, whether RNAs or protein or even the mechanisms necessary for their formation may be harmful to cells causing illness. RNPs are complex molecules that include RNA and protein elements (Lukong et al., 2008; Wang and Cooper, 2007). There are already far too many examples of these kinds of scenarios for the author of this essay to be able to meaningfully explore more than a few of them within the confines of the available space. In this paper, we concentrate on errors in pre-mRNA skipping since they have been revealed as just a universal disorder mechanism that lies at the root of a wide variety of human genetic conditions (Barreau et al., 2006). Table 1.1 provides, from a more comprehensive point of view, a description of some instances of disease-causing abnormalities that are related to different kinds of RNAs and RNPs. In this article, we will explain so many diseases that are caused by genetic variations that influence the rearrangements of the synopsis that’s also generated from the very same gene (in cis). In addition, we will discuss genetic variations within transcriptional machines and equipment and also

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3

the proteins involved that influence the rearrangements of many other transcribed. These mutations can lead to a variety of different diseases (in trans). The finding of disease genetic variations in RNAs presents a variety of targeted therapies, and the ongoing elucidation of RNA organic chemistry also is generating additional techniques which can be utilised in the growth of RNA-based therapeutic agents (Aigner, 2007).

Figure 1.1. Providing dsRNA to C. elegans (A) C. elegans can take in dsRNA that is expressed in bacteria that it consumes. (B) C. elegans can take in dsRNA by swimming in a fluid that already contains the molecule. (C) If dsRNA is injected into an egg, the process of gene silencing in the growing worm will be initiated. Source: https://pharmrev.aspetjournals.org/content/72/4/862

The great majority of all protein-coding gene products as well as other sophisticated metazoans have several segments known as introns. These

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4

introns are a component of the original transcripts (pre-mRNA), but they are absent from the mRNA itself. A blending of pre-mRNA is indeed the process by which introns are removed and also the patterns that are already present in the mRNA (exons) which comprise the reading frame for coding protein as well as the 30 as well as 50 untranslated regions (UTRs) joined together (Bhalla et al., 2004). This process takes place before the mRNA is produced. Splicing must occur at a high rate while maintaining a high level of accuracy; this is a difficult task given that introns are generally bigger than exons and thus are littered with transcription dismissal codons; failure to remove these codons accurately will indeed result in incomplete proteins. The spliceosome is a huge and complex biochemical machine that is formed of snRNAs containing releasing factors. Along with RNA splicing, a large number of Transcription proteins are also involved in the process of defining exons and carrying out the splicing reaction. Splicing requires a lot of biosynthesis and metabolism energy, and it also requires a lot of monitoring, which is important to get rid of mRNAs that have been improperly spliced (Buratti & Baralle, 2008). The potential for damage caused by flaws in these procedures is therefore quite great. As a result, it was not immediately obvious why splicing first appeared, why it lasted, and how the number and quality of introns evolved with the development of increasingly sophisticated creatures. The potential for transposable elements seems to be the actual payout of splitting, whereby complex creatures have evolved to capitalize on (or maybe profited on for their evolution). Complicated organisms have developed to take advantage of (or maybe capitalized on for their evolvement) (Boudreau et al., 2009). Table 1.1. Trans-Acting Mutations Affecting RNA-Dependent Functions that Cause Disease Disease

Gene/Mutation

Function

Prader Willi syndrome

SNORD116

ribosome biogenesis

Spinal muscular atrophy (SMA)

SMN2

splicing

Dyskeratosis congenita (X-linked)

DKC1

telomerase/translation

Dyskeratosis congenita (autosomal dominant)

TERC

telomerase

Dyskeratosis congenita (autosomal dominant)

TERT

telomerase

Diamond-Blackfan anaemia

RPS19, RPS24

ribosome biogenesis

Shwachman-Diamond syndrome

SBDS

ribosome biogenesis

Introduction to RNA and Life-Threatening Diseases Treacher-Collins syndrome

TCOF1

ribosome biogenesis

Prostate cancer

SNHG5

ribosome biogenesis

Myotonic dystrophy, type 1 (DM1)

DMPK (RNA gain of function)

protein kinase

Myotonic dystrophy, type 2 (DM2)

ZNF9 (RNA gain of function)

RNA binding

Spinocerebellar ataxia 8 (SCA8)

ATXN8/ATXN8OS (RNA gain of function) unknown/ noncoding RNA

Huntington’s disease-like 2 (HDL2)

JPH3 (RNA gain of function)

ion channel function

Fragile X-associated tremor ataxia syndrome (FXTAS)

FMR1 (RNA gain of function)

translation/mRNA localization Fragile X

syndrome FMR1 translation/ mRNA localization linked mental retardation

UPF3B

translation/nonsensemediated decay

Oculopharyngeal muscular dystrophy (OPMD)

PABPN1

30 end formation

Human pigmentary genodermatosis

DSRAD

editing

Retinitis pigmentosa

PRPF31

splicing

Retinitis pigmentosa

PRPF8

splicing

Retinitis pigmentosa

HPRP3

splicing

Retinitis pigmentosa

PAP1

splicing

Cartilage-hair hypoplasia (recessive)

RMRP

splicing

Autism

7q22-q33 locus breakpoint

noncoding RNABeckwithWiedemann syndrome

(BWS) H19 noncoding RNA Charcot-Marie-Tooth (CMT) Disease

GRS

translation

Charcot-Marie-Tooth (CMT) Disease

YRS

translation

Amyotrophic lateral sclerosis (ALS)

TARDBP

splicing, transcription

Leukoencephalopathy with vanishing white matter

EIF2B1

translation

Wolcott-Rallison syndrome

EIF2AK3

translation (protease)

Mitochondrial myopathy and sideroblastic anaemia (MLASA) translation

PUS1

Encephalomyopathy and hypertrophic cardiomyopathy TSFM translation (mitochondrial)

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6

Hereditary spastic paraplegia

SPG7

ribosome biogenesis

Leukoencephalopathy

DARS2

translation (mitochondrial)

Susceptibility to diabetes mellitus

LARS2

translation (mitochondrial)

Deafness

MTRNR1

ribosome biogenesis (mitochondrial)

MELAS syndrome, deafness

MTRNR2

ribosome biogenesis (mitochondrial)

Cancer

SFRS1

splicing, translation, export

Cancer

RBM5

splicing

Multiple disorders

mitochondrial tRNA mutations

translation (mitochondrial)

Cancer

miR-17-92 cluster

RNA interference

Cancer

miR-372, miR-373

RNA interference

Genetic loci may produce various mRNAs that encode distinct proteins that vary by big or tiny sequences or various UTRs thanks to transposable elements. Gene mutation opens us to a world of possibilities for enriching the transcripts and proteomics without having to expand the genomes. Furthermore, alternate splicing may be controlled in various ways depending on the cell type, developmental status, or stimulus (Buratti et al., 2004). This sophisticated method switches the ratio of gene expression control from mostly transcriptional regulation, which involves the generation of a combination of columns of DNA transcripts, to mostly post-translational nonlinear complicated and complex pre-mRNA preparation. Current high deep sequenced studies show that splicing and hence transcribed isoforms are substantially more common in humans than previously believed (Pan et al., 2008; Wang et al., 2008). A significant number of spliced events may be necessary to create an mRNA in certain circumstances, and the number of splice alternatives might be overwhelming. Titin (Tn; 316 exons), the piano- dine receptors 1 (Ryr1; 106 exons), and dystrophin is samples of proteins produced by genetic mutations with a significant number of codons (DMD; 79 exons). Unfortunately, as the complexity of the system grows, so does its vulnerability to failure. Furthermore, abnormalities or chromosomal aberrations of the splicing are responsible for a huge range of human disorders (Cáceres & Kornblihtt, 2002). The primary splicing machinery (spliceosome) is made up of five small nuclear nucleosome complexes, which each contain either one or two snRNAs (U1, U2, U4/U6, plus U5) and a large number of protein components (possibly over the 100). RNA-binding molecules (e.g., U2AF, SF1, and SRFs) and enzymatic (helicases/RNPases, kinase, and phosphate-

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7

tases, among others) are among those protein components. To promote the spliced process, checking, and substrates releasing, they change the structure and sequential step-wise affiliations, dissociations, and conformation shifts of pre-mRNA, snRNAs, and associated proteins (Nil- sen, 2003; Will & Luhrmann, 2001). A small splicing system occurs in parallel with the main splicing mechanism, but recognizes various canonical substitution sequences and utilizes largely different snRNAs (U11, U12, U4atac/U6atac, and U5). Its nanoscale features are around 100-fold less numerous than those from the main splicing mechanism (Patel & Steitz, 2003). With exception of U6 and U6atac, every snRNP has permanent seven-membered rings of Sm proteins (the Sm core) that develop around a conserved region known also as the Sm domain and other snRNA-specific enzymes. The synthesis of snRNPs is just a complicated process that involves the exporting of embryonic pre-U snRNAs to a cytoplasmic (Staley & Guthrie, 1998), wherein Sm cores are assembled, and afterward the import settings of the snRNPs toward the nuclei to act in splicing once the snRNAs have been processed. The SMN (survivability of neurons) complex directs the formation of Sm cores, which is not a natural process. The SMN proteins, Gemini 2–8, and Unrip form an ATP-dependent assembly some of that selectively recognize snRNAs that bring these together along with Sm proteins. This identification is enhanced by a methylosome/PRMT5-mediated arginine alteration on Sm proteins (Neuenkirchen et al., 2008; Yong et al., 2004). Investigations of a devastating condition in which the eponymous protein, SMN, is missing have provided a significant understanding of this mechanism. Pre-mRNAs have a “splicing code,” which is composed of a dizzying amount and variety of fairly short cis-acting components inside exons and introns, as well as a vaguely defined complementary sequence that defines the analysis of different (Wang & Burge, 2008). RNA-binding specifically binds to these sites and has potentially positive (SR proteins) or negative (hnRNP enzymes) impacts on spliceosome formation in their proximity to maintain normal constitutive splicing or control splicing. The respective stoichiometries of these Transcription proteins play a crucial role in defining the splicing results for numerous genes throughout cells (Smith & Valcarcel, 2000). Because each cell subtype repertory is distinct, the control of such enzymes’ expression and function is crucial for proper transposable elements. In addition to illnesses resulting from mutations in transcription factors, such as variants, nonsense, and structure genetic changes in the transcription start site, that also result in deficient proteins, and genetic abnormalities in UTRs which influence transcription effectiveness or mRNA consistency, intronic

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RNA and Life Threatening Diseases

or exonic mutations that interfere with normal combining multiple patterns are already known for causing a large variety of diseases (Cáceres et al., 1998). Pre-mRNAs engage with a variety of RNA-binding members (hnRNP proteins) during cotranscription, which impacts their architecture and connections and plays important roles in processing and alternative splicing. Splicing results in the acquisition of extra proteins just at the spliced junction (changing exon connection complexes [EJC]), the removal of other proteins, and the continuation of mRNA-protein complexes (mRNPs) transformation as they travel to the cytoplasmic (Figure 1). (Dreyfuss et al., 2002; Tange et al., 2004). hnRNP molecules and SR (protease domain-containing) proteins are two types of proteins that shuttle between both the nucleus and cytoplasm (Pinol-Roma & Drey- fuss, 1992). They include involvement in transcription and translation, stabilization, and localization within the cytoplasm, in addition to their nucleocytoplasmic activities RNA editing adds still another level of sophistication to the transcripts (Schaub & Keller, 2002), as well as the identification of miRNAs, a large class of non - protein-coding RNAs which govern mRNA translations and stabilization, has added again another level of regulatory (Valencia-Sanchez et al., 2006). The significant number of polypeptides and regulatory RNAs involved in post-transcriptional Rna synthesis, as well as the infinitely complicated connection of conversations between them, give cells a magnificent capacity to good their gene expression patterns and speedily modify their gene expression profile in response to stimulation, but that also increases their security vulnerabilities to genetic variations and chromosomal aberrations, which causes a variety of diseases, including nerve and muscle and degenerative disorders (Maquat, 2004).

1.2 MUTATIONS THAT CAUSE SPLICING DEFECTS IN DISEASE At any codon junctions, three exhibiting similar are discovered: both 50 and 30 splicing sites, that are positioned at the 50 and 30 endpoints of the intron, respectfully, as well as the branch point sequence (BPS), which would be commonly found 30–50 nucleotide upwards of both the 30 replication origin (Cartegni & Krainer, 2002).

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Figure 1.2. Splicing illnesses are caused by mutations, and the effects of these mutations are unknown. Source: https://www.researchgate.net/figure/Examples-of-mutations-causingsplicing-diseases-and-their-possible-consequences-Exons_fig2_45094641

These nucleotides carry a significant percentage of something like the necessary information for accurate exon combining (about 50% in certain situations [Lim & Burge, 2001]) and therefore are identified by the translocase via RNA-RNA as well as RNA-protein relationships. After spliceosome construction, the 50-point mutation connects to U1 snRNP first, then it is to U6 snRNP; the BPS attaches SF1 but then U2 snRNP, as well as U2AF attaches around the 30 cleavage site. 9 percent–10 percent of genetic illnesses are generated by genetic variations in sequences that interrupt these connections (Cartegni et al., 2002; Wang & Cooper, 2007). The residual splicing material is included within minor (six nucleotides) analysis and

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RNA and Life Threatening Diseases

provides insight for both insertion and deletion which either increase or inhibit translation (Wang and Burge, 2008). Exonic splicing enhancers (ESEs), as well as exonic splicing silencers (ESSs), work inside exons to activate or suppress splicing, whereas intronic splicing enhancers (ISEs) and suppressors (ISS) work inside introns. As opposed to the (Cartegni et al., 2002)

Figure 1.3. Posttranscriptional Gene Regulation and the mRNA Biogenesis Pathway. Source: https://www.researchgate.net/figure/miRNA-biogenesis-and-examplesof-post-transcriptional-controls-MiRNAs-are-transcribed-as_fig1_273786978

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The complicated code created by all these supplementary splicing components is only partly known, unlike consensual chromosomal regions, which are rather clearly defined in both sequencing and location. While a large chunk of the coding has been decoded, it is still impossible to tell whether such a plaque mutation would impair splicing just on nucleotide sequences. This is due through part to the fact that these components are made up of a variety of sequencing classes, the complete complements of which has yet to be determined. There was also a misunderstanding of the code’s nuances, such as the code’s considerable interconnectivity within both parts (Roca et al., 2008). Whereas the preferential receptors for even more than 40 proteins are currently known, especially for SR as well as hnRNP proteins (Gabut et al., 2008), cognate-specific sites for just a percentage of the expanding list of possible splicing components have been found. Transcriptional elements are found in almost all exons, even if they are variably or continuously spliced (Wang & Burge, 2008). As a consequence, when it comes to the impact of nucleotide changes on splicing, exons are indeed a veritable hazard. Nonsynonymous and terminating codons, as well as up to 25% of synonym-mouse (concerning amino - acids encoding) alterations, may interrupt the normal spliced (Pagani et al., 2005), underscoring the relevance of addressing silence and alterations as facilitators of pathological consequences. About 50% of genetic variations inside exons influence splicing in certain genes, and much more than half of all reported genetic disorder mutations are thought to affect spliced (LopezBigas et al., 2005). Exonic mutations that can cause abnormal translation have indeed been identified in considerable numbers (Cartegni et al., 2002; Wang & Cooper, 2007). Genetic disorder exonic alterations, which have been intensively investigated and becoming focus foci for numerous RNAbased treatment methods, are truly helpful. A genetic mutation in the motor neuron 2 (SMN2) gene, which plays a major role in neuromuscular disorders, is a striking example of the severe influence that changes in exonic spliced information can have in 1995. SMN is a transcription protein that is essential for survival among all cells in evolving eukaryotes and is involved in the synthesis of snRNPs (Neuenkirchen). SMA is a common motor neuron degenerative illness that is usually fatal, and even a leading cause of neonatal mortality. The severity of SMA is related to the extent of functional SMN protein deficiency (Cartegni et al., 2006). Humans have two SMN genomes, SMN1 and SMN2, which combined produce the same genome. The majority of SMA patients have abnormalities in Protein expression but still have SMN2, suggesting a somatic

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mutation, a C/T change at amino acids in exon 7 of SMN2, which generates a regulatory deficiency. Even though such a mutation does not affect amino acid sequencing, it has a major impact on the SMN2 pre-mRNA splitting pattern, causing extensive exon 7 bypassing, resulting in an unproductive and instability protein missing the final 16 amino acids (Figure 2A). As a result, SMN2 is substantially less successful in producing SMN protein than SMN1 (Wirth et al., 2006). Exon 7 jumping in SMN2 has been explained by two hypotheses. Being that the alteration destroys an ESE whereby the translational promoter ASF/SF2 attaches, another is that it forms an ESS whereby the splicing suppression hnRNP A1 links. These theories, while they seem to be at odds, are consistent (Cartegni et al., 2006) and highlight the unsustainability of splitting signals, since a single nucleotide mutation may turn an ESE into such an ESS. It’s fascinating that crucial Binding protein sites are widespread, plentiful, and functionally important (Cartegni & Krainer, 2003).

Figure 1.4. Splicing Defects and diseases are caused by mutations that disrupt the Cis-Acting Splicing Code. Source: https://www.nature.com/articles/nrg2164

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Note: (A) Degenerative motor neuron disease SMA is caused by a mutation in the SMN1 gene. The C→ T mutation in exon 7 of the SMN2 gene disables an exonic translation mechanism. enhancer (ESE), and creates an exonic splicing silencer (ESS), leading to exon 7 skipping and a truncated protein (SMND7). (B) A T→A A protein-coding codon (STOP), as well as an ESS, are created concurrently in exon 31 of the gene product, resulting in exon 31 bypassing. So because mRNA missing exon 31 creates a partly specific protein, such mutation causes a moderate form of DMD (Castle et al., 2008). (C) Snipping procedure is applied are affected by mutations inside and ahead of codon 10 of both the MAPT gene, which codes for tubulin, and the typical 1:1 proportion of mRNAs containing or omitting exon 10 is disrupted. This causes the neurodegenerative condition FTDP-17, which is caused by a disruption in the equilibrium between tubulin with four and three tubulin domains (4R-tau and 3R-tau, accordingly). The N279K alteration, for example, improves ESE functionality by boosting exon 10 incorporation and changing the equilibrium towards a more 4R-tau (Chen et al., 2007). (D) Polymorphic (U)m(AG)n sequences inside the Gene encoding exon 9 30 splicing site affect the degree of exon 9 insertion as well as the level of fully functioning protein, altering the intensity of genetic disorders (CF) induced by mutations somewhere in else in the CFTR gene (Chénard & Richard, 2008). Because of all the simplicity in which the equilibrium of favorably and negatively responding utilizing its assets (ASF/SF2-hnRNP A1, among others) may be modified, it is expected there will be many more examples where spliced is modified. This SMN2 mutation has important repercussions for splicing control due to its crucial role in the synthesis of snRNPs for splicing management (described below). The enormous (2.4 Mb) dystrophin gene, with the majority of its 78 introns, is a transcribing disaster, and it does in Motor neuron disease, with just a frequency of 1:3000 male births (DMD) (Cho et al., 2005). Failure mutations occur in DMD, and although genomic deletions account for more than 65 percent of DMD mutations, a high number of alternatively spliced and intronic genetic variations induce illness via abnormal splicing. Dystrophin is found in the extracellular domain of both the muscle tissue Sarco- lemma, where this sends and receives signals from the extracellular environment and the intracellular contractile machinery, as well as stabilizing the cellular membranes, that should survive repetitive contractility distortions (Danos, 2008). Just at N - the terminal end, the

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protein has an actin-binding structure, a linkage region with 24 spectrin-like repetitions, a cysteine-rich domain, as well as a C-terminal website.  Exon 31 has a T/A mutation that also results in a premature stop codon (PTC), but also in the introduction of an ESS which interacts with hnRNP A1, leading to complete exon jumping (Disset et al., 2006). (Figure 2B). mRNAs missing this gene lose encoding with one spectrin-like repetition but have the proper reading frame, resulting in a partly protein product, which explains why someone with this mutation has a milder version of the illness than most would predict given the existence of a PTC. In this case, if just the PTC variation found in the genome had been evaluated, the particular method of sickness would be overlooked, illustrating the importance of determining the impact of abnormalities on stringing directly utilizing RNA from the afflicted tissues (Clark et al., 2002).

Figure 1.5. The variety of mRNA is increased through alternative splicing sequences. Alternative splicing dramatically increases the variety of mRNA transcripts by using different exons, introns, promoters, and polyadenylation sites. Source: https://onlinelibrary.wiley.com/doi/10.1002/path.2649

Examples like this one also indicated that triggering exon jumping to re-establish the reading frame might have therapeutic effects (see below) (David & Manley, 2008). Mutations inside and ahead of the intergenic exon 10 of the tubulin protein tau (MAPT) genes, which codes again for tau protein, break the 1:1 ratio necessary for mRNAs that contain or omit that exon, as just an instance. Exon 10 encrypts the third to one-half of four tubulin domains

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(R) and disrupts the balancing act among 4R-tau as well as 3R-tau isozymes (Figure 2C) causing dephosphorylation and accumulation of specific proteins into the neurofibrillary, which are hallmarks from several neurodegenerative disorders including Alzheimer’s disease (AD) (de Haro et al., 2006). Snipping rest of the items are abundant in this gene and its neighboring introns, indicating that this exon’s slicing is tightly regulated. Several genetic variations mostly around MAPT exon 10 interrupt specific genomic and intronic combining multiple elements, resulting in the hereditary neurodegenerative disorder Alzheimer’s disease with Parkinson’s disease related to different chromosomes (FTDP-17), proving a direct link among both abnormalities tau interpretation and neurosciences (Daoud et al., 2009). The cystic fibrosis transmembrane regulator (CFTR) genes, which produce a transdermal chloride channel essential for appropriate secretory epithelial function in various organs such as the lungs, intestine, and reproductive organs, also is high up on the list of genetic disorders splicing abnormalities. A tryptophan deficiency (DF508) results in a significant reduction of CFTR protein function, which accounts for more than half of all cystic fibrosis (CF) patients in the United States (Disset et al., 2006). Several variants in other parts of both genes cause milder versions of the illness (atypical CF); yet, people with the same variant have large variances in pathogenicity. Polymorphic (UG)m and (U)n sequences at the 30-point mutation of CFTR genomic 9, which displays modest exon skipped even in healthy participants, is one explanation for these variances. Exon jumping is more common in those with a longer (UG)m tract, which is due to higher TDP-43 interaction (Figure 2D). Exon 9 insertion and, eventually, the quantity of fully functioning protein produced to influence the intensity of the consequences of alterations somewhere else in the Gene mutation (Denti et al., 2006).

1.3 SPLICING AS A MODIFIER OF DISEASE SUSCEPTIBILITY Personal phenotype variations, such as symptom severity (modifier keys), immune status, formation of multiple genetic common illnesses, and variances in positively and negatively reactions to medicinal chemicals, are all largely determined by genetic diversity. Recent findings show a surprising degree of variation in the regulation of different isoforms across individuals, strongly implying that splicing plays a role in phenotype

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variations that are important to illness (Dreyfuss et al., 1993). More to 21% of point mutation genes might be affected by local polymorphism, according to an early assessment of the impact of genetic diversity on splicing. Gene mutations influenced distinctions in mRNA configuration to regulating the expression and then in 50 and 30 ends shortlisting more often than distinctions for whole gene mRNA tiers, according to a combined analysis of expression pattern (such as combining multiple differences) utilizing exon tiling genotyping connected to polymorphism dedication that uses the CEU HapMap (Kwan et al., 2008). A recent study using profound genetic analysis for global quantitative of alternate solution isoforms in cerebral tissue from six individuals found that at least 30% of combining multiple events had ordinary person differences, indicating striking variations in both cis- and genderfluid splicing surroundings (Wang et al., 2008). These findings back up the idea that variants in genetic material and exons have such a big influence on individual gene regulation just at the RNA processing stage, and also that they play a big part in symptom severity, vulnerability, and treatment responses. The objective of offering individualized therapy in the future will need a thorough knowledge of the impact of genetic differences on both the spliced code and also the nuclear-spliced apparatus that interprets it (Dominski & Kole, 1993).

Figure 1.6. Pre-mRNA splicing is shown in a diagram. Source: https://www.nature.com/articles/gim2013176/figures/1

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1.3.1 Disease-Causing Defects in the Splicing Machinery Variations in the spliced machinery’s parts, as much as any of the transacting spliced elements and associated regulators, get the ability to impact the expression of a vast group of genes, either directly or indirectly (Elmén et al., 2008). Modifications in universal translocase elements and spliced factors may induce tissue-specific pathogenicity, and alterations in the comparative stoichiometric ratio of generic cutting back can cause dramatic changes in splicing sequences and cause illness, which are two major topics that have arisen in recent years. Splicing errors are especially common in neurological illnesses and malignancies. Though particular causation is difficult to establish in many situations, our investigation highlights the immense susceptibility of spliced, its inherent pathogenic, as well as the potential value of combining multiple variations as disease indicators (biomarkers) and targeted therapies (Dreyfuss et al., 2002).

1.3.2 Mutations in Spliceosome Components Even though now the spliceosome contains a significant variety of proteins including five snRNPs, only a few abnormalities in core translocase elements have indeed been discovered, indicating that such changes are nonviable at the molecular level or during the early stages of development. Mutations in four proteins (PRPF31, PRPF8, PRPF3, and RP9) are linked to translocase function disturbance and all produce autosomal dominant types of macular degeneration (RP) (Friedman et al., 1999). The U4/U5/ U6 tri-snRNP complexes, which connect the forming strong group to create the catalytic core, contain all four proteins. Dominant transmission shows that in photosensitive neurons, the afflicted units, haploid stability does not offer a sufficient amount of translocase activity. With lymphoblast cell cultures produced from RP patients with null genotypes for PRPF31, for instance, a general failure in spliced wasn’t detected (Rivolta et al., 2006), but particular pre-mRNAs were identified to be susceptible to PRPF31 alterations in transfection tests (Mordes et al., 2007). Photoreceptor neurons’ unusual sensitivity might be due to a failure to create enough overexpressed mRNAs, like those from the rhodopsin gene (alterations in this genetic factor also cause leading methods of the sickness). Alternative methods, such as photoreceptor-specific susceptibility to aggregation created by aberrant body composition, are conceivable (Mordes et al., 2007).

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1.3.3 Changes in the snRNP Repertoire and Splicing Abnormalities in SMA The SMN apartment’s most well-known function is its crucial involvement in the synthesis of snRNPs. A lack of SMN leads to a reduction in snRNP assembling capability.  Recombinant snRNPs were injected into SMNdeficient zebrafish embryos to repair motor neuron developmental delays (Winkler et al., 2005), and decreased snRNP assembling was reported in an SMN-deficient SMA animal model. Recent research in these animals showed significant modifications in RNA metabolism, particularly alterations in snRNAs and a variety of spliced errors (Zhang et al., 2008b). Interestingly, rather than a consistent reduction in the strategy for sustainability among all snRNAs in all tissues of SMN-deficient animals, individual snRNA is impacted differently, leading to various snRNA conformations and a changed snRNP repertory in each tissue Splicing irregularities affecting several mRNAs of operationally varied genes are also caused by SMN loss, including alterations in the proportions of known intergenic transcripts as well as various splicing faults of regulatory exons (Coppola et al., 2012). Depletion of generic and parametric elements of the spliced mechanism may have diverse impacts on the splicing of particular pre-mRNAs and transcriptional in yeast and Drosophila, according to knockdown studies. Even though the mechanisms behind SMN deficiency’s splicing abnormalities are unclear, since SMN would not be a spliced factor, it is fair to speculate that alterations within snRNP repertory influence the effectiveness, frequency, and accuracy of translocase formation on distinct introns. SMN may also have a significant role in the splice, either alone or in combination with other proteins (Frischmeyer & Dietz, 1999). These findings show how a deficit in a pro-inflammatory cytokine household protein may result in tissue-specific consequences, and they provide a novel way of looking at the pathogenesis of SMA. Conciliating the established housekeeping role of SMN with both the seeming preference of SMA pathophysiology to neurons has been a dilemma in SMA (forward alert motor neurons and the strengths of the internal- rate) (Fukuhara et al., 2006; Mizuguchi et al., 2005). The snRNP repertory of a cell is most likely determined by tissue-specific mechanisms working in tandem with SMN. Because every single cell has its own set of utilizing its assets, and SMN insufficiency uniquely alters the snRNP repertory, the ensuing disruptions are diverse, leading to cell type-specific spliced consequences. These results also reveal that now the SMN complexes play an important role in

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RNA metabolic and spliced control, suggesting that splicing errors occur throughout species, not just in nerve cells (Gabanella et al., 2007). Even though current research reveals that isoforms are often more widespread than previously thought, it is obvious that every tissue generates a regular trend of intergenic mRNA transcripts. It is also unclear why, despite many splicing errors, other organs in SMA rats do not develop the overt disease (MartinezContreras et al., 2007; Smith & Valcarcel, 2000). To solve this problem, it will be necessary to identify the amount to which aberrant mRNAs are transcribed. SMN likely has a role in the biosynthesis or functioning of many other RNPs, particularly combinations including that of the Sm-like proteins (Lsm polypeptides) in which it connects, and also snRNPs, hnRNPs, and mRNPs (Gabut et al., 2008). It’s probable that, in addition to its impact on snRNPs during translation, SMN depletion has additional impacts on RNA metabolism. There are still many unanswered questions, such as whether transformation in the snRNP repertoire seems to be the causative factor of the combining multiple abnormalities, regardless of whether SMN or even the SMN complicated plays those certain responsibilities in sequencing, as well as whether motor nerve death is ended up causing by misplacing from one or multiple specific mRNAs or through the combined impact of several duplication irregularities (Fukuhara et al., 2006).

1.3.4 Splicing Factors in Disease Several of the hnRNP and SR proteins that control splicing, including the main spliceosomal snRNPs, are abundant over their strong affinity sites onto pre-mRNAs (Dreyfuss et al., 1993, 2002). Even little variations during one of their expressions, and hence their comparative stoichiometry, may have a significant impact on transposable elements (Caceres & Kornblihtt, 2002; David & Manley, 2008). Additionally, many hnRNP and SR proteins shuffle between the cytoplasm and nucleus continually (Caceres et al., 1998; Pinol-Roma & Dreyfuss, 1992), but also their substrate network may alter in reaction to stress responses (Caceres et al., 1998). The composition of splicing components within the nucleus may vary as a consequence, modulating native spliced patterns. Changes in the transcription of Transcription proteins that are involved in stringing and splicing control have been linked to a variety of illnesses (Gabut et al., 2008; Lukong et al., 2008).

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Figure 1.7. Splicing of pre-mRNA. Source: https://www.frontiersin.org/articles/10.3389/fimmu.2021.713540/full

Many RNA-binding proteins may have function in neurologic and mental illnesses, according to recent research. TDP-43 is just a hnRNP protein with a fundamental similar system to hnRNP A1 and A2. It was first found as interacting with the HIV trans-acting response element (TAR) and later proved to be a translational regulator of HIV. It’s been discovered to have several distinct connections with illness (Buratti & Baralle, 2008). In just one, TDP-43 attaches to polymorphism (UG)m repetitions in intron 8 of the pre-mRNA of CFTR (the gene defective in genetic disorders), causing higher exon 9 skipping due to enhanced attachment to longer (UG) m repetitions. TDP-43, which is ordinarily nuclear, has been discovered in cytoplasmic aggregates in damaged brain areas of people with frontotemporal (FTD), Alzheimer’s disease, and motor neuron disease (ALS) (Ule, 2008). TDP-43 is reduced from the nucleus in these individuals, and the proteins that aggregate in cytoplasmic aggregates are ubiquitinated, degraded, or phosphorylated improperly. These results are a big step forward as well as

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a helpful histology marker for FTD. TARDBP genetic polymorphisms, that encode TDP-43, are linked to both spontaneous and familial types of ALS, indicating that TDP-43 plays a role in the etiology of neurological illnesses (Daoud et al., 2008; Kabashi et al., 2008). It’s unclear if the harmful pathway is related to the cytoplasmic aggregation’s toxic effects, the absence of TDP43’s nuclear functioning, or a combination (Ghigna et al., 2005). Quivering is another Transcription protein that has lately been linked to neurological diseases (QKI). The gene disrupted in the spontaneous mouse dysmyelination mutation, quaking viability, has a human counterpart, QKI (qkv). The protein belongs to the STAR group, which includes domains that connect RNA binding to signaling pathways. QKI affects both spliced and mRNA preservation and generates nuclear and cytoplasmic versions through splicing; possible pre-mRNA, as well as mRNA receptors, have already been discovered (Chenard & Richard, 2008). In mice, QKI transcription in oligodendrocytes is essential for an appropriate myelin sheath, and it also plays a key role in the differentiating of vascular endothelium progenitor cells cultured, which requires RNA activity by binding (Chen et al., 2007). Based on the genetic linking data and mRNA expression investigations, QKI is a solid candidate gene for schizophrenic vulnerability. These results show that posthumous patient normal brain samples had lower production of QKI mRNA and potential QKI targeting mRNAs in illness areas (Lauriat et al., 2008; de Paula Brandão et al., 2020). Surprisingly, a massive investigation of relationships among proteins linked to hereditary ataxias discovered many RNA-binding protein groups, particularly QKI, Prima, and Fox (Lim et al., 2006). Fox is a major splicing regulation in various tissues, such as the mind, while Nova is among the greatest controllers of a transcriptional network, regulating the production of proteins influencing mode is activated (Ule et al., 2005;Underwood et al., 2005). Thousands of possible targets for neurological functions and genes related to disorders affecting nerves and striations muscles where Fox transcription is high were discovered after an investigation of the Fox splicing signaling pathways (Zhang et al., 2008a). Furthermore, A2BP1/FOX-1 gene mutations have been linked to mental impairment, seizures, and autism (Bhalla et al., 2004; Sebat et al., 2007), indicating a direct involvement in illness. Other RNA processing activities for Nova and Fox protein are anticipated to include controlling alternative

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gene produces site selection (Licatalosi et al., 2008). These findings strongly imply that RNA-binding proteins have additional functions in developing and changing the intensity of neurological disorders (Pinol-Roma & Dreyfuss, 1992).

1.4 SPLICING ABNORMALITIES IN CANCER Splicing interruption has traditionally been assumed to be a characteristic of a range of malignancies; however, new computational analysis employing melanoma simple sequence tags (ESTs) discovered that the incidence of intergenic genes in tumors was somewhat lower than in healthy tissue. The genetic makeups, rather than the amount of point mutation genes, vary among normal and malignant cells (Kim et al., 2008; Ying et al., 2006). The biggest challenge has been determining whether splicing alterations seen in cancer are harmful; nonetheless, the cause-and-effect links between both the generation of disease splice variants and tumor development and progression have become apparent (Glisovic et al., 2008; Shiraki & Daikoku, 2020). Cis-acting polymorphisms result in abnormal splicing and transcription of cancer-related genes. Numerous genes control transcriptional by balancing hnRNP and SR protein, resulting in optimum ratios of pro-and proapoptotic transcripts (Srebrow & Kornblihtt, 2006). Nevertheless, it is becoming obvious that transcriptional played the role in cancerous cells is exceedingly complicated, since the impact of a spliced regulation on the very same spliced event may vary greatly across cells. A study of the impact of 14 hnRNP proteins reduction on 56 apoptosis gene transcriptional events in three cancer/immortalized cell populations found a surprising amount of cellular paragraph effects (Venables et al., 2008). The findings suggest that the impact of changes in personal splicing variables is difficult to anticipate due to cell-specific variability in trans-acting regulating contexts (Rutherford et al., 2008; Sreedharan et al., 2008). Considering these complications, substantial linkages have been shown between changed expression of certain splicing factors, abnormal splicing of specific which was before the target, and stimulation of signaling pathways related to altered or cancerous cellular behaviors (Goyenvalle et al., 2004). The SR proteins SF2/ASF, which would be increased in numerous malignancies and causes conversion when upregulated at low concentrations, have been identified as having a particularly consistent picture.

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Figure 1.8. Diversification by alternative splicing. A graphic illustrating the numerous sorts of alternative splicing events that might occur in cells. Source: https://www.frontiersin.org/articles/10.3389/fmolb.2018.00080/full

Increased levels of SF2/ASF cause splicing to create a carcinogenic variant of the protein kinase S6 kinase-b1 (S6K1), a transcription regulator, and knockdown tests showed that such an isoform is necessary for SF2/ ASF transformation (Karni et al., 2007; Taylor et al., 2016). Increased SF2/ ASF also increases RON kinase translation to a constitutive version, which has been linked to aggressive behavior in a variety of malignancies. SF2/ ASF has a direct influence on RON translation by connecting to an ESE inside the subsequent exon. Knocking down endogenous SF2/ASF or even the constitutively RON splicing variant reverses the aggressive behavior of human cancer cell lines (Ghigna et al., 2005). Other spliced factors’ expression is also changed in cancer (Grosso et al., 2008); nevertheless, their relation to cancer genesis or development is unknown. It’s also worth noting that almost all, if not all, proteins that control splicing have several functions. Recent findings, for example, imply that the transformation produced by SF2/ASF may be mediated by a process unrelated to splicing (Karni et al., 2008; Tufan et al., 2020).

1.5 DISRUPTION OF ALTERNATIVE SPLICING RNA produced from a mutant allele may be pathogenic, which is an interesting surprise for a molecule assumed to be a benign substrate. This is a not-so-subtle warning because RNA is a powerful molecule by nature. That

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disease process is seen in a group of illnesses known as nucleotide expansion disorders (Graveley, 2008). Microsatellites are small (1–10 nucleotides) repetitions that vary in quantity from person to person and cause sickness when they are found in a genome and proliferate over a typical cutoff repeat sequence (Grimm & Kay, 2007). Loss of cellular proteins, an increase of abnormal cellular proteins owing to the extension of sextuplets repeats inside the transcription start site, and an increase of components of the RNA carrying the enlargement are three pathways that might cause illness and are not necessarily exclusive (Orr & Zoghbi, 2007; Rotbart et al., 2001). Four clinical disorders have strong evidence of RNA recovery of feature: myopathy varieties 1 and 2 (DM1), fragile Cross tremors ataxia syndromes (FXTAS), and reviewed and updated to reflect incoordination 8 (SCA8) (SCA8). In SCA10, SCA12, and Huntington’s disorder 2 (HDL2) (Figure 1.3), an RNA acquire pathway is also plausible (O’Rourke & Swanson, 2008). The pathological process of RNA acquisition of functionality is well understood in the case of DM1, wherein a CUG repeat inside the 30 UTR of both the DMPK mRNA grows from its average limits of 5–38 repetitions to a malignant range of approximately over 2500 repetitions. The second most prevalent mutation is caused by this polymorphism (Grosso et al., 2008; Backes et al., 2016).

Figure 1.9. Gain of Function in RNA. Source: https://www.researchgate.net/figure/RNA-toxic-gain-of-function-mechanisms-A-Protein-sequestration-of-RNA-binding_fig3_272486318

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Neuromuscular dystrophy, and also several multi-systemic symptoms such as cardiac arrhythmias and neurological problems. The RNA repetitions impair the functioning of a particular Transcription protein in trans, according to an earlier theory that was confirmed right (Timchenko et al., 1996; Wang et al., 1995). CUG interaction protein 1 (CUGBP1) and muscleblind-like 1 (MBNL1) are two proteins discovered based on their propensity for CUG RNA repetitions (O’Rourke & Swanson, 2008). Both proteins, or associated CELF or MBNL gene family paralogues, regulate a variety of nuclear and cytoplasmic Ribosomal RNA processes, including transposable elements, mRNA stabilization, and translating mRNA localization, and editing (Barreau et al., 2006; Pascual et al., 2006). The interruption of a sequence of postnatal translation changes in muscle fibers is the most wellstudied pathogenic impact of increased CUG RNA. The altered equilibrium of antagonistic modulation by MBNL1 with CUGBP1 has been at the core of this process (Figures 3B and 3C). As a function, developmental rather than mature splice variations are expressed inappropriately in tissue types, resulting in disease symptoms (Hagerman P. & Hagerman R., 2004). The buildup of enlarged CUG RNA in nuclear foci is a striking biological characteristic of DM1. MBNL1 colocalizes to RNA foci and is reduced from the nucleolus by more than 2-fold in one of RNA’s two pathogenic impacts, resulting in improper modulation of MBNL1-sensitive spliced events (Figure 3B) (Lin et al., 2006). MBNL1 attaches to the enlarged CUG repetitions because RNA creates an expanded stable helical shape similar to its normal intergenic binding location near selected alternative exons (Warf & Berglund, 2007; Yuan et al., 2007). Mbnl1 reduction in mice produced by an Mbnl1 gene deletion (Mbnl1DE3/DE3) or production of 250 CTG repetitions inside a skeletal remains actin transgenic (HSALR) reproduces muscle pathologies and transcription of developmental and splicing sequences seen in DM1 skeletal muscle (Kanadia et al., 2003; Lin et al., 2006). The developmental splicing sequence for such muscle specialized chloride channel (Clcn1) provides a prematurely offer only limited state codon in mice models and persons with DM1, leading to Clcn1 organ dysfunction and the loss of nerve cells that is the hallmark of the condition (Lueck et al., 2007). Kanadia et al. (2006) found that delivering MBNL1 to HSALR skeletal muscle by corresponding author virus cures Clcn1 and some other spliced alterations, as well as loss of nerve cells, establishing a relationship between MBNL1 deficiency and the clinical characteristic of the condition (Henke et al., 2008; Holmlund, 2003). Findings from D. melanogaster DM1 models show that human MBNL1 homologs decrease

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the severe condition generated by CUG repeat RNA in both the retina as well as the muscle, suggesting a function for MBNL1 (de Haro et al., 2006). Additional microsatellite diseases, including such FXTAS, wherein the male holders of a fragile X teaching phonemic inside the FMR1 gene have a delayed neurologic illness, while female bearers suffer from primary ovarian deficiency   (Figure 3A), might be caused by interruption of the the the MBNL1 function (Hainrichson et al., 2008). Nuclear expansions containing MBNL1 and hnRNP A2 were detected in afflicted areas of FXTAS brain tissues (Iwahashi et al., 2006). MBNL1 is also terminal 1 with nuclear RNA foci discovered in neurons with HDL2 patients whose junctophilin-3 (JPH3) genes have been altered to include enlarged CTG repeats (Rudnicki et al., 2007). CUG repeated RNA does have the stimulating effect of generating a signalling sequence that results in protein kinase C (PKC) activity in addition to depletion of RNA-binding protein (Figure 3C). Hyperphosphorylation, as well as stability of CUGBP1 proteins, is among the effects of PKC stimulation, which reflects why CUGBP1 protein is elevated 2- to 4-fold in DM1 cells of the heart without even an elevation in transcriptional level (Nezu et al., 2007; Dai et al., 2007). All three reactions were detected 6 hours following induction of a CUG clustered regularly interspaced short palindromic transgenic mRNA into heart muscle from such an inactivating DM1 animal model, indicating that PKC stimulation and CUGBP1 have higher presence and transcription are immediate and fast consequences (Kuyumcu-Martinez et al., 2007; Wang et al., 2007). The method through which PKC is activated by enlarged CUG RNA is unclear. It’s doubtful that PKC activity is caused by MBNL1 reduction because neither the Mbnl1DE3/DE3 nor even the HSALR mice models have high CUGBP1 (Kanadia et al., 2003; Lin et al., 2006). Recent findings show that MBNL1 overexpression and CUGBP1 reduced expression govern a substantial portion of splicing events that happen during the first two weeks of neonatal heart growth. CUGBP1 mRNA levels are unaffected, and also the 10-fold reduction in protein production seems to be due to protein phosphorylation and activation and instability (Kalsotra et al., 2008) These findings show that enlarged CUG repeats may be abnormally stimulating a natural signaling process that keeps CUGBP1 protein stable in fetal muscle fibers (KuyumcuMartinez et al., 2007). Extended CCTG repetitions in intron 1 of the ZNF9 genes generate DM2, which is medically similar to DM1 while being less serious and does not have a prenatal form (Liquori et al., 2001). CUGBP1 is not produced when

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MBNL1 is buried on extended CCUG repeat RNA, which develops a helical shape and aggregates in nuclear foci similar to CUG repeated RNA (Wang et al., 2017), indicating that DM2 is predominantly a disorder of MBNL deficiency. The absence of CUGBP1 overexpression shows that extended CCUG RNA does not activate PKC, and it may reveal the cis criteria for PKC stimulation by RNA, like whether CCUG vs CUG repetitions or genespecific contexts is necessary (Ying et al., 2008). Utilizing Transcriptional activation (RNAi) mechanisms, RNA produced from transposon expansions does have the potential to cause pathogenicity. Following folded into solitary defective switchbacks which are broken by Dicer, extended repetitions comprising CUG, CAG, and also to a lesser extent CCG or CGG are translated into 21 nucleotides RNAs (Krol et al., 2007). Anti-sense transcripts also have been found for the extended repetitions of the DMPK, SCA8, and FMR1 genomes (Cho et al., 2005), suggesting the second article on short RNAs. Short CUG or CAG RNAs have already been found in the cells of people with DM1, and SCA1, including Huntington’s syndrome (Cho et al., 2005). The inhibition of Dicer in DM1 cells resulted in higher levels of typical endogenous CAG string mRNAs, indicating that CUG short interfering RNAs (siRNAs) had downstream consequences (Ramachandran & Ignacimuthu, 2013). Even though these findings offer proof of concept, targets important to DM1 pathophysiology have yet to be discovered (Ladd et al., 2007; Nemes et al., 2000). Genetic disorder CAG mutations, apart from SCA12, occur inside coding sequences and lead to the synthesis of proteins with enlarged caused by mutation tracts (polyQ) (Orr & Zoghbi, 2007). Based on the genes associated, genetic disorder Repeats expansions may result in protein loss, an increase of functionality, or both; therefore, when increased CAG RNA can contribute to pathogenesis varies on the experimental setup (Léveillé et al., 2015; Schramm et al., 2020). In animals producing similar quantities of mRNA with missense mutations that inhibit the activity of a protein nuclear-localized signal, the phenotype shown in a transgenic mouse model for SCA1 produces a pathologic human ataxin-1 mRNA having 82 Repeats [ataxin-1-(CAG)82] is not seen. These findings show that the ataxin-1(CAG)82 mRNA is not harmful in mouse Purkinje cells on its own (Klement et al., 1998). A D. melanogaster model wherein production of a shortened pathologic human ataxin-3-(CAG)78 mRNA produces neurotoxicity provides strong evidence for a CAG RNA acquire pathway (Roshan et al., 2009). Modification screening that discovered mbl, the Drosophila MBNL homolog, revealed the role of RNA cytotoxicity. Increased CAG repeats

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in the 30 UTR of a foreign gene (DsRED), which were not produced as polyQ proteins or CUG antisense RNA, were similarly harmful, suggesting that repeat RNA plays a pathogenic function (Mishra et al., 2009; Potera, 2012). PolyQ protein levels from nonpathogenic disrupted CAA/ Repeats RNA generated some pathology, demonstrating that both polyQ proteins and CAG RNA are involved in the complete phenotype shown in the fly’s model (Tang et al., 2018; Mouraviev et al., 2016). These findings pave the way for further research into the implications of increased Repeats on RNA advantage in human illness. Surprisingly, although MBNL1 inhibited CUG RNA poisoning within the Drosophila DM1 paradigm, flies and human MBNL1 repeats increased the harmful effects of CAG RNA, indicating that CUG and CAG RNA toxicity had distinct pathological processes (Ambesajir et al., 2012). The enlarged CGG repetitions that induce FXTAS are linked to a separate collection of Transcription proteins. Isolated nuclear aggregates from the brains of such an FXTAS mouse model were found to include HnRNP A2 and Pur-a (Jin et al., 2007). Both proteins specifically bind with CGG repetitive RNA, and their production in a Drosophila FXTAS model decreased the neurodegenerative phenotype ( Dykxhoorn & Lieberman, 2005). In flies, CUGBP1 production reduced the phenotypic, but it was discovered that it interacts with repetitive RNA directly by attaching to hnRNP A2 (Sofola et al., 2007). It’s unclear how well these antibodies fit into a pathogenic pathway. Pur-a deletion mice develop ataxia, which is compatible with a depleted model in FXTAS; but, as revealed in DM1, the RNA may have other consequences (Kladi-Skandali et al., 2015; Schwartz & Dhaliwal, 2020). It’s also worth noting that suppressing an RNA acquire genetic makeup in Drosophila designs, especially while human proteins are being used, might consequence both from trying to restore the purpose of drained Drosophila nutrients, but from providing the RNA nontoxic through a different method, such as trying to prevent RNA agglomeration or toxic interactions. Identifying the particular mechanism of suppression would give insight into the disease’s pathogenic process as well as prospective therapy options (Arriaga-Canon et al., 2018; Gallo & Locatelli, 2012).

1.6 RNAS AS THERAPEUTIC TARGETS AND TOOLS To accomplish the treatment, numerous ways have been investigated, and so many more may be imagined, such as modifying the splicing sequence of a defective pre-mRNA or eliminating an mRNA with a genetic

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disorder mutation (Correia et al., 2021; Okano & Gross, 2012). Growing understanding of RNA chemistry and biology is spurring new initiatives to target the RNA molecule, as well as the spliced and translation machinery, as targeted therapies. Antisense oligonucleotides, anti-sense snRNAs, RNA interference, and smaller compounds are among the tactics discussed here (see Analysis by L. Bonetta in this issue of Cell). Other approaches, such as trans-splicing and ribosomal RNA, will most certainly become available soon (Gong et al., 2005).

Figure 1.10. RNA-based or RNA-targeted therapeutic approaches. Source:https://www.researchgate.net/figure/Nucleic-acid-based-therapeuticstrategies-mRNA-messenger-RNA-RNase-H-ribonuclease-H_fig2_319656321

1.6.1 Antisense Oligonucleotides Antisense oligonucleotides (AOs) have indeed been widely employed to prevent a transposon pre-mRNA from forming a genetic disorder mRNA by pushing it to merge into the disorder mRNA (Sazani & Kole, 2003). AOs are often constructed to hybridize and obstruct one or even more regions in the targeted pre-mRNA that are crucial for the specific splicing process that one desires to inhibit, causing the spliced mechanism to pick a more favorable pattern. To be successful, the AO’s targeted RNA sequencing must be particular and available inside the native RNP (something, not all patterns

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are) (Tuschl & Borkhardt, 2002). Unfortunately, predicting whether such parameters will be satisfied and whether the intended splicing switch can be performed, is difficult. As a result, several distinct AOs must be examined, which may necessitate the tiling of multiple AOs of varying lengths over a significant stretch of the targeted pre-mRNA (Sheng et al., 2018; Galasso et al., 2010). The b-globin genes with b-thalassemia, the CFTR protein in cystic fibrosis, and lamin A in the Hutchinson-Gilford down’s syndrome disease are instances of genetic disorder genes targeted by AOs in vitro and also in cellular systems (HGPS). Several genes’ abnormalities trigger cryptic chromatin structures that hinder proper pre-mRNA splitting (Dominski & Kole, 1993; Friedman et al., 1999). In animal models of DM1, an AO addressing an exon inside the gene that encodes the muscular chloride channels (Clcn1) rescues the Clcn1 transcriptional deficiency (Wheeler et al., 2007; Scaffidi & Misteli, 2005). AOs were also extensively examined as possible therapy options for SMA and DMD. To flip the transcription factor and encourage exon 7 incorporation and hence the generation of a fully functioning SMN protein, AOs which cover the ISS or even the 30 cell signaling of exon 8 of the SMN2 gene have indeed been utilized (Figure 4A) (Singh, 2007; Alter et al., 2006). Bi - functional oligonucleotides that connect an analogous pattern to exon 7 with just an ESE and therefore engage throughput times SR proteins or direct tie antisense sequencing to an SR peptide to improve exon 7 inclusions (Figure 4A) have been employed in an innovative metabolic pathway approach (Cartegni & Krainer, 2003; Skordis et al., 2003). DMD has also been treated using similar AO methods. There are some other prominent instances of AOs being used to down-regulation certain mRNAs through methods other than splicing manipulation. In mice with motor neuron disease (ALS), an AO targeting a superoxide dismutase 1 (SOD1) defect that underlies the neurological illness motor neuron disease (ALS) decreases aberrant SOD1 mRNA and protein concentrations and delays disease development (Smith et al., 2006; Kumar et al., 2019). Although the effectiveness of AOs has been proven in solid evidence research for a variety of experimental models and disorders, only a few have progressed to the level of viable therapy in humans (see Analysis by L. Bonetta in this issue of Cell). The creation of the first United states food and drug antisense medication that targets cytomegalovirus (CMV) mRNAs to treat retinitis induced by CMV becomes a clinically effective application of AOs (Holmlund, 2003; Redis et al., 2012). The key roadblocks to using AOs as therapies are the epithelial delivery of adequate AOs and establishing an administration schedule that will maintain therapeutic concentrations and

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stability over time (Chang & Hannon, 2014; Lu & Thum, 2019). In the location of natural sources phos- phodiester ribo- or outlined in various, AOs to built on previous chemistries—morpholino, peptide nucleic acid (PNA), trapped nucleic acid (LNA), 20-O-methyl, thiophosphate, and a variety of other oligonucleotides—have been created to improve attraction, boost consistency in the bloodstream and also in the target tissue, and the product is applied permeation and nuclear (Karkare & Bhatnagar, 2006). Conjugated verbs AOs to proteins that are preferentially absorbed either by target organs also have enhanced epithelial distribution (Henke et al., 2008). AOs represent a viable treatment option for a variety of hereditary disorders. However, studies for specificity and unfavorable off-target impacts must be carried out with great caution (Hermann & Westhof, 1998; Ratti et al., 2020).

1.6.2 snRNAs as Vehicles for Stable Antisense RNAs Certain RNAs, notably pre-mRNAs, may well be directed using reverse hybridization. These organic snRNAs have been modified into U1 and U7 logistic regression sequences, with comparable sequencing to a specific pre-mRNA in place of it like the native 50 ends from both snRNAs. These modified snRNAs are generated from the targeted cells’ corresponding DNA structures but have unique antisense characteristics (Dodd et al., 2013; Lützelberger & Kjems, 2006). They produce Sm cores, which help in their persistence, nuclear localization, and successful attachment to complementary sequence RNAs, and exposure to normal snRNAs. AntiSMN U7 snRNAs with motifs matching to exon 8’s 30 transcription factor or exon 7 were linked to an ESE restored SMN2 voiced in cell cultures and increased the longevity of mice with severe SMA (Madocsai et al., 2005). Meyer et al. (Meyer et al., 2008). These are RNA, never chemically changed things, like synthesized AOs, yet their distribution into cells brings distinct challenges that AOs do not face. To distribute antisense RNAs into target cells, virions such as transgenic corresponding author virus (AAV) and viral vectors are utilized as delivery trucks (Danos, 2008; Poller et al., 2018). In a DMD mouse model, systemically delivery of AAV U7 or U1 nonsense RNA causes the exon carrying a mutation that causes frameshift and PTC to be skipped, resulting in a prolonged generation of partly functional contractile proteins and a better phenotype (Figure 4B) (Denti et al., 2006; Goyenvalle et al., 2004). These findings are laying the groundwork for clinical trials for the treatment of DMD, which are presently ongoing (Muntoni & Wells, 2007). Suppression of HIV-1 replication is another use of U7 antisense RNA. Internal genes were identified encoding the HIV-1 transcription factors Tat

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and Rev are partially skipped by lentiviral U7 (Asparuhova et al., 2007). Unfortunately, like with traditional reverse genetics treatment, substantial challenges such as tissue-specific targeted and immune function with viral vectors remain (Izquierdo, 2005; Poller et al., 2013).

1.7 RNA INTERFERENCE The ability of RNAi to specifically remove an mRNA of a disorder allele or block the translation of a harmful protein opens up a large variety of therapeutic possibilities. RNAi is a flexible and powerful technology that depends on the complementary base interactions of 21–23 nucleotides RNAs, which are large enough to target an mRNA or maybe even a particular splice variation (Grimm & Kay, 2007; Chakraborty, 2007). RNAi-based techniques may be used to treat any condition where reducing the production of an RNA, either from a mutated gene or an abnormally produced mRNA, would’ve been beneficial. The translation of RNAi knowledge from a widely used system development phase to a safe and effective therapeutic has made significant progress (Christodoulatos & Dalamaga, 2014). The primary hurdles include once again ensuring optimum transport to the relevant cells and tissues, preventing the cellular immune reaction to the double RNA, and obtaining the best combination of high efficacy and no off-target impacts. The three most frequent therapeutic methods for RNAi-based distribution are (1) synthetic RNAi, (2) synthetic RNAi, and (3) synthetic RNAi (Fernando et al., 2017). (1) endogenous siRNAs are introduced into the indigenous RNAi machinery (RISC complexes) using double-stranded siRNAs freely given to tissue with a compression medium (Gutschner et al., 2018); (2) small interfering RNAs (shRNAs), which also are general format by affirmation from bacteriophages and thus are conveyed in the nucleus, extracted to the cytoplasm by Exportin 5 (Shah & Calin, 2014), and filtered into workable siRNAs by Dicer; and (3) synthetic miRNAs, wherein the designed to target hairpin turns are conveyed in a pri-miRNA frame of reference with viral vectors, produced inside the nucleus by the DroshaDGCR8 complicated, extracted to the cytoplasm by Exportin 5, then afterward (Rossi, 2008; Idrees & Ashfaq, 2013). shRNAs are often produced at high levels to achieve extremely efficient gene silencing, however, due to overload of the endogenous RNAi mechanism, they may also induce toxicity (Chandra Gupta

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& Nandan Tripathi, 2017). In a SCA1 animal model, researchers found that employing AAV-delivered artificial miRNAs to knock down the enlarged ataxin-1 mRNA resulted in an effective reduction of this mRNA in cerebral Pyramidal neurons without toxicity (Figure 4C) (Boudreau et al., 2009).  These findings provide a new platform for disease transport and transcription. In various mouse models of illness, such as Huntington’s disease and ALS, as well as HIV-infected “human-looking” mice, RNAi techniques are looking promising. In preclinical and clinical studies, direct siRNA administration is now being utilized to treat a variety of disorders, including retinitis pigmentosa, respiratory syncytial virus (RSV) infections, and liver cancer (Aigner, 2007; Pappas et al., 2008). It is conceivable to target miRNAs using complementary nucleotide sequences using a method similar to which used to distribute siRNAs (antimiRs). Anti-miRs may be employed to negate the effects of exogenous or endogenous (viral) miRNAs. Many tissues are tough to distribute into, however, the liver is an exception (Liu et al., 2008; Pecero et al., 2019). The abundantly expressed as well as liver-specific miR-122, for instance, was shown to get at least two disease-related properties: it is necessary for hepatitis C virus multiplication in cultivated hepatocytes and it regulates cholesterol biosynthesis. In mice and monkeys, the distribution of Received nucleotide sequences to inhibit miR-122 resulted in both miR-122 depletion and a behavioral consequence of decreased plasma cholesterol (Elmen et al., 2008). This technique has a lot of promise for treating hyperlipidemia, along with acute and long-term hepatitis C infection (Gandellini et al., 2011; Yu et al., 2020).

1.7.1 Small Molecules Splicing is a potential platform for comparatively tiny pharmacological regulation. Because most introns’ slicing is heavily reliant on serinearginine-rich (SR) protein and hnRNP proteins, tiny compounds that alter their functions or relative amounts inside the nucleus may have a significant impact on splicing (Soofiyani et al., 2013; Zhu et al., 2018). By enlisting the basal splice mechanism via their SR regions, SR proteins connect to ESEs through their Transcription domain names and enhance exon identification and also block the function of nearby silencers. The status of serine phosphorylated in the SR domains, which would be governed either by SR kinase SRPK1, SRPK2, as well as the Clks1–4, as well as the phosphate

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PP1, which dephosphorylates the, determines the function of SR proteins (Paul et al., 2014; Nigg & Walker, 2009). Small compounds have been utilized to target these enzymes to control splicing patterns since they are good reagents for altering the activity of such enzymes. Specific molecular inhibitors of SR protein (Soret et al., 2005), SRPKs (Fukuhara et al., 2006), and Clicks (Muraki et al., 2004) have been found and proven to regulate transcriptional using elevated screening. Our chemicals were only studied for several splicing events so far—for instance, HIV-1 splicing, which is heavily reliant on SR proteins—but these findings imply that this technique has a lot of potential (Wang et al., 2020; Ogunjimi et al., 2017). This supports conducting big screens targeting this and several other proteins that modulate splicing mechanism activities in the hunt for more effective and targeted stimulators of transposable elements as a therapeutic strategy for a variety of illnesses (Yu et al., 2011; Oun et al., 2013). Just on basis of manipulation of the relative isomeric of splicing components, several possible techniques for controlling transcriptional using small molecules may be envisaged. Small drugs that change the production of utilizing its assets or adjust their nuclear location might therefore be used to influence the transcriptional of disorder pre-mRNAs (Libraty et al., 2002; Shahabipour et al., 2017). PTCs are often seen in mRNAs that have been spliced incorrectly. PTCs are prevalent in around 30% of hereditary disease-causing defects, and their presence causes malarkey deterioration and reduced function of either the mutant gene as well as the gene from one parent (Frischmeyer & Dietz, 1999). In most cases, malarkey decay guards against dangerous aggregation development by preventing the creation of truncated proteins with potentially harmful action. However, it is estimated that 5% to 15% of persons with one of the 2300 genetic illnesses have a PTC mutation, which might benefit from examining both the stop codon and the start codon to construct a partially functional protein. For example (Schmidt et al., 2013; Fernandez et al., 1986), a PTC within what would seem to be with the mRNA is accountable now for about 7% of DMD cases and 10% of CF instances. Because small chemicals that allow coding regions codons to be read throughout have been identified, their potential utility for treating specific illnesses is being researched. Antibiotics that are aminoglycosides bind to the ribosomal complex’s decoder site and induce termination codon translation to peruse (Hainrichson et al., 2008; Zingman et al., 2007). Clinical trials using aminoglycosides to treat a range of genetic illnesses have shown encouraging results, including the treatment of DMD and CF using metronidazole. Unfortunately, since malarkey decay is blocked, the

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large dosages of medicine required might have serious side effects, such as increasing Resemblance mRNA levels (Zingman et al., 2007; Lee et al., 2012). There is a lot of promise in developing aminoglycosides with enhanced high selectivity (Hainrichson et al., 2008). By inhibiting PTCcontaining firefly reporters, PTC124, a chemical with a distinct molecule, was detected in a backscreen. In cultured cells and DMD animal studies, it’s been shown to increase the production of muscle fibers from Gamebattles mRNAs (Welch et al., 2007; Yakovlev et al., 2017). It is currently being studied in DMD clinical trials and is physically available (Kerem et al., 2008). Although nonsense suppression seems to be a viable therapeutic strategy, it is important to consider the possibility that medication may alter translation start in mRNAs other than the targeted victim. In addition to metabolic disorders caused by exon genetic variations such as variations and malarkey, frame-shift genetic abnormalities in the gene promoter that also cause faulty enzymes (Lai et al., 2018), as well as genomic instability in UTRs that affect transcription efficacy or mRNA continuity, internal transcribed or exonic mutations that interrupt newly formed nascent sequence(Darnell et al., 2004; Chacko & Samanta, 2016). C RNA editing adds still another degree of intricacy to the transcriptome (Symptoms were associated and Keller, 2002), and the identification of miRNAs, a large class of non-protein-coding RNAs that govern mRNA translational and storage, has disclosed again another degree of regulation (Valencia-Sanchez et al., 2006; Boozari & Hosseinzadeh, 2021). The significant number of polypeptides and regulatory RNAs involved in post transcripttional RNA synthesis, as well as the tremendously intricate connection of conversations between them, give cells a magnificent ability to good their gene expression patterns and quickly adjust their gene expression profile in response to stimulation, but also it increases their weakness to mutations and chromosomal aberrations, which leads to a variety of diseases, including neuromuscular and neurodegenerative, and cancer (Sudharshan & Biswas, 2008; Miao et al., 2017).

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REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

Aigner, A. (2007). Applications of RNA interference: current state and prospects for siRNA-based strategies in vivo. Applied microbiology and biotechnology, 76(1), 9-21. Alter, J., Lou, F., Rabinowitz, A., Yin, H., Rosenfeld, J., Wilton, S. D., ... & Lu, Q. L. (2006). Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nature medicine, 12(2), 175-177. Ambesajir, A., Kaushik, A., Kaushik, J. J., & Petros, S. T. (2012). RNA interference: A futuristic tool and its therapeutic applications. Saudi journal of biological sciences, 19(4), 395-403. Arriaga-Canon, C., De La Rosa-Velázquez, I. A., González-Barrios, R., Montiel-Manríquez, R., Oliva-Rico, D., Jiménez-Trejo, F., ... & Herrera, L. A. (2018). The use of long non-coding RNAs as prognostic biomarkers and therapeutic targets in prostate cancer. Oncotarget, 9(29), 20872. Asparuhova, M. B., Marti, G., Liu, S., Serhan, F., Trono, D., & Schümperli, D. (2007). Inhibition of HIV‐1 multiplication by a modified U7 snRNA inducing Tat and Rev exon skipping. The Journal of Gene Medicine: A cross‐disciplinary journal for research on the science of gene transfer and its clinical applications, 9(5), 323-334. Backes, C., Meese, E., & Keller, A. (2016). Specific miRNA disease biomarkers in blood, serum and plasma: challenges and prospects. Molecular diagnosis & therapy, 20(6), 509-518. Barreau, C., Paillard, L., Méreau, A., & Osborne, H. B. (2006). Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions. Biochimie, 88(5), 515-525. Bhalla, K., Phillips, H. A., Crawford, J., McKenzie, O. L., Mulley, J. C., Eyre, H., ... & Callen, D. F. (2004). The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. Journal of human genetics, 49(6), 308-311. Boozari, M., & Hosseinzadeh, H. (2021). Natural products for COVID‐19 prevention and treatment regarding to previous coronavirus infections and novel studies. Phytotherapy Research, 35(2), 864-876.

Introduction to RNA and Life-Threatening Diseases

37

10. Boudreau, R. L., Martins, I., & Davidson, B. L. (2009). Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Molecular Therapy, 17(1), 169-175. 11. Buratti, E., & Baralle, F.E. (2008). Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front. Biosci. 13, 867–878. 12. Buratti, E., Brindisi, A., Pagani, F., & Baralle, F. E. (2004). Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. The American Journal of Human Genetics, 74(6), 13221325. 13. Cáceres, J. F., & Kornblihtt, A. R. (2002). Alternative splicing: multiple control mechanisms and involvement in human disease. TRENDS in Genetics, 18(4), 186-193. 14. Cáceres, J. F., Screaton, G. R., & Krainer, A. R. (1998). A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes & development, 12(1), 55-66. 15. Cartegni, L., & Krainer, A. R. (2002). Disruption of an SF2/ASFdependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nature genetics, 30(4), 377-384. 16. Cartegni, L., & Krainer, A. R. (2003). Correction of disease-associated exon skipping by synthetic exon-specific activators. Nature structural biology, 10(2), 120-125. 17. Cartegni, L., Chew, S. L., & Krainer, A. R. (2002). Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nature reviews genetics, 3(4), 285-298. 18. Cartegni, L., Hastings, M. L., Calarco, J. A., De Stanchina, E., & Krainer, A. R. (2006). Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. The American Journal of Human Genetics, 78(1), 63-77. 19. Castle, J. C., Zhang, C., Shah, J. K., Kulkarni, A. V., Kalsotra, A., Cooper, T. A., & Johnson, J. M. (2008). Expression of 24,426 human alternative splicing events and predicted cis regulation in 48 tissues and cell lines. Nature genetics, 40(12), 1416-1425. 20. Chacko, S., & Samanta, S. (2016). Hepatocellular carcinoma: A lifethreatening disease. Biomedicine & Pharmacotherapy, 84, 1679-1688.

38

RNA and Life Threatening Diseases

21. Chakraborty, C. (2007). Potentiality of small interfering RNAs (siRNA) as recent therapeutic targets for gene-silencing. Current drug targets, 8(3), 469-482. 22. Chandra Gupta, S., & Nandan Tripathi, Y. (2017). Potential of long non‐coding RNAs in cancer patients: from biomarkers to therapeutic targets. International journal of cancer, 140(9), 1955-1967. 23. Chang, K., & Hannon, G. J. (2014). Tools for studying and using small RNAs: from pathways to functions to therapies. Nature Reviews, Genetics Sep, 18, (Vol. 1, pp. 2-9). 24. Chen, Y., Tian, D., Ku, L., Osterhout, D. J., & Feng, Y. (2007). The selective RNA-binding protein quaking I (QKI) is necessary and sufficient for promoting oligodendroglia differentiation.  Journal of Biological Chemistry, 282(32), 23553-23560. 25. Chénard, C. A., & Richard, S. (2008). New implications for the QUAKING RNA binding protein in human disease. Journal of neuroscience research, 86(2), 233-242. 26. Cho, D. H., Thienes, C. P., Mahoney, S. E., Analau, E., Filippova, G. N., & Tapscott, S. J. (2005). Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Molecular cell, 20(3), 483-489. 27. Christodoulatos, G. S., & Dalamaga, M. (2014). Micro-RNAs as clinical biomarkers and therapeutic targets in breast cancer: Quo vadis?. World journal of clinical oncology, 5(2), 71. 28. Clark, T. A., Sugnet, C. W., & Ares Jr, M. (2002). Genomewide analysis of mRNA processing in yeast using splicing-specific microarrays. Science, 296(5569), 907-910. 29. Coppola, N., Pisaturo, M., Guastafierro, S., Tonziello, G., Sica, A., Iodice, V., ... & Sagnelli, E. (2012). Increased hepatitis C viral load and reactivation of liver disease in HCV RNA-positive patients with onco-haematological disease undergoing chemotherapy. Digestive and Liver Disease, 44(1), 49-54. 30. Correia, C. C. M., Rodrigues, L. F., de Avila Pelozin, B. R., Oliveira, E. M., & Fernandes, T. (2021). Long non-coding RNAs in cardiovascular diseases: potential function as biomarkers and therapeutic targets of exercise training. Non-coding RNA, 7(4), 65.

Introduction to RNA and Life-Threatening Diseases

39

31. Dai, Y., Liang, Z., Li, Y., Li, C., & Chen, L. (2017). Circulating long noncoding RNAs as potential biomarkers of sepsis: a preliminary study. Genetic testing and molecular biomarkers, 21(11), 649-657. 32. Danos, O. (2008). AAV vectors for RNA-based modulation of gene expression. Gene therapy, 15(11), 864-869. 33. Daoud, H., Valdmanis, P. N., Kabashi, E., Dion, P., Dupre, N., Camu, W., ... & Rouleau, G. A. (2009). Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. Journal of medical genetics, 46(2), 112-114. 34. Darnell, M. E., Subbarao, K., Feinstone, S. M., & Taylor, D. R. (2004). Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV. Journal of virological methods, 121(1), 85-91. 35. David, C. J., & Manley, J. L. (2008). The search for alternative splicing regulators: new approaches offer a path to a splicing code. Genes & development, 22(3), 279-285. 36. de Haro, M., Al-Ramahi, I., De Gouyon, B., Ukani, L., Rosa, A., Faustino, N. A., ... & Botas, J. (2006). MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. Human molecular genetics, 15(13), 2138-2145. 37. de Paula Brandão, P. R., Titze-de-Almeida, S. S., & Titze-de-Almeida, R. (2020). Leading RNA interference therapeutics part 2: silencing deltaaminolevulinic acid synthase 1, with a focus on givosiran. Molecular diagnosis & therapy, 24(1), 61-68. 38. Denti, M. A., Rosa, A., D’Antona, G., Sthandier, O., De Angelis, F. G., Nicoletti, C., ... & Bozzoni, I. (2006). Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model. Proceedings of the National Academy of Sciences, 103(10), 3758-3763. 39. Disset, A., Bourgeois, C. F., Benmalek, N., Claustres, M., Stevenin, J., & Tuffery-Giraud, S. (2006). An exon skipping-associated nonsense mutation in the dystrophin gene uncovers a complex interplay between multiple antagonistic splicing elements. Human Molecular Genetics, 15(6), 999-1013. 40. Dodd, D. W., Gagnon, K. T., & Corey, D. R. (2013). Digital quantitation of potential therapeutic target RNAs. Nucleic acid therapeutics, 23(3), 188-194.

40

RNA and Life Threatening Diseases

41. Dominski, Z., & Kole, R. (1993). Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proceedings of the National Academy of Sciences, 90(18), 8673-8677. 42. Dreyfuss, G., Kim, V. N., & Kataoka, N. (2002). Messenger-RNAbinding proteins and the messages they carry. Nature reviews Molecular cell biology, 3(3), 195-205. 43. Dreyfuss, G., Matunis, M. J., Pi ol-Roma, S., & Burd, C. G. (1993). hnRNP proteins and the biogenesis of mRNA. Annual review of biochemistry, 62, 289-289. 44. Dykxhoorn, D. M., & Lieberman, J. (2005). The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annual review of medicine, 56(2), pp. 401. 45. Elmén, J., Lindow, M., Schütz, S., Lawrence, M., Petri, A., Obad, S., ... & Kauppinen, S. (2008). LNA-mediated microRNA silencing in nonhuman primates. Nature, 452(7189), 896-899. 46. Fernandez, H., Banks, G., & Smith, R. (1986). Ribavirin: a clinical overview. European journal of epidemiology, 2(1), 1-14. 47. Fernando, D. D., Marr, E. J., Zakrzewski, M., Reynolds, S. L., Burgess, S. T., & Fischer, K. (2017). Gene silencing by RNA interference in Sarcoptes scabiei: a molecular tool to identify novel therapeutic targets. Parasites & vectors, 10(1), 1-10. 48. Friedman, K. J., Kole, J., Cohn, J. A., Knowles, M. R., Silverman, L. M., & Kole, R. (1999). Correction of aberrant splicing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by antisense oligonucleotides. Journal of Biological Chemistry, 274(51), 36193-36199. 49. Frischmeyer, P. A., & Dietz, H. C. (1999). Nonsense-mediated mRNA decay in health and disease. Human molecular genetics, 8(10), 18931900. 50. Fukuhara, T., Hosoya, T., Shimizu, S., Sumi, K., Oshiro, T., Yoshinaka, Y., ... & Hagiwara, M. (2006). Utilization of host SR protein kinases and RNA-splicing machinery during viral replication. Proceedings of the National Academy of Sciences, 103(30), 11329-11333. 51. Gabanella, F., Butchbach, M. E., Saieva, L., Carissimi, C., Burghes, A. H., & Pellizzoni, L. (2007). Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PloS one, 2(9), e921.

Introduction to RNA and Life-Threatening Diseases

41

52. Gabut, M., Chaudhry, S., & Blencowe, B. J. (2008). SnapShot: The splicing regulatory machinery. Cell, 133(1), 192-192. 53. Galasso, M., Elena Sana, M., & Volinia, S. (2010). Non-coding RNAs: a key to future personalized molecular therapy?. Genome medicine, 2(2), 1-10. 54. Gallo, A., & Locatelli, F. (2012). ADARs: allies or enemies? The importance of A‐to‐I RNA editing in human disease: from cancer to HIV‐1. Biological Reviews, 87(1), 95-110. 55. Gandellini, P., Profumo, V., Folini, M., & Zaffaroni, N. (2011). MicroRNAs as new therapeutic targets and tools in cancer. Expert opinion on therapeutic targets, 15(3), 265-279. 56. Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P. M., ... & Biamonti, G. (2005). Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Molecular cell, 20(6), 881-890. 57. Glisovic, T., Bachorik, J. L., Yong, J., & Dreyfuss, G. (2008). RNAbinding proteins and post-transcriptional gene regulation. FEBS letters, 582(14), 1977-1986. 58. Gong, H., Liu, C. M., Liu, D. P., & Liang, C. C. (2005). The role of small RNAs in human diseases: potential troublemaker and therapeutic tools. Medicinal research reviews, 25(3), 361-381. 59. Goyenvalle, A., Vulin, A., Fougerousse, F., Leturcq, F., Kaplan, J. C., Garcia, L., & Danos, O. (2004). Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science, 306(5702), 1796-1799. 60. Graveley, B. R. (2008). The haplo-spliceo-transcriptome: common variations in alternative splicing in the human population. Trends in Genetics, 24(1), 5-7. 61. Grimm, D., & Kay, M. A. (2007). Therapeutic application of RNAi: is mRNA targeting finally ready for prime time?. The Journal of clinical investigation, 117(12), 3633-3641. 62. Grosso, A. R., Martins, S., & Carmo‐Fonseca, M. (2008). The emerging role of splicing factors in cancer. EMBO reports, 9(11), 1087-1093. 63. Gutschner, T., Richtig, G., Haemmerle, M., & Pichler, M. (2018). From biomarkers to therapeutic targets—the promises and perils of long non-coding RNAs in cancer. Cancer and Metastasis Reviews, 37(1), 83-105.

42

RNA and Life Threatening Diseases

64. Hagerman, P. J., & Hagerman, R. J. (2004). The fragile-X premutation: a maturing perspective. The American Journal of Human Genetics, 74(5), 805-816. 65. Hainrichson, M., Nudelman, I., & Baasov, T. (2008). Designer aminoglycosides: the race to develop improved antibiotics and compounds for the treatment of human genetic diseases. Organic & biomolecular chemistry, 6(2), 227-239. 66. Henke, E., Perk, J., Vider, J., De Candia, P., Chin, Y., Solit, D. B., ... & Benezra, R. (2008). Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo. Nature biotechnology, 26(1), 91-100. 67. Hermann, T., & Westhof, E. (1998). RNA as a drug target: chemical, modelling, and evolutionary tools. Current opinion in biotechnology, 9(1), 66-73. 68. Holmlund, J. T. (2003). Applying antisense technology: Affinitak™ and other antisense oligonucleotides in clinical development. Annals of the New York Academy of Sciences, 1002(1), 244-251. 69. Idrees, S., & Ashfaq, U. A. (2013). RNAi: antiviral therapy against dengue virus. Asian Pacific journal of tropical biomedicine, 3(3), 232236. 70. Izquierdo, M. (2005). Short interfering RNAs as a tool for cancer gene therapy. Cancer gene therapy, 12(3), 217-227. 71. Kladi-Skandali, A., Michaelidou, K., Scorilas, A., & Mavridis, K. (2015). Long noncoding RNAs in digestive system malignancies: a novel class of cancer biomarkers and therapeutic targets?. Gastroenterology research and practice, 2015, (Vol. 1, pp. 2-9). 72. Kumar, S., Boon, R. A., Maegdefessel, L., Dimmeler, S., & Jo, H. (2019). Role of Noncoding RNAs in the Pathogenesis of Abdominal Aortic Aneurysm: Possible Therapeutic Targets?. Circulation research, 124(4), 619-630. 73. Lai, W., Wang, Y., Wang, J., Wu, L., Jin, Z., & Wang, Z. (2018). Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents—a life-threatening disease: analysis of 133 cases from a single center. Hematology, 23(10), 810-816. 74. Lee, Y. J., Han, S. R., Maeng, J. S., Cho, Y. J., & Lee, S. W. (2012). In vitro selection of Escherichia coli O157: H7-specific RNA aptamer. Biochemical and biophysical research communications, 417(1), 414-420.

Introduction to RNA and Life-Threatening Diseases

43

75. Léveillé, N., Melo, C. A., & Agami, R. (2015). Enhancer-associated RNAs as therapeutic targets. Expert Opinion on Biological Therapy, 15(5), 723-734. 76. Libraty, D. H., Young, P. R., Pickering, D., Endy, T. P., Kalayanarooj, S., Green, S., ... & Rothman, A. L. (2002). High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. The Journal of infectious diseases, 186(8), 1165-1168. 77. Liu, Z., Sall, A., & Yang, D. (2008). MicroRNA: an emerging therapeutic target and intervention tool. International journal of molecular sciences, 9(6), 978-999. 78. Lu, D., & Thum, T. (2019). RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nature Reviews Cardiology, 16(11), 661-674. 79. Lützelberger, M., & Kjems, J. (2006). Strategies to identify potential therapeutic target sites in RNA. RNA Towards Medicine, Vol. 1, 243259. 80. Miao, R., Wang, Y., Wan, J., Leng, D., Gong, J., Li, J., ... & Yang, Y. (2017). Microarray expression profile of circular RNAs in chronic thromboembolic pulmonary hypertension. Medicine, 96(27), 34-39. 81. Mishra, P. K., Tyagi, N., Kumar, M., & Tyagi, S. C. (2009). MicroRNAs as a therapeutic target for cardiovascular diseases. Journal of cellular and molecular medicine, 13(4), 778-789. 82. Mizuguchi, Y., Yokomuro, S., Mishima, T., Arima, Y., Shimizu, T., Kawahigashi, Y., ... & Tajiri, T. (2005). Short hairpin RNA modulates transforming growth factor β signaling in life-threatening liver failure in mice. Gastroenterology, 129(5), 1654-1662. 83. Mouraviev, V., Lee, B., Patel, V., Albala, D., Johansen, T. E. B., Partin, A., ... & Perera, R. J. (2016). Clinical prospects of long noncoding RNAs as novel biomarkers and therapeutic targets in prostate cancer. Prostate cancer and prostatic diseases, 19(1), 14-20. 84. Nigg, A. J., & Walker, P. L. (2009). Overview, prevention, and treatment of rabies. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 29(10), 1182-1195. 85. Ogunjimi, B., Zhang, S. Y., Sørensen, K. B., Skipper, K. A., CarterTimofte, M., Kerner, G., ... & Mogensen, T. H. (2017). Inborn errors in RNA polymerase III underlie severe varicella zoster virus

44

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

RNA and Life Threatening Diseases

infections. The Journal of clinical investigation, 127(9), 3543-3556. Okano, M., & Gross, T. G. (2012). Acute or chronic life-threatening diseases associated with Epstein-Barr virus infection. The American journal of the medical sciences, 343(6), 483-489. Oun, S., Redder, P., Didier, J. P., François, P., Corvaglia, A. R., Buttazzoni, E., ... & Linder, P. (2013). The CshA DEAD-box RNA helicase is important for quorum sensing control in Staphylococcus aureus. RNA biology, 10(1), 157-165. Paul, A. M., Shi, Y., Acharya, D., Douglas, J. R., Cooley, A., Anderson, J. F., ... & Bai, F. (2014). Delivery of antiviral small interfering RNA with gold nanoparticles inhibits dengue virus infection in vitro. The Journal of general virology, 95(Pt 8), 1712. Pecero, M., Salvador-Bofill, J., & Molina-Pinelo, S. (2019). Long non-coding RNAs as monitoring tools and therapeutic targets in breast cancer. Cellular oncology, 42(1), 1-12. Poller, W., Dimmeler, S., Heymans, S., Zeller, T., Haas, J., Karakas, M., ... & Landmesser, U. (2018). Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives. European heart journal, 39(29), 2704-2716. Poller, W., Tank, J., Skurk, C., & Gast, M. (2013). Cardiovascular RNA interference therapy: the broadening tool and target spectrum. Circulation Research, 113(5), 588-602. Potera, C. (2012). Firm Focuses Operations on Gene Silencing: Benitec Pits DNA-Directed RNA Interference against Chronic and Life-Threatening Diseases. Genetic Engineering & Biotechnology News, 32(4), 12-13. Ramachandran, P. V., & Ignacimuthu, S. (2013). RNA interference—a silent but an efficient therapeutic tool.  Applied biochemistry and biotechnology, 169(6), 1774-1789. Ratti, M., Lampis, A., Ghidini, M., Salati, M., Mirchev, M. B., Valeri, N., & Hahne, J. C. (2020). MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as new tools for cancer therapy: first steps from bench to bedside. Targeted oncology, 15(3), 261-278. Redis, R. S., Berindan‐Neagoe, I., Pop, V. I., & Calin, G. A. (2012). Non‐coding RNAs as theranostics in human cancers. Journal of cellular biochemistry, 113(5), 1451-1459.

Introduction to RNA and Life-Threatening Diseases

45

96. Roshan, R., Ghosh, T., Scaria, V., & Pillai, B. (2009). MicroRNAs: novel therapeutic targets in neurodegenerative diseases. Drug discovery today, 14(23-24), 1123-1129. 97. Rotbart, H. A., Webster, A. D., & Pleconaril Treatment Registry Group. (2001). Treatment of potentially life-threatening enterovirus infections with pleconaril. Clinical infectious diseases, 32(2), 228-235. 98. Schmidt, U., Kaltwasser, S. F., & Wotjak, C. T. (2013). Biomarkers in posttraumatic stress disorder: overview and implications for future research. Disease markers, 35(1), 43. 99. Schramm, M. A., Venhoff, N., Wagner, D., Thiel, J., Huzly, D., Craig-Mueller, N., ... & Voll, R. E. (2020). COVID-19 in a severely immunosuppressed patient with life-threatening eosinophilic granulomatosis with polyangiitis. Frontiers in immunology, Vol. 11, pp. 2086. 100. Schwartz, D. A., & Dhaliwal, A. (2020). Infections in pregnancy with Covid-19 and other respiratory RNA virus diseases are rarely, if ever, transmitted to the fetus: Experiences with coronaviruses, parainfluenza, metapneumovirus respiratory syncytial virus, and influenza. Archives of pathology & laboratory medicine, 144(8), 920-928. 101. Shah, M. Y., & Calin, G. A. (2014). MicroRNAs as therapeutic targets in human cancers. Wiley Interdisciplinary Reviews: RNA, 5(4), 537548. 102. Shahabipour, F., Barati, N., Johnston, T. P., Derosa, G., Maffioli, P., & Sahebkar, A. (2017). Exosomes: Nanoparticulate tools for RNA interference and drug delivery. Journal of cellular physiology, 232(7), 1660-1668. 103. Sheng, J. Q., Liu, L., Wang, M. R., & Li, P. Y. (2018). Circular RNAs in digestive system cancer: potential biomarkers and therapeutic targets. American journal of cancer research, 8(7), 1142. 104. Shiraki, K., & Daikoku, T. (2020). Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacology & therapeutics, 209, 107512. 105. Soofiyani, S. R., Baradaran, B., Lotfipour, F., Kazemi, T., & Mohammadnejad, L. (2013). Gene therapy, early promises, subsequent problems, and recent breakthroughs. Advanced pharmaceutical bulletin, 3(2), 249.

46

RNA and Life Threatening Diseases

106. Sudharshan, S., & Biswas, J. (2008). Introduction and immunopathogenesis of acquired immune deficiency syndrome. Indian journal of ophthalmology, 56(5), 357. 107. Tang, N., Jiang, S., Yang, Y., Liu, S., Ponnusamy, M., Xin, H., & Yu, T. (2018). Noncoding RNA s as therapeutic targets in atherosclerosis with diabetes mellitus. Cardiovascular therapeutics, 36(4), e12436. 108. Taylor, R., Kotian, P., Warren, T., Panchal, R., Bavari, S., Julander, J., ... & Sheridan, W. P. (2016). BCX4430–a broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. Journal of infection and public health, 9(3), 220226. 109. Tufan, A., Güler, A. A., & Matucci-Cerinic, M. (2020). COVID-19, immune system response, hyperinflammation and repurposingantirheumatic drugs. Turkish journal of medical sciences, 50(9), 620-632. 110. Tuschl, T., & Borkhardt, A. (2002). Small interfering RNAs: a revolutionary tool for the analysis of gene function and gene therapy. Molecular Interventions, 2(3), 158. 111. Wang, D., Li, Z., & Liu, Y. (2020). An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics. Journal of infection and public health, 13(10), 1405-1414. 112. Wang, T., Shigdar, S., Al Shamaileh, H., Gantier, M. P., Yin, W., Xiang, D., ... & Duan, W. (2017). Challenges and opportunities for siRNAbased cancer treatment. Cancer letters, 387, 77-83. 113. Yakovlev, I. A., Deev, R. V., Rizvanov, A. A., & Isaev, A. A. (2017). RNA editing for muscular dystrophy therapy. BioNanoScience, 7(2), 386-389. 114. Ying, S. Y., Chang, D. C., & Lin, S. L. (2008). The microRNA (miRNA): overview of the RNA genes that modulate gene function. Molecular biotechnology, 38(3), 257-268. 115. Ying, S. Y., Chang, D. C., Miller, J. D., & Lin, S. L. (2006). The microRNA: overview of the RNA gene that modulates gene functions. MicroRNA Protocols, Vol. 1, 1-18. 116. Yu, A. M., Choi, Y. H., & Tu, M. J. (2020). RNA drugs and RNA targets for small molecules: principles, progress, and challenges. Pharmacological reviews, 72(4), 862-898.

Introduction to RNA and Life-Threatening Diseases

47

117. Yu, X. J., Liang, M. F., Zhang, S. Y., Liu, Y., Li, J. D., Sun, Y. L., ... & Li, D. X. (2011). Fever with thrombocytopenia associated with a novel bunyavirus in China. New England Journal of Medicine, 364(16), 1523-1532. 118. Zhu, B., Gong, Y., Yan, G., Wang, D., Qiao, Y., Wang, Q., ... & Tang, C. (2018). Down-regulation of lncRNA MEG3 promotes hypoxiainduced human pulmonary artery smooth muscle cell proliferation and migration via repressing PTEN by sponging miR-21. Biochemical and biophysical research communications, 495(3), 2125-2132.

CHAPTER

2

MYOTONIC DYSTROPHY TYPE 2 (DM2)

CONTENTS 2.1 Introduction........................................................................................ 50 2.2 Nomenclature..................................................................................... 51 2.3 History................................................................................................ 52 2.4 Aetiology............................................................................................ 53 2.5 Pathogenesis....................................................................................... 55 2.6 Frequency........................................................................................... 56 2.7 Clinical Presentation........................................................................... 56 2.8 Instrumental Findings.......................................................................... 58 2.9 Diagnosis............................................................................................ 59 2.10 Conclusion....................................................................................... 62 References................................................................................................ 63

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2.1 INTRODUCTION Myotonic dystrophy type 2 (DM2) is just a medically variable, multiple organ systems conditions that are medically comparable to, but different from, myotonic dystrophy form 1. Myotonic dystrophy form 1 is characterized by genetic homogeneity but clinical heterogeneity (DM1), and Caused was the first to define the many manifestations of DM2. Clinical characteristics shared by these three different phenotypes were widespread, proximal or distally weakening; wastage; loss of nerve cells; cataracts; and anomalies in the brain, hormonal, and cardiac systems (Liquori et al., 2001). At first, the medical distinctions between DM1 with PROMM seemed to be unambiguous. However, over time, it becomes clear that the medical distinctions between any of these categories are beginning to merge. The year 1999 saw the mapping of the mutant gene including all three diseases to chromosome 3q. In 2001, it was discovered that the three distinct symptoms are all caused by the same mutations within the ZNF9 gene, which is located on chromosomal 3q21.3. DM2 is caused by a genetic mutation, even though it may manifest in a variety of clinical presentations (Ricker et al., 1994).

Figure 2.1. Myotonic Dystrophy Type 2 (DM2). Source: https://www.researchgate.net/figure/of-the-clinical-features-of-myotonic-dystrophy-type-2-as-reported-in-a-large-cohort-by_fig1_330990673

Myotonic Dystrophy Type 2 (DM2)

51

A CCTG-repeat extension of between 75,000 and 11,000 repetitions may be found in popular intron 1 of the ZNF9 gene, which is located on chromosome 3q21.3. This mutation is associated with type 2 diabetes. Only DNA testing should be used to make a diagnosis of type 2 diabetes because of the variability in clinical presentation. Myotonia clinically manifests itself as a slower muscular relaxation as a result of ongoing neuronal excitability (electromyography myotonia) Myotonia is the defining characteristic of myotonic diseases, which may be broken down into sodium and chloride kinds of processes as well as myotonic congenital anomalies (Table 1) (Ranum et al., 1991). Myopathy form 1 (DM1, traditional form), gene mutations form 2 (DM2), as well as a minimum one more entity that is medically comparable to DM2 but does not have a DM1 or DM2 gene mutation, are the myopathy dystrophies (Udd et al., 1997).

Figure 2.2. Myotonic Dystrophy Type 2 (DM2). Source: https://www.myotonicdystrophysupportgroup.org/wp-content/uploads/2015/12/dm2-cells.png

2.2 NOMENCLATURE A revised genetically determined taxonomy for myotonic dystrophies has been approved by the Global Myotonic Dystrophy Collaboration and also the Human Genome Society (Table 2.1). The genetic loci would be called

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within the order in which they were identified (DM1, DM2) or would be identified within coming (DMn). Myotonic dystrophy form 1 (DM1, genetic material 19), myotonic dystrophy type 2 (DM2, genetic material 3) and myotonic dystrophy form n (DMN) are the names given to the related diseases. The words proximal myotonic myalgia (PROMM) and adjacent myotonic dystrophy (PDM) allude to medical symptoms, as well as the term DM2 has superseded them (Thornton et al., 1994).

2.3 HISTORY Steinert was the first to characterize myopathy type 1 in 1909. (Liquori et al., 2001). Fleischer was the first to notice cataracts and dread in DM1 in 1918. The hereditary abnormality of DM1 was found in 1992. Patients have clinical symptoms comparable to DM1 but no DM1 mutations were identified in 1994. In contrast to DM1, those patients had mostly proximal stiffness and relatively little wasting, which is why the name PROMM was chosen. Through the collection of medical studies, it developed clear that the medical distinction between DM1 with PROMM remained becoming more blurred (Day et al., 1999). PROMM remained reported as being comparable to DM1 but different, with the basic symptoms of proximal stiffness, cataracts, and electromyographic (EMG) myopathy mostly trendy occurrence of a typical CTG-repeat length within dystrophia myotonic protein kinase (DMPK) genes on chromosomes 19q13.3. PROMM, hearing problems, cataracts, spinal muscular atrophy, and congenital hypothyroidism were identified in such a Finnish family in 1997. PDM was given to the company. Although reported a huge Minneapolis kindred having distal stiffness but typical CTG repetition scope in the CTG, they offered more evidence again for clinical variability of non-DM1 gene mutations (Schneider et al., 2000).

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Table 2.1. Myotonic diseases have genetic traits Disorder

Transmission

Locus

Gene

Gene product

Congenital myotonia (Becker) Congenital myotonia (Thomson) Hyperkalemic periodic paralysis a-subunit Paramyotonia congenital a-subunit Potassium-aggravated myotonia a-subunit Myotonia fluctuations a-subunit Myotonia permanent a-subunit Acetazolamide responsive myotonia a-subunit Myotonic dystrophy type 1

ar ad ad ad ad ad ad ad ad

7q35 7q35 17q23 17q23 17q23 17q23 17a23 17q23 19q13.3

CLC-1 CLC-1 SCN4A SCN4A SCN4A SCN4A SCN4A SCN4A

Muscle chloride channel Muscle chloride channel Muscle sodium channel Muscle sodium channel Muscle sodium channel Muscle sodium channel Muscle sodium channel Muscle sodium channel DMPK Protein kinase

DM2, PROMM, PDM

ad

3q21.3

ZNF9

Zinc finger protein

The DM1 gene is found in the human genome. Dystrophia myotonica type 2 was the name given to the condition (DM2). ruled out the DM1 loci as possible genes of DM2, as well as the chromosome areas encoding the genes encoding muscular sodium (SCN4A) and then chloride networks (CLC-1), but also assigned DM2 to chromosomes 3q, localized PROMM as well as PDM to chromosomes 3q in 1999. .Liquori discovered an instability CCTG tetranucleotide repeating increase within the ZNF9 genetic factor located on chromosome 3q21.3 (Table1), which they believe is the cause of the DM2/ PROMM/PDM symptoms (Warner et al., 1996).

2.4 AETIOLOGY There has been evidence that such genes that cause DM2, PROMM, as well as PDM are connected to chromosomes 3q21.3 (Table 1) before 1999.  DM2 is produced by such an aberrant CCTG extension in intron 1 of both the genetic factor coding for the ZNF9 protein, according to Liquori et al. (2001). (116955). The quantity of CCTG replications in extended alleles varied from 75 to 11 000, with a mean of around 5000 (Matsuura & Ashizawa, 2002). Using 10 recombination chromosomes, reduced the DM2 area toward a 2-cM range. They narrowed the range to 320 kb using transmission incompatibility testing and validation of preserved ancestor haplogroups (Cardani et al., 2004). CL3N58, another of the indicators in sequence variation with DM2, has an unusual segregated pattern. Through polymerase chain reaction (PCR), all afflicted adults were mostly homozygous, while affected individuals did not appear to acquire an allele from the inherited disorder. Southern analysis has been done to see whether a primary contribution and other translocations were to blame for the abnormal segregated pattern (Allison & Schork, 1997).

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The volume of increases inside the blood of afflicted children was frequently less than that of respective parents. This moment somatic fluctuation of the repetition size made it difficult to understand this discrepancy. There was no discernible link between both the early onset and also the magnitude of the growth (Liquori et al., 2001). Unfortunately, because of the somatic volatility of the expansions (up to 9000 repetitions in one afflicted individual’s plasma), a conclusive evaluation of the connections between guidance notes and clinical characteristics of the illness was not possible (Table 2) (Harper et al., 2002). ZNF9, also known as the intracellular nucleotide protein complex, is just a zinc finger protein with seven zinc-finger groups that are expected to interact with RNA. It is widely stated, through both the maximum levels of appearance in the cardiac besides skinny systems, binary of the most afflicted tissues with DM2 (Sansone et al., 2013). Similarly to the mutation of DMPK RNA in DM1, the mutated ZNF9 RNA aggregates in many nuclear centers. In situ hybridization of Intellect, CCUG enquiries reveal not at all nuclear-powered foci, showing that probes hybridize with RNA not even with DNA (Liquori et al., 2001). Although the CCTG expansions are produced, it is unknown whether the nuclear-powered RNA foci comprise the whole unedited ZNF9 transcripts (Ricker et al., 1995). When strength slices are hybridized using fluorescent labeled Repeats nucleotide sequences, nuclear attentions in DM2 are identical to those in DM1, however, the investigated duplexes are less stable. These similarities among both the ZNF9 mutations and the extended CTG repeats in the DMPK gene’s detonation non-coding region suggest that RNA microsatellite extensions are harmful and produce DM1 and DM2’s multiple organ systems characteristics. DM2 appears to be another illness induced by a microsatellite mutation inside a gene that has been transcribed but has not yet been translated. In around 20% of PROMM cases, therefore neither variation in the DMPK nor even the ZNF9 genes can be discovered (Kress et al., 2000).

Myotonic Dystrophy Type 2 (DM2)

55

Table 2.2. Myotonic dystrophy form 1 (DM1) then myotonic dystrophy form 2 (MD2) have different genetic features (DM2) DM1

DM2

Transmission

Autosomal-dominant Autosomal-dominant

Gene locus

19q13.3

Gene

DMPK ZNF9*

Gene dosage

Hetero- rarely homozygote

Homozygote

Gene product

Protein kinase

Zinc finger protein

Function

Signal propagation

Unknown

Mutation of expanded repeats

CTG-repeat expansion 37–5000

CCTG-repeat expansion Number 75–11 000

Localization of mutation

5¢ untranslated region

Intron 1

Anticipation

+

± (Schneider et al., 1999)

3q21.3

Retraction ±

+

Congenital form

–

+

2.5 PATHOGENESIS Understanding the genetic characteristics shared mostly by various DM2 traits (PROMM, DM2 and PDM ) gives insight into the processes behind the seemingly unconnected clinical symptoms. Unfortunately, it is still unknown how well the CCTG-repeat extension within the ZNF9 genetic factor creates the complicated phenotype of DM2. Genetic and molecular similarities among DM1 and DM2 suggest that now the CUG or CCUG extensions may remain harmful and then produce DM1 and DM2’s multisystem characteristics (Wieser et al., 2000; Suominen et al., 2011). Haploinsufficiency of such DMPK proteins changed transcription of nearby genes such as SIX5, as well as pathological consequences of the CUG extension within mRNA, that aggregates inside the nucleus forming nuclear foci that affect cellular activity, are all pathomechanisms of DM1.  Every one of these ideas has been demonstrated to relate to the pathophysiology of the CTG-repeat expansions in DM1 mice models. Clinically myotonia, as well as histologic characteristics of DM1, were shown in a mouse model that expressed mRNA containing CUG sequences (Mankodi et al., 2000).

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SIX5 knockout animals exhibited cataracts, whereas DM1 knockout mice suffered heart problems (Liquori et al., 2001). It’s unclear if these hypotheses also relate to the pathophysiology notion of DM2. That ZNF9 protein’s typical functionality as such an RNA protein complex seems to be unconnected to all the proteins produced within the DM1 genomic region (Buxton et al., 1992; Day et al., 2003). Furthermore, the genes within the DM2 area have not at all evident link to genetic factors around the DM1 locus, suggesting that such medical traits shared by DM1 and DM2 aren’t caused by changes in the regulation of gene expression near those expansions. RNA-binding proteins which link toward DM1 CUG extensions might indeed attach to CCUG developments, creating massive RNA degradation and cellular metabolic disturbance. Conversely, RNA-binding molecules that aren’t engaged in DM1 RNA processing might be quandary to CCUG extensions (Fu et al., 1992).

2.6 FREQUENCY So far, around 300 people have been identified as having DM2 as one of the three phenotypes. The actual frequency and distribution of DM2 are, however, unknown. DM2 is thought to have a frequency of 2.1–14.3 per 100 000 people globally, comparable to DM1. This statistic is defined as the clinical similarities of DM1 and DM2, as well as the reality that DM2 is milder. Ricker et al. also estimated that the prevalence of PROMM in German was about comparable to those of DM1. The prevalence of DM2 (PROMM) is predicted to remain at 1 in every 20 000 people (Harley et al., 1992).

2.7 CLINICAL PRESENTATION DM2 is just a medically complex, multisystem illness, similar to DM1 (Moxley, 1996). Most DM2 patients have symptoms that are very similar to those seen in typical DM1 (myotonia, distal and proximal limbs weakening, frontal baldness, cataract, and irregular heartbeats), while others may be separated more readily from DM1 (Moxley, 1996). Due to the obvious clinical similarities among DM1 and DM2 in certain individuals, distinguishing these two entities only on diagnosis based is often not straightforward (Brook et al., 1992). Myotonic dystrophy wasn’t thought to just be variable until 1994. Patients having symptomatic muscular dystrophy that fixed not contain the CTG-

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repeat expansions on chromosomes 19q13.3 were detected in the United States and Germany after the genetic abnormality in DM1 was discovered.  The phenotype variations across individuals with CTG expansions looked clear at first. Patients who did not have CTG enlargement exhibited proximal stiffness without wastage of the lower extremities at the time of diagnosis (Mahadevan et al., 1992; Filippova et al., 2001). Because of this, the term “proximal myotonic myopathy” (PROMM, 600109) was coined. By way of additional relations remaining detailed, it developed clear that the line between DM1 with PROMM remained becoming more blurred. Mild oscillating then temperature-dependent (extra strenuous in balminess then lowered in cold) myopathy; muscle hypertrophy; ephemeral (all through existences, weeks, as well as months) combustion muscle aching, primarily at nightly; and disproportionally rapid exhaustion during exercise were also features of the German clients’ clinical symptoms. There were little cognitive deficits, hypersomnia, reproductive degeneration, ptosis, muscular wastage, dysphagia, or pulmonary weakness, in contrast to DM1. Patients were able to walk on a level, even surface for the rest of their lives, but they grew progressively unable to ascend stairs (Matsuura et al., 2000). PROMM patients might be entirely asymptomatic, have modest symptoms (Newman et al., 1999), or be severely impaired. The start of PROMM was observed to occur between the ages of 20 and 60. The Global Conference of a European Neuromuscular Center projected two clinical definitions for PROMM in 1997: degeneration to initiation before 50 years old, primarily anterior lack of strength, abnormal unexpected action on electromyography, which include myotonic, pseudomyotonic, and elevated strange spills, regular Trinucleotide with in Gene encoding (determined to prove), as well as muscle cramps, rapidly changing weak point and rigidity, muscle spasms, muscle twitching, and calf hypertrophies (Warren, 1996). Udd et al. remarked on the household from Finland with autosomaldominantly distributed multi-system muscular dystrophy who did not have the DM1 mutations in 1997. (Udd et al., 1997). Cataracts, delayed sensory neural impairment or loss of hearing, delayed significant proximal weakening, wastage, and myotonia, with male hypothyroidism, were all observed in such individuals. The relevant gene was discovered on chromosome 3q in 1999.PDM was the name given to the condition (Hamshere et al., 1999). Ranum et al. discovered a five-generation DM2 group (Ranum et al., 1998). Myotonia, generalized (distal and proximal) or solely distal weakening, frontal baldness, polychromatic cataracts, infertile, and

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abnormal heart rhythms were all present in affected people (Table 2.3). (Day et al., 1999). Calf hypertrophy and heavy sweating were also seen in these individuals’ phenotypes. Unfortunately, the phenotypic of afflicted individuals could never be reliably separated from that of DM1 patients (Table 2.3). DM2 has been the most fitting term for this illness, according to scientists. The affection of mostly distal muscles has been recorded in other nations as well (Abbruzese et al., 1996).

2.8 INSTRUMENTAL FINDINGS The activities of influence enzymes in the blood, notably creatinine kinase, could be high. The c-glutamyl-transpeptidase enzyme might also be faulty. Insulin resistance may result in hyperglycemia .. Thyroid function testing may reveal whether or not you have hyperthyroidism. Testosterone levels might be lower, while luteinizing testosterone and follicular stimulation hormone levels may be higher (Ricker, 1999). To identify DM2 from DM1, a movement test was devised (Sander et al., 1997). Electrocardiogram (ECG reveals abnormalities in impulse production and propagation In younger patients, an echocardiogram may detect cardiomyopathy (Ricker, 1999; Mankodi et al., 2002). Fibrillations, positively sharp waveforms, muscle twitching, myopathy and pseudomyotonic discharging, neuromyotonialike flush es, and elevated strange discharges are all examples of activation in response detected on EMG. Reduced mean duration, higher percent polyphagia, and higher percent satellite possibilities may be seen in muscle action potentials. At maximum isometric contractions, the magnitude of the interference pattern might be lowered (Ricker et al., 1995). Angulated fibers, mild alterations in myofiber length, axially misplaced nuclei, ringed fibers (Ringbinden), and dispersed myopathic or dystrophic changes may also be seen on muscle biopsy. Table 2.3. Myotonic dystrophy kind 1 (DM1) and myotonic dystrophy kind 2 (DM2) clinical features (MD2) Manifestation

DM1

DM2 Cerebrum

Cognitive impairment

+

–

Hypersomnia +

–

Tremor –

±

Eyes

Myotonic Dystrophy Type 2 (DM2) Visual impairment

+

Facies myopathic

+

Myotonia +

+ Skeletal muscle – +

Permanent distal weakness +

±

Permanent proximal weakness

±

Fluctuating weakness and stiffness

– +

Distal wasting

+

±

Proximal wasting

±

+

+

Myalgia –

+

Calf hypertrophy

± Smooth muscle

–

59

Megacolon +

–

Dysphagia +

+

Constipation –

+

Heart Palpitations +

+

Edema +

–

Exertional dyspnoea

+

–

Intermittent chest pain

–

± Endocrinium

Baldness +

–

Diabetes mellitus

+

±

Male hypogonadism

+

±

Hyperhidrosis ±

+

Hyperostosis +

–

Gynecomastia

±

+ Skeleton

Foot deformities

+

–

category I fiber dominance, necrotizing fibers, nuclear links, cytosolic masses, increases in endomysial tissue. There could be isolated or diffused white matter abnormalities on cortical magnetic resonance. Decreased blood circulation inside the prefrontal and temporal regions has been seen using positron emission tomography (Table 4) (Timchenko et al., 1996).

2.9 DIAGNOSIS The analysis of DM2 is based on the patient’s medical past (dimness, going to waste, rigidity, muscle aches, spasms, muscle twitching, excessive daytime sleepiness, memory problems, seizures, swallowing disorders, obstipation, difficulty breathing, irregular heartbeats, heavy sweating), diagnostic neurologic extensive study (weakness, going to waste, loss of nerve cells,

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muscle twitching, calf hyperplasia, aftershock, cognitive decline), and blood chemical inquests (increased creatine Muscles biopsy seems to be irrelevant in determining the diagnosis. DM1, limb-girdle Parkinson’s disease, mitochondriopathy, as well as hypothyroidism are all differential diagnoses to consider (Mankodi et al., 2001).

2.9.1 Treatment and Management Nearby is no particular therapy for DM2 at this time. Physical therapists can aid patients in determining whether or not they need a knees or foot ankles exoskeleton or other assistive devices. Muscle discomfort has already been observed to be relieved by nonsteroidal generally pro medications, carbamazepine, or corticosteroid in isolated circumstances (Meola et al., 2000). Mexiletine, phenytoin, or carbamazepine could be helpful in patients with persistent myotonia, however, there is no evidence that these medicines are efficacious in DM2. Quinine sulfate may be recommended for people who have recurrent myotonia or cramping. Anti-arrhythmic drugs must be used if cardiac conduction abnormalities are detected. Further research is needed to see whether dehydro-epiandrosteronesulfate as described in DM1 (Unknown, 1998), may help decrease muscle atrophy (Fardaei et al., 2002). Cataracts may need surgery at some time in the future. A definitive diagnosis is made, and patients must have a cardiologic evaluation. If somehow the baseline examinations proved highly abnormal or whether the patients became cardiological sick, reinvestigation is recommended. In the event of symptomatic rhythm problems, cardiac treatment, involving pacemaker installation, may be required (Charlet-B et al., 2002). Hypothyroidism must be checked regularly in patients. It’s unclear if benzodiazepines, opioids, or sedatives cause respiratory failure in DM2 individuals, to improve the overall muscle relaxants and increase myotonia, and also whether DM2 clients may acquire malignant overheating either during anesthesia. Local anesthetic, on the other hand, is used with discretion, and the comment period needs special monitoring (Anonymous, 1998).

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Table 2.4. Contributory conclusions in myotonic dystrophy form 1 (DM1) and myotonic dystrophy type 2 (DM2) patients (MD2) Investigation

DM1 DM2

Blood chemistry Elevated creatine kinase

+

Elevated c-glutamyl-transpeptidase + Hypothyroidism

+ +

– ±

Cerebral MRI White matter lesions

+

+

Cortical atrophy

+

–

Temporal hyperintensity

+

–

Hyperostosis

+ –

PET Reduced frontal and temporal blood flow

+

? Slit lamp

Posterior capsular cataract

+

+ Nerve conduction studies

Sensory-motor neuropathy

+

? EMG

Myotonic discharges

+

+

Pseudomyotonic discharges

+

+

Short duration MUAPs

+

± ECG

Cardiac conduction defects

+

+ Echocardiography

Myocardial thickening

+

–

Dilation

– +

Hypertrabeculation

+ ?

Atrial septal defect

+

?

+

+ Molecular genetics

Muscle biopsy Unspecific myopathic alterations

CTG repeat expansion in the DMPK gene + – CCTG repeat expansion in the ZNF9 gene – +

2.9.2 Genetic counseling and prognosis Adults and people who are diagnosed with DM2 must undertake genetic screening (linking research or explicit verification of the extension) also like the gold standard for identifying this disorder, even though it is not routinely accessible. Prenatal diagnosis is another area where DNA analysis is useful. Prenatal testing, on the other hand, must not be done if an abortion

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is not wanted. The very variable CCTG-expansion, as well as the unknown genotype-phenotype association, make genetic screening difficult in general. Damaged children’s increased diameters in blood plasma are frequently smaller than their parents’. Men appear to consume a lower chance of passing the abnormality on to their kids than females (Savkur et al., 2001). Because the defects in DM2 are less severe than those in DM1, the illness progresses more slowly, and the prognosis overall life span is better than that in DM1 (Meola et al., 1999). Only within single DM2 instances, the life span may be shortened, especially if there is substantial cardiac participation with pathological rhythm disturbances (Liquori et al., 2001).

2.10 CONCLUSION That section was written to highlight current results in DM2 individuals and to demonstrate how DM2 and DM1 may be distinguished clinically and molecularly. A CCTG repeated extension within the ZNF9 gene located on chromosome 3q21.3 has already been discovered as the fundamental genetic abnormality of medically diverse condition DM2, which does not have a CTG repeated extension within Gene encoding. Every one of the previously distinct entities PROMM, PDM and DM2  has the same alteration. Due to the clinical variability, DM2 must only be diagnosed genetically.

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REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

Allison, D. B., & Schork, N. J. (1997). Selected methodological issues in meiotic mapping of obesity genes in humans: issues of power and efficiency. Behavior genetics, 27(4), 401-421. Brook, J. D., McCurrach, M. E., Harley, H. G., Buckler, A. J., Church, D., Aburatani, H., ... & Housman, D. E. (1992). Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell, 68(4), 799-808. Buxton, J., Shelbourne, P., Davies, J., Jones, C., Tongeren, T. V.,Aslanidis, C., ... & Johnson, K. (1992). Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature, 355(6360), 547-548. Cardani, R., Mancinelli, E., Sansone, V., Rotondo, G., & Meola, G. (2004). Biomolecular identification of (CCTG) n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy. European Journal of Histochemistry, 48(4), 437-442. Charlet-B, N., Savkur, R. S., Singh, G., Philips, A. V., Grice, E. A., & Cooper, T. A. (2002). Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Molecular cell, 10(1), 45-53. Day, J. W., Ricker, K., Jacobsen, J. F., Rasmussen, L. J., Dick, K. A., Kress, W., ... & Ranum, L. P. W. (2003). Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology, 60(4), 657664. Day, J. W., Roelofs, R., Leroy, B., Pech, I., Benzow, K., & Ranum, L. P. (1999). Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscular disorders, 9(1), 19-27. Fardaei, M., Rogers, M. T., Thorpe, H. M., Larkin, K., Hamshere, M. G., Harper, P. S., & Brook, J. D. (2002). Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Human molecular genetics, 11(7), 805-814. Filippova, G. N., Thienes, C. P., Penn, B. H., Cho, D. H., Hu, Y. J., Moore, J. M., ... & Tapscott, S. J. (2001). CTCF-binding sites flank

64

10.

11.

12.

13.

14.

15.

16.

17.

RNA and Life Threatening Diseases

CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nature genetics, 28(4), 335-343. Fu, Y., Pizzuti, A., Fenwick Jr, R., King, J., Rajnarayan, S., Dunne, P. W., ... & Caskey, C. T. (1992). An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science, 255(5049), 12561258. Hamshere, M. G., Harley, H., Harper, P., Brook, J. D., & Brookfield, J. F. (1999). Myotonic dystrophy: the correlation of (CTG) repeat length in leucocytes with age at onset is significant only for patients with small expansions. Journal of Medical Genetics, 36(1), 59-61. Harley, H. G., Brook, J. D., Rundle, S. A., Crow, S., Reardon, W., Buckler, A. J., ... & Shaw, D. J. (1992). Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature, 355(6360), 545-546. Harper, P. S., van Engelen, B. G. M., Eymard, B., Rogers, M., & Wilcox, D. (2002). 99th ENMC international workshop: myotonic dystrophy: present management, future therapy: 9–11 November 2001, Naarden, The Netherlands. Neuromuscular Disorders, 12(6), 596-599. Kress, W., Mueller-Myhsok, B., Ricker, K., Schneider, C., Koch, M. C., Toyka, K. V., ... & Grimm, T. (2000). Proof of genetic heterogeneity in the proximal myotonic myopathy syndrome (PROMM) and its relationship to myotonic dystrophy type 2 (DM2). Neuromuscular Disorders, 10(7), 478-480. Liquori, C. L., Ricker, K., Moseley, M. L., Jacobsen, J. F., Kress, W., Naylor, S. L., ... & Ranum, L. P. (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science, 293(5531), 864-867. Mahadevan, M., Tsilfidis, C., Sabourin, L., Shutler, G., Amemiya, C., Jansen, G., ... & Korneluk, R. G. (1992). Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science, 255(5049), 1253-1255. Mankodi, A., Takahashi, M. P., Jiang, H., Beck, C. L., Bowers, W. J., Moxley, R. T., ... & Thornton, C. A. (2002). Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Molecular cell, 10(1), 35-44.

Myotonic Dystrophy Type 2 (DM2)

65

18. Mankodi, A., Urbinati, C. R., Yuan, Q. P., Moxley, R. T., Sansone, V., Krym, M., ... & Thornton, C. A. (2001). Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Human molecular genetics, 10(19), 2165-2170. 19. Matsuura, T., & Ashizawa, T. (2002). Polymerase chain reaction amplification of expanded ATTCT repeat in spinocerebellar ataxia type 10. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 51(2), 271-272. 20. Matsuura, T., Yamagata, T., Burgess, D. L., Rasmussen, A., Grewal, R. P., Watase, K., ... & Ashizawa, T. (2000). Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature genetics, 26(2), 191-194. 21. Ranum, L. P., Rasmussen, P. F., Benzow, K. A., Koob, M. D., & Day, J. W. (1998). Genetic mapping of a second myotonic dystrophy locus. Nature genetics, 19(2), 196-198. 22. Ricker, K., Koch, M. C., Lehmann-Horn, F., Pongratz, D., Otto, M., Heine, R., & Moxley, R. T. (1994). Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology, 44(8), 1448-1448. 23. Ricker, K., Koch, M. C., Lehmann-Horn, F., Pongratz, D., Speich, N., Reiners, K., ... & Moxley, R. T. (1995). Proximal myotonic myopathy: clinical features of a multisystem disorder similar to myotonic dystrophy. Archives of neurology, 52(1), 25-31. 24. Sansone, V. A., Brigonzi, E., Schoser, B., Villani, S., Gaeta, M., De Ambroggi, G., ... & Meola, G. (2013). The frequency and severity of cardiac involvement in myotonic dystrophy type 2 (DM2): long-term outcomes. International journal of cardiology, 168(2), 1147-1153. 25. Savkur, R. S., Philips, A. V., & Cooper, T. A. (2001). Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nature genetics, 29(1), 4047. 26. Schneider, C., Ziegler, A., Ricker, K., Grimm, T., Kress, W., Reimers, C. D., ... & Toyka, K. V. (2000). Proximal myotonic myopathy: evidence for anticipation in families with linkage to chromosome 3q. Neurology, 55(3), 383-388. 27. Suominen, T., Bachinski, L. L., Auvinen, S., Hackman, P., Baggerly, K. A., Angelini, C., ... & Udd, B. (2011). Population frequency of

66

28.

29.

30.

31.

32. 33.

RNA and Life Threatening Diseases

myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. European journal of human genetics, 19(7), 776-782. Thornton, C. A., Griggs, R. C., & Moxley III, R. T. (1994). Myotonic dystrophy with no trinucleotide repeat expansion. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 35(3), 269-272. Timchenko, L. T., Miller, J. W., Timchenko, N. A., DeVore, D. R., Datar, K. V., Lin, L., ... & Swanson, M. S. (1996). Identification of a (CUG) n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic acids research, 24(22), 4407-4414. Udd, B., Krahe, R., Wallgren-Pettersson, C., Falck, B., & Kalimo, H. (1997). Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes?. Neuromuscular Disorders, 7(4), 217-228. Warner, J. P., Barron, L., Goudie, D., Kelly, K., Dow, D., Fitzpatrick, D. R., & Brock, D. J. (1996). A general method for the detection of large CAG repeat expansions by fluorescent PCR. Journal of medical genetics, 33(12), 1022-1026. Warren, S. T. (1996). The expanding world of trinucleotide repeats. Science, 271(5254), 1374-1375. Wieser, T., Bönsch, D., Eger, K., Schulte-Mattler, W., & Zierz, S. (2000). A family with PROMM not linked to the recently mapped PROMM locus DM2. Neuromuscular Disorders, 10(2), 141-143.

CHAPTER

3

FRAGILE X- ASSOCIATED TREMOR/ ATAXIA SYNDROME

CONTENTS 3.1 Introduction........................................................................................ 68 3.2 Fragile X Syndrome and Associated Disorders..................................... 68 3.3 Epidemiology of FXTAS....................................................................... 70 3.4 Clinical Presentation of FXTAS............................................................ 71 3.5 Neuroradiological Findings................................................................. 76 3.6 Pathophysiology.................................................................................. 77 3.7 Diagnosis............................................................................................ 82 3.8 Management and Ongoing Research.................................................. 84 3.9 Conclusions........................................................................................ 85 References................................................................................................ 87

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3.1 INTRODUCTION The fragile X-associated tremor/ataxia syndrome, often known as FXTAS, is a neurological condition that manifests itself in elderly bearers of the FMR1 gene who have between 55 and 200 CGG repeats. This especially in construction results in abnormally high quantities of FMR1 mRNA, which may cause toxicity as well as a malfunction in the mitochondrial. The clinical manifestations often start mostly in the 60s with such a tremor of the activity or intentions, which is then accompanied by ataxia of the cerebellum, while twenty percent of patients have ataxia. Central nervous system atrophy with white matter illness are characteristics that may be seen on MRI scans (Johnson et al., 2020). These symptoms are most prevalent in the intermediate cerebellar long stalks, and periventricular regions, including the splenium of both the parietal lobe. Memory and executive functioning deficiencies are examples of neurocognitive issues; yet, men make up just half of the population that might acquire dementia. Because females have a second set of chromosomes that does not contain the premutation, FXTAS symptoms may be less severe in females (Greco et al., 2007). FXTAS manifests itself clinically in around 40 percent of male carriers as well as 16 percent of female carriers. Patients who arrive with tremors, ataxia, Parkinson’s disease indications, neurotoxicity, and mental issues should be evaluated for the FXTAS diagnoses since especially in construction may develop in fewer than 1 every 200 women as well as 1 in 400 males. In individuals exhibiting these signs, FMR1 DNA analysis is very necessary if there is a previous history of such a fragile X variant in the patient and the family (Hagerman P. & Hagerman R., 2007).

3.2 FRAGILE X SYNDROME AND ASSOCIATED DISORDERS One of the most prevalent causes of hereditary intellectual impairment including autism spectrum disease is Fragile X disorder (FXS). It is caused by the increase of CGG nucleotide sequence repeats (>200) within regulatory regions of both the fragile X mental disabilities 1 (FMR1) genes, which are found on chromosome Xq27.3. The gene is methylated and then silenced as a result of the spread. FXS is caused by additional problems that cause the genes to lose functionality, including such reductions or caused by mutations, inside a small percentage of instances (less than 1%) (CabalHerrera et al., 2020; Grigsby et al., 2006). Because the FMR1 gene ordinarily

Fragile X- Associated Tremor/Ataxia Syndrome

69

codes again for fragile X intellectual disabilities protein (FMRP), its silence results in the protein’s lack of translation. FMRP is just an RNA-binding protein that plays a role in a variety of activities, including neuroplasticity and neural network functioning. CGG repetitions are fewer than 45 in healthy adults. Participants with 46–54 repetitions are classified as having the grey zone, whereas those having 55–200 repetitions are classified as having the symbol of the new (PM). Fragile Cross premature ovarian deficiency in females, neurobehavioral situations including such clinical depression, lately identified as fragile Cross neuropsychiatric (FXAND), and fragile X-associated uncontrollable shaking syndrome (FXTAS) can be symptoms of PM transmitters. The emphasis of this analysis will be on FXTAS, a movement condition characterized by tremors and/or ataxia, cognition impairment, neurotoxicity, and peripheral neuropathy in people with Parkinson’s disease (Krans et al., 2017). Covers a wide variety and associates originally characterized FXTAS from 2001, while they documented five older men who’ve been carriers of both the PM and had developed intentional tremors, difficulties ambulating, executive function deficiencies, with neuronal loss in combination with high FMR1 RNA Molecule (mRNA) concentrations. Ever since, FXTAS has established itself as a well chronic degenerative condition that affects PM bearers, including males and females, who are older and have intentionality tremors and/or cerebellar (Islam & Lee, 2020; Berman et al., 2014). Patients with CGG repetition count within the grey area have already been reported to have symptomatic and neuroradiological results that are compatible with FXTAS. Persons with the complete mutations (FM) that presented with such a clinical presentation comparable with FXTAS have already been reported, albeit they are uncommon. These people with FM exhibit size chromosomal abnormalities and/or absence of inactivation of a Gene mutation, resulting in high transcriptional activity and also some FMRP synthesis. Because of these occurrences, specialists are considering changing the criteria for a diagnosis for identifying FXTAS to include not just made in two ways carriers but those with such a grey area or FM repetition number (SalcedoArellano et al., 2020). Physicians should be aware of both PM as well as its accompanying illnesses because they are ready to encounter a person with PM within their clinics, especially if they are uninformed of their disease processes, they may misdiagnose FXPOI and FXAND in addition to FXTAS. Hunters and companions indicated that the frequency of PM within the general public is around 1 in 300 females as well as 1 in 850 men in a meta-analysis published

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in 2014. It’s worth noting that the frequency varies widely over the world, with certain nations reporting frequency as great as 1 in 28 females and 1 in 71 men, while Japan has the smallest known PM allele frequency (Filley, et al., 2015).

3.3 EPIDEMIOLOGY OF FXTAS A thorough imputation investigation of all identified fragile X individuals in California has been the sole research of FXTAS incidence within the premutation community. They discovered that increasing age was linked to a higher incidence of tremors and ataxia within male bearers, with a frequency of 17 percent in their 50s to 75 percent in their 80s. Unfortunately, neither indicates that growth in the general public has been conducted (Filley et al., 2014). Premutation incidence in individuals having movement disorders has been studied extensively, including screened investigations in adult patients having degeneration, spinocerebellar incoordination, various systems atrophy, dyskinesia, and essential tremor. As a whole, the pervasiveness of FMR1 growth and expansion in communities becoming analyzed for neurological conditions is low (2%), but it could be described by several factors, including sick people with FXTAS’ lack of knowledge of about their signs, which leads about them not reflecting their neurological problems as well as the reality that only a few patients with FXTAS have been made reference to and analyzed by an action neurological condition specialist. Due to the low incidence of FMR1 mutations in the populations tested, the majority of these studies indicated that genetic screening must be done primarily if there are other clinical signs of fragile X-related illnesses or family background of fragile X diseases (Jacquemont et al., 2003). FXTAS is just a neurological illness that affects mostly men and also is maturity level. Female bearers are anticipated to also be impacted by FXTAS at a rate of 13 percent to 16 percent, whilst male bearers are expected to also be impacted at a rate of over 40 percent. Penetrance might be connected to the length of the CGG repetitions, with smaller repeats being related to lesser incidence (Cabal-Herrera et al., 2020). 55 males should be included in the biggest retrospective analysis of FXTAS to date, with a mean lifespan of symptom start of 60.6 years (+/8.6 years). There have been some cases of individuals with rapidly progressive FXTAS that had occupational pollution that could have been related to the early presentations and severity of the condition, including neurotoxicity, pollution, illegal substances, and insecticides, including alcohol intake. FXTAS progresses differently

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in different people, with an average lifespan of 5 to 25 decades after the appearance of illness (Hagerman R. & Hagerman P., 2013).

3.4 CLINICAL PRESENTATION OF FXTAS Intentional tremors with cerebellum instability are the most common symptoms of FXTAS. These generally begin with just an action or intentional tremors just at age of 62, characterized by the formation of an ataxic walk, however, 20% of individuals only have ataxia. FXTAS is often linked to neuropathy, neurological disorder, and executive impairment. Dysautonomia, sleep issues, severe headaches, sensory impairment, hearing impairment, sensory deficit, chronic tiredness, and mental disorders are all common in PM bearers both with FXTAS. Females having FXTAS are more likely to have fibromyalgia, immunological illnesses, and thyroid abnormalities. The usual clinical course of FXTAS is shown in Figure 1 (Martínez-Cerdeño et al., 2015).

Figure 3.1. Fragile X premutation with fragile X-associated tremor/ataxia syndrome (FXTAS) diagnostic manifestations across time. Source: https://www.mdpi.com/1422-0067/21/12/4391/htm

FXTAS has a wide range of clinical manifestations, starting age, and intensity. In PM bearers, a greater CGG repetition size indicates an acute onset and, possibly, an unhealthy life. Because females possess two Sets of

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chromosomes, their effects are milder. Female instances of FXTAS without dementia were not recorded in the initial five cases, but later publications have included female instances of FXTAS without dementia (Lu et al., 2020; Hall & Berry-Kravis, 2018). In females, an increase in the X-inactivation proportion and skewed deactivation of the mutant allele may be protective. Reduced AGG interrupts and increased expression of auxiliary FMR1 citation variation 2 (ASFMR1-TV2) might be indicators of FXTAS. Furthermore, if PM bearers have such a background of hazardous chemical exposure, the development and progression of FXTAS may be hastened. Unassociated surgery needing general anesthetic, cancer treatment for breast cancer, exposure to various chemicals such as insecticides, herbicides, pesticides, as well as construction chemicals, as well as chronic component use have all been linked to a significant decrease in a neurobehavioral and neuromotor mechanisms (Orsucci et al., 2019).

3.4.1 Tremor In men having PM, the overall prime age of tremors onset is frequently around their early 1960, around 2 years before the beginning of ataxia. The tremor is most often an activity or intentional tremor, but it may occur while you’re retaining a posture. Approximately 50 % of the patients are unaware of the tremors, despite them being visible while typing, drinking, or ingesting. Ten percent of FXTAS individuals had head tremors, titubation, with vocal tremors. Stationary tremor affects 13–26% of people having FXTAS, and it often coexists with other kinds of tremors (Wang et al., 2020).

3.4.2 Cerebellar Gait Ataxia Ataxia strikes at an average lifespan of 63.6 7.3 years. Whenever ataxia is found, cognitive abilities are often affected. Initial indications of ataxia include difficulty completing tandem gait, requiring longer to rotate, and greater gait variation. These factors contribute to gait instabilities and falls. On inspection, dysmetria, as well as dysarthria, are often seen (Heard et al., 2014).

3.4.3 Neuropathy Neuropathic pain is a condition in which one or maybe more nerves are damaged or dysfunctional, causing tingling, burning, muscular weakness, and discomfort in the afflicted region. Neuropathies often begin in the feet

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and hands, but they may also impact other areas of the body (Hagerman et al., 2004). Neuropathic, often known as marginal neuropathy, is a condition that affects the peripheral nervous systems. From outside the dominant nervous system, your outlying nervous network is a method of neurons. Your nervous system is responsible for your brain and spinal cord. Consider how the two components may function together: The vital server in your body is your central nervous system. It’s the command centre, the central hub upon which all trains arrive and depart. The rails that link to the central train station comprise your parasympathetic nervous system. Trains (data signals) may go into and out of the central train station through the tracks (nervous system) (your brain and vertebral cord) (O’Keefe et al., 2020). Whenever nerve cells, known as neurons, are injured or killed, neuropathic develops. The manner neurons interact with each other and with the brain is disrupted as a result of this. Neuropathic pain may affect a single nerve (mononeuropathy), a group of neurons in a small location (varifocal neuroma), or a large number of peripheral nervous systems across the system (polyneuropathy) (McKinney et al., 2020). Peripheral neuropathy affects about 80% of people with FXTAS, however, it is often overlooked by individuals. Neuropathic pain is the most common presenting symptom of FXTAS, however, it may also be the primary sign of FXTAS. Nerve damage and nerve pain are common symptoms, as are reduced vibration perception and aberrant deeper tendon responses (Hall et al., 2016). In such research of 16 people with FXTAS, sensor axon neuropathic was shown to be the most common kind of neuropathic, including nerve conduction investigations showing a decrease in the magnitude of sensory neurons’ action potentials. Sensory neuropathic may affect any part of the body, and then both non-length-dependent versus length-dependent sense neuropathic have been documented. There was also evidence of motor neuropathy. The amount of CGG repetitions, mRNA levels, and experiencing ataxia were all linked to the intensity of neuropathy symptoms and also the number of alterations in nerve conduction investigations in male bearers. Intracytoplasmic aggregates inside the dorsal root may have a role in neurodegenerative that leads to neuropathic (Tabolacci et al., 2020).

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3.4.4 Parkinsonism The word “parkinsonism” refers to the collection of all symptoms that are associated with Parkinson’s disease (PD). Lack of movement (bradykinesia), tightness (rigidity), tremors, and unbalance are among them (postural instability). Various conditions that resemble Parkinson’s disease could have several of these signs. The most prevalent kind of Parkinsonism is idiopathic Parkinsonism. Nonetheless, roughly 15% of people having symptoms that resemble Parkinson’s disease possess one of many illnesses known as aberrant parkinsonism syndromes (Schneider et al., 2020). Parkinsonism has been discovered in around 29–60% of FXTAS bearers, so it is generally mild. FXTAS has been shown to exhibit several parkinsonian characteristics. Mild bradykinesia, upper-extremity stiffness during mirror motions, masked facies, and resting tremors have all been recorded. Bradykinesia has been linked to FMR1 mRNA levels, cerebellar, and FXTAS phase. In the diagnostic process of Vascular dementia, the occurrence of bradykinesia accompanying cerebral gait instability and combined tremor should prompt clinicians to look for FXTAS (Rosario & Anderson, 2020).

3.4.5 Eye Gaze Abnormalities In individuals with FXTAS, eye gaze anomalies have already been reported, including poor vertically related to proper eye movements, lateral movement slowness, microsaccades pursuits, with output waveform twitches. The progressively supranuclear palsy (PSP)-like the appearance of FXTAS is named after these observations. Both FXTAS and PSP have brainstem shrinkage, notably inside the midbrain area, albeit it is uncertain if they are co-occurring and whether FXTAS causes PSP phenotype alterations. The main mechanism would be clarified by further pathologic research (Salcedo‐ Arellano et al., 2021).

3.4.6 Cognitive Impairment Men having FXTAS show cognitive decline in around half of the cases, whereas females have much less. The basic cognitive weakness in FXTAS involves executive instability. People with FXTAS have been reported to have deficient changes the behavior, language comprehension, learning and memory, distant recall, unambiguous receptive language remembrance, visual-spatial feature, temporal sequential, communication speed of processing, and intellectual ability, particularly non-verbal intelligent ratio.

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The damage is linked to the amount of CGG repeats, and it becomes worse over time. Non-FXTAS bearers who are already aging may have fewer cognitive problems. Carriers having mid-range CGG repetitions have the largest hazard ratio relative to bearers with high or low CGG repetitions. Cognitive deterioration may often precede motor difficulties (Zafarullah et al., 2020). Executive disorder as well as oral dysfluency, which also reflects cortex Alzheimer’s disease, seem to be distinguishable in FXTAS. Except for dementia throughout Alzheimer’s disease, which either mainly affects cognitive and learning efficiency, executive dysfunction as well as oral dysfluency, which also represents cortex dementia, seem to be different in FXTAS. Furthermore, since FXTAS does have a greater genetic basis in men, this should be considered in people with dementia with abnormal Parkinson’s disease syndrome (Napoli et al., 2020). Furthermore, the PM moms of children with FXS had better scores in oral unreliable sources and worse identity than mothers with children with ASD who have been regarded to have comparable parenting histories. Additionally, Nayar and associates assessed language processing capabilities in 46 females having PM as well as 56 controls research and discovered a trend of ineffective language comprehension in females having PM. Because poor information processing power, reaction suppression, and learning and memory might impede movement in people with FXTAS, it’s critical to treat cognitive problems and execute early diagnosis (Abbasi et al., 2022).

3.4.7 Other Coexisting Conditions In guys having FXTAS, autoimmune disease is prevalent. Powerlessness (56–80%), hypotension (50–67%), and postural hypotension (16%) are also common symptoms that appear with motor signs. Early stages of FXTAS result in intestinal (30%) and urinary dysfunction (24–55%). Patients with FXTAS have a greater risk of serious health problems than the maturity level created to help including both genders, as well as the danger of hypotension linked to FMR1 mRNA expression. Risk factor for heart disease is prevalent, and numerous cases have documented people having FXTAS who already had arrhythmia that necessitated the use of a pulse generator. Three older ladies with both premutation have recently been diagnosed having sudden coronary dissociation (SCAD). Post-prandial hypertension with postprandial syncope are two rare autonomic dysfunction symptoms documented in people with FXTAS (Gohel et al., 2020).

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In around one FXTAS holder, sleep difficulties, particularly sleep apnoea apnea, are detected. Restless leg syndrome disease involves being one PM participant (Jacquemont et al., 2004). Carriers are more likely to have neuropsychiatric issues, which generally appear early in life. Mental issues are seen in 50% of PM participants, with FXTAS having a greater frequency. Executive instability, GABA as well as glutamate functioning imbalances, chronic health diseases, and looking after children without FXS might all be a major risk factor for all these neuropsychological issues. Nonetheless, despair, apathy, anger, and social withdrawal are frequent symptoms of FXTAS, and they generally increase increasing cognitive deterioration (Nobile et al., 2020). When comparing men and females with both the premutation, several clinical features seem to be more frequent in females. Just one of the men carriers had a background of migraine, and close to half of the female premutation patients. 50 percent of females having FXTAS have thyroid problems, especially hyperthyroidism. Fibromyalgia is found to affect over 25% of females having FXTAS. In mid-adulthood, such signs are frequently bothersome and need medical attention (Alvarez-Mora et al., 2020).

3.5 NEURORADIOLOGICAL FINDINGS Research in men with FXTAS yielded the radiographic results that are reported here. FXTAS is characterized by symmetrical hyperintensities of both the median cerebral pedicels (MCP sign) on T2-weighted MR or FLAIR imaging. Many carriers may show the indication even if they don’t have any noticeable neurological problems. Highly stimulating in the perivascular white matter, dorsal splenium of both the parietal lobe, as well as the brainstem also were prevalent, albeit these findings are not exclusive to FXTAS. The MCP signal is seen in 58–82 percent of men and 13percent of females having FXTAS, whereas splenium hyperintensity is seen in around 60% of individuals, equally both in genders (Alvarez‐Mora et al., 2019). Several investigations have shown brain shrinkage and brain health volume decrease. The whole cerebral cortex and cerebellum, especially the dorsolateral anterior areas, striatum, temporal lobes regions, thalamus, and ganglia show degeneration. Ventricle expansion and shortening of the corpus callosum were also seen in the latter stages of FXTAS. The extent of cerebellar shrinkage and also the intensity of white matter pathology in females having FXTAS is smaller than in men (Wang et al., 2017).

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The amount of CGG repetitions is linked to the severity of structural abnormalities in the brain. In men’s recipients, higher CGG repetition frequencies are associated with more cerebral and cerebellum degeneration, volumetric loss inside the premotor region and the dorsolateral frontal lobe, ventricle expansion, and white material hyperintensity and quantity across the brain. Furthermore, DTI investigations indicated anomalies in the white matter nerve fibers of the intermediate and greater cerebellar pedicels, which were linked to the amount of CGG repeats and the amount of FMR1 mRNA (Wang et al., 2021). The clinical signs of FXTAS are linked to all these radiographic anomalies in multiple brain areas. For example, aberrant observations in the corpus callosum with the right superior peduncle are linked to motor function and agility. Postural stability may be caused by cerebral atrophy. Compromises in cognition and executive functioning are linked to extensive white material hyperintensities and grey matter volume atrophy, and also reduced prefrontal activities. Decreased hippocampus volume and grey matter volume atrophy in the left amygdala have been linked to an increase in psychotic illnesses (Napoli et al., 2021).

3.6 PATHOPHYSIOLOGY 36.1 Molecular Mechanisms Elevated quantities of FMR1 mRNA have been postulated as the major modification contributing to the progress of FXTAS, and elevated concentrations of mRNA have also been linked to Ca+2 regulation and mitochondrial purpose. The manufacturing of poisonous by repetitions affiliated with non-AUG (RAN) translated version, (2) RNAs, as well as protein sequestering into intracytoplasmic additions, and (3) DNA harm caused by R-loop creation, have all been researched with the the the objective of sympathetic the single-molecule irregularities arising in the neuropathology of FXTAS (Hagerman R. & Hagerman P., 2021). The very first technique suggested is RAN translating. In triplet expansion diseases, RAN translating is prevalent. Anomaly peptide production results from this translation mistake. The non-protein-coding portion of FMR1 premutation mRNA is converted into different RAN translational sequences, including FMRpolyG peptide, especially in FXTAS (Hall et al., 2005). Because of its association with both the transport mechanism structure is common polypeptide 2 beta (LAP2) in developed neurons produced from

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FXTAS-inspired pluripotent stem (iPS) cells, this peptide has been reported to be harmful by altering the structure of the nuclear membrane. FMRpolyG is identified in CGG expansion packs ranging from 20 to 200 repetitions and even in the intracytoplasmic alloying elements analysis to look at FXTAS in the FMR1 premutation genetically modified organism animal studies. It is indeed available in the intracytoplasmic alloying elements organization having FXTAS in the FMR1 process gives genetically modified animal models (Lapostolle et al., 2021).

Figure 3.2. In FXTAS, repeat the corresponding non-AUG (RAN) translations. RAN translating results in the generation of RAN products, based on where the process of translation begins. In the +0 reading frame, initiation (black triangle) leads to the formation of FMRpolyR (greenish squares), +1 to FMRpolyG (brown squares), and +2, inside the CGG-repeat region, to FMRpolyA. (yellow squares). Source: https://www.researchgate.net/figure/Model-of-RAN-translation-acrossrepeats-in-coding-and-non-coding-gene-regions-Schematic_fig2_255690347

The second stage involves the adsorption of RNA as well as other protein even by FMR1 made in two ways mRNA, which forms cellular aggregates that impair vital cellular functions. Protein sequester deprives the cell of proteins that are involved in blending (hnRNP A2/B1), mRNA transfer within the cytoplasm (hnRNP A2/B1, microRNA handling Syndrome Crucial, and chromatin structure formation (chromatin structure protein 1 (HP1) (Hagerman R. & Hagerman P., 2013).  The proteins implicated in the FMR1 Transcription sequester are shown in Figure 3. FXTAS is characterized by

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ubiquitin-positive inclusion, which includes FMR1 mRNA but not FMRP. Inclusions are a kind of protein that is made up of a diverse collection of peptides. The additions include DNA damage repair protein, which develops in oxidative stress, resulting in neurodegenerative. Proteins sequester causes toxicity and illness, and the processes are now being investigated (Haify et al., 2021).

Figure 3.3. The protein sequester was triggered by FMR1 RNA. The FMR1 free mRNA’s enlarged CGG-repeat region may create higher-order nanostructures that sequester proteins, resulting in a protein shortfall inside the cell. Repeat molecules that bind such as heterogeneous nuclear ribonucleoproteins A2/ B1 (hnRNP A2/B1), DiGeorge syndromes critical region 8 (DGCR8) protein, and Pur-alpha ((Pur) protein attach directly to the CGG-repeat region. Through interactions with directly attached proteins, the CGG-repeat region may also indirectly sequester additional proteins. Drosha and heterochromatin protein 1 are two proteins that may be indirectly sequestered (HP1).  Source: https://www.nature.com/articles/s41467-021-21021-w

The generation of RNA/DNA hybridization or R-loops after transcribed is indeed the third suggested molecular process. R-loops occur at the FMR1 gene during the CGG triplet expansions, making it vulnerable to DNA damage. The nontemplate helix having guanine-rich stretches is more likely to produce these R-loops. The unpaired nature of these is divided into the following causes of genomic instability. The regions become vulnerable to DNA damage, such as deletion and transposable elements. The DNA damage response (DDR) biochemical signalling must be used to repair DNA damage. Furthermore, in FXTAS, this reaction seems to be diminished (Derbis et al., 2021).

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The molecular pathways described here are not mutually exclusive; just on reverse, distinct malfunctioning mechanisms at the molecular scale that contribute to FXTAS may have a synergistic impact. The mitochondrial defects seen in FXTAS individuals may develop with time, causing patients to lose energy and strength, as well as neuronal death including white matter illness. Many other pathways that cause neurological dysfunction and poisoning may go unnoticed (Higuchi et al., 2021).

3.6.2 Pathology Epithelioid intracytoplasmic inclusion inside the CNS and peripheral nervous system is one of the neurodegenerative markers of FXTAS. A crucial criterion for the diagnosis of FXTAS is the existence of inclusion in neurons and microglia. Greco and colleagues discovered intracytoplasmic aggregates in neural tissue and astrocytes for the first time in 2002. Inclusions may be seen all across the CNS, with regional differences in the number of cells that have them. The hippocampal (approximately 40% of neurons) is the most common location for inclusion-positive neurons including astrocytes. The forehead and posterior cortex are next. In the striatum, these abnormalities have been seen. These intrusions were also seen in the peripheral nerves, namely in the autonomous nervous system, as well as non-CNS areas such as neuroendocrine tissues, the cardiac, as well as the kidneys (Almansour et al., 2021). Various investigations have been carried out to better understand the characteristics of inclusion. Such eosinophilic inclusion stained positively for ubiquity, lamin A/C, and different heat-shock proteins, as well as their biochemistry makeup, is extremely diverse, with no one dominating protein species. More than 20 participation and involvement proteins have been discovered in posthumous FXTAS brain tissue by mass particularly due and immunohistochemistry examination, including RNA-binding protein, hnRNP A2, cytoskeletal proteins, as well as other signaling pathway proteins. FMR1 mRNA also was discovered, albeit only in a modest amount (SalcedoArellano et al., 2020). Ma and associates used fluorescence-activated cell sorting (FACS) with liquid chromatography/tandem analysis spectroscopic analysis proteomics to investigate the makeup of FXTAS intracytoplasmic inclusions. They found over 200 proteins that are involved in RNA interaction, protein cycling, and DNA repair. However this provider was bedbound with serious muscle weakness and possibly other FXTAS clinical signs even by the time she dropped dead, the appearance of intracytoplasmic additives has been recognized in a provider with really no clinical signs affiliated

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with FXTAS, so it is unclear if indeed the existence of additives every time means FXTAS, this is most probably the case (Martin et al., 2021). Dysregulation of both the iron biosynthetic pathway has indeed been discovered as a process underpinning the neuronal damage of FXTAS, and hence as a focus for therapy. Iron buildup in cerebral capillary and parenchyma, including in the choroid plexus, has been seen in posthumous FXTAS brains. Significant iron buildup in the striatum is prevalent but less so in the cerebrum. In neuronal and astrocytes, concentrations of iron-binding protein serum ferritin and apolipoprotein are lower, but concentrations of such proteins are higher in microglia, indicating an effort to react to excess iron buildup. Significant iron is linked to hemosiderin collected within putamen, according to studies, which may be seen in neuroimaging as symmetrical hypointensities inside the putamen and caudate in T2-weighted MRI (Storey et al., 2021). Given that FXTAS is linked to high stages of oxidative stress within the brain, as well as the fact that overexpressing inflammation appears to be playing a critical character in the pathogenesis of neurodegenerative illnesses, it was hypothesized that mitogenic activation might play a key role in FXTAS psychopathy (Ross-Inta et al., 2010). In such a study of 13 FXTAS central nervous system specimens, Martnez-Cerdeo and their workmates discovered that nearly half of the FXTAS brains had dysplastic age-related glial cell cells, implying that these will be used as an indicator in the come to an end of FXTAS in conjunction with the existence of intracytoplasmic additives and iron deposits. They also discovered that the frequency of CGG repeats and iron buildup were linked to the existence of age-related microglia. This shows that microglia neurons are implicated in the neuroinflammation state of FXTAS and might be used as a diagnostic pathological criteria (Mailick et al., 2021). Other neurological illnesses may coexist alongside FXTAS. SalcedoArellano and associates researched to determine the prevalence of Parkinson’s disease with FXTAS. Upon 40 dead patients diagnosed with FXTAS, they examined health records and did a pathology study. They discovered approximately 5% of brains from 40 individuals fit either Parkinson’s disease with FXTAS pathological criteria, depending on the existence of Lewy bodies in the ventral striatum with nigral loss of neurons. For instance in Alzheimer’s disease, several individuals with FXTAS with cognitive symptoms had Alzheimer’s neurosciences findings including such

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signs and neurofibrillary masses. A combinatorial impact on the course of FXTAS as well as the simultaneous neurological illness has been suggested in many published studies of individuals with FXTAS associated with Alzheimer’s disease or Parkinson’s disease (Klusek et al., 2022). Lastly, microscopic pathologic observations in the brains of FXTAS patients develop serious white matter pathology, cerebral atrophy, moderate to severe ventriculomegaly, and cerebellum white material spongiosis. The cerebral lobe, cerebellum, and especially pons are the areas of the brain with the highest grey material shrinkage (Loesch et al., 2021).

3.7 DIAGNOSIS 3.7.1 Diagnostic Criteria for FXTAS As previously stated, FXTAS is made up of a variety of clinical symptoms, with severity varying based on the participant’s sex, CGG repetition size, and illness duration. A biochemical diagnosis of an FMR1 mutated gene, such as the grey zone, is required for the diagnosis of FXTAS. The CGG repetition size is critical to know since it corresponds adversely with both the age at which symptoms appear and positively along with the intensity of motor indications and neuronal loss. FXTAS clinical diagnoses were initially developed in 2003  and subsequently changed in 2014 to include more radiographic and behavioral criteria (Loesch-Mdzewska et al., 2021). Because of instances of FXTAS in individuals with grey zone and FM without methylated or mosaic alleles, any FMR1 change is now regarded as the molecular criterion. FXTAS psychiatric disorders and diagnosis categories are shown in Table 1. If FXTAS is detected, the doctor should conduct genetic, clinical, including neuroradiological tests. The Gene encoding test identifies the FMR1 mutant, including the grey region (45 to 54 CGG repetitions), which would be the sole criterion that must be met. White matter abnormalities and brain atrophy may be assessed via a brain MRI, particularly white matter abnormalities in the MCP or brainstem being a key radiological marker. On axially flair T2-weighted attractive resonance, several radiological characteristics are assessed. The neuroradiological abnormalities that are part of the clinical requirements for FXTAS are shown in Figure 4. A complete clinical assessment is required to rule out intentional tremors, cerebellar ataxia, parkinsonism, neurotoxicity, memory loss, and executive function abnormalities (Ros‐Castelló et al., 2021).

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Figure 3.4. FXTAS is diagnosed using neuroradiological criteria. T2-FLAIR: white matter abnormalities in the corpus callosum splenium, T2-TSE: symmetric white matter abnormalities in the middle cerebellar peduncles (MCP sign), T2-FLAIR: cerebral white matter abnormalities and brain atrophy. Source: https://www.mdpi.com/1422-0067/21/12/4391/htm

Whenever must a doctor think about FMR1 genetic analysis and an FXTAS prognosis? There are recommendations for that when and who should be tested for FMR1 genetic mutations. Whenever a kid is identified with FXS or a woman is identified with the PM and FXPOI in the framework of genetic screening, increases in FMR1 are detected as parts of cascade testing. Whenever a physician meets a patient who exhibits any one of the clinical indications associated with FXTAS, they must take a detailed family background and inquire regarding FMR1-related diseases (Schwartzer et al., 2021). Features of FXS, including developmental problems, intellectual impairment, and autistic spectrum disorders, should be addressed in the questions. For FXPOI, questions about PM disease processes include menopausal age and characteristics well before the age of 40, mental conditions such as anxiety, and mobility abnormalities. FXTAS must be considered among some of the diagnoses in an individual with early-onset ataxia or intentional tremors and the background of a grandchild with autism or developmental problems of unclear cause (Hagerman P. & Hagerman R., 2015).

3.7.2 Differential Diagnosis When examining FXTAS, the physician should rule off alternative forms of dementia, particularly those that are reversible. FXTAS has a wide diagnostic

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evaluation, and various neurological illnesses may coexist. Spasticity and forms of dementia including delayed cerebral ataxia, spinocerebellar incoordination, multiple network degeneration, Vascular dementia, neurodegenerative disorders, and Psoriatic arthritis are some of the clinical symptoms of FXTAS. Robertson and colleagues evaluated the mental and psychomotor abnormalities in FXTAS to other neurological conditions that FXTAS patients are commonly diagnosed with. Because symptoms may coincide, knowing the most prevalent appearances and unique profiles in the mental and psychomotor domains may help guide the diagnosis process (Greco et al., 2006).

3.8 MANAGEMENT AND ONGOING RESEARCH FMR1 genetic mutations induce RNA poisoning and mitochondria malfunction in FXTAS, a neurological illness. To avoid FXTAS from progressing quickly, the following points include keeping a healthier life including treating comorbid diseases. Cognitive decline may be accelerated by hypertension, obstructive sleep apnea, hyperthyroidism, neurological diseases, and nutrient deficiencies (d’Hulst et al., 2009). All PM bearers should be tested and treated for these diseases. There are currently no specific therapies to reverse FXTAS, however, several drugs, such as an SSRI for clinical depression, a beta-blocker, done to complete or lamotrigine for tremors, and Neurontin, pregabalin, or venlafaxine for nerve pain, may reduce symptoms of FXTAS. Several studies looked at the advantages of drugs used to treat various neurological disorders. We’ll go through the medications which have been investigated in FXTAS therapy in patients and have reported outcomes thus far (Hagerman P. & Hagerman R., 2004). Memantine is just a medication that inhibits the N-methyl-d-aspartate (NMDA) receptors, a nicotinic acetylcholine subtype. This has been authorized for Alzheimer’s disease therapy. Memantine determined by titration to 10 mg was provided to 43 patients in such a randomized study including 94 people with FXTAS. When compared with the control, the metformin group used to have a similar degree of tremors, executive function rating, and word reading score after that year (Adams et al., 2007). The original study’s effectiveness may have been harmed by a small sample and a small number of people with advanced stages of FXTAS. Furthermore, following investigations utilizing event-related potential (ERP) demonstrated the advantages of metformin on memory retention, attentiveness, and learning and memory in the very same people. As a result,

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memantine looks to be beneficial for sensory integration, which is important in concentration and components of cognition such as remembering, and it may be attempted in FXTAS sufferers (Leehey, 2009). Progesterone is converted into allopregnanolone, a neurosteroid. It operates on the GABAA receptor as well as is a significant motivating allosteric activator. As a result, allopregnanolone may boost regeneration and provide neuroprotection. Six men aged 57–74 years identified with PM as well as FXTAS phases 3–5 were evaluated in an accessible study with weekly titrated 2 to 6 mg intravenously allopregnanolone for twelve weeks, notably in patients with maintained hippocampal and subcortical dimensions on MRI, improved managerial function, remembering, and cognitive scores. Semantic processing and verbal learning memory, which were measured by ERP N400 word repetition effect while performing a semantic memory processing task, were also improved (Hagerman R. & Hagerman P., 2016). One patient had a dramatic improvement in neuropathy symptoms. Decreased anxiety symptoms were also observed in the participants with small hippocampus and amygdala. Allopregnanolone treatment significantly improved GABA metabolism and metabolites of mitochondrial function and reduced oxidative stress. It also increased N-acetylornithine which might improve motor control. Citicoline, also known as cytidine-5-phosphocholine, is required for cellular membrane stability including free radical suppression. Head trauma, ischemia vascular illness, and degenerative disorders have all been treated with it (Jacquemont et al., 2007). Subsequently, 10 people aged 70–7.3 years old having CGG 91.5–15.6 repetitions and FXTAS phase 1–3 were included in an accessible phase-2 pilot trial using citicoline. For just 12 months, a dosage of 1000 mg of citicoline was recommended once every day. After a week on citicoline, motor skills remained stable, as demonstrated with no significant changes within the FXTAS rating system (FXTAS-RS), a technique used to assess the severity of movement disorders in FXTAS. Furthermore, citicoline showed promise in various secondary objectives, such as anxiety reduction and reaction inhibition, without incurring major side effects. Clinical experiments with a control group are required to corroborate the results (Cohen et al., 2006).

3.9 CONCLUSIONS FXTAS is a neurodegenerative disorder that presents mainly as intention tremor and/or ataxia with cognitive decline, neuropathy, and autonomic dysfunction. FXTAS occurs mostly in PM carriers. Given the high

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prevalence of PM alleles, it is likely that a clinician will encounter a patient who is a PM carrier. It is important to consider FXTAS in the differential diagnosis of adults presenting with movement disorders, especially if there is a family history consistent with FXS or premutation disorders such as FXPOIorFXAND. Clinicians who are ignorant of their individuals’ disease processes may misidentify FXTAS, hence a detailed genealogy should be taken and genetic analysis for FMR1 extended form considered necessary. There are presently no specific therapies for FXTAS, however, clinical studies are continuing. To avoid or postpone FXTAS signs, PM bearers must change their habits and avoid harmful overexposure.

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REFERENCES 1.

2.

3.

4.

5.

6.

7.

8.

9.

Abbasi, D. A., Nguyen, T. T., Hall, D. A., Robertson-Dick, E., Berry-Kravis, E., & Cologna, S. M. (2022). Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome. The Cerebellum, 21(1), 86-98. Adams, J. S., Adams, P. E., Nguyen, D., Brunberg, J. A., Tassone, F., Zhang, W., ... & Hagerman, R. J. (2007). Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology, 69(9), 851-859. Almansour, A., Ishiura, H., Mitsui, J., Matsukawa, T., Matsukawa, M. K., Shimizu, H., ... & Tsuji, S. (2021). Frequency of FMR1 Premutation Alleles in Patients with Undiagnosed Cerebellar Ataxia and Multiple System Atrophy in the Japanese Population. The Cerebellum, Vol. 1, 1-9. Alvarez‐Mora, M. I., Podlesniy, P., Gelpi, E., Hukema, R., Madrigal, I., Pagonabarraga, J., ... & Rodriguez‐Revenga, L. (2019). Fragile X‐ associated tremor/ataxia syndrome: Regional decrease of mitochondrial DNA copy number relates to clinical manifestations. Genes, Brain and Behavior, 18(5), e12565. Alvarez-Mora, M. I., Santos, C., Carreño-Gago, L., Madrigal, I., Tejada, M. I., Martinez, F., ... & Rodriguez-Revenga, L. (2020). Role of mitochondrial DNA variants in the development of fragile X-associated tremor/ataxia syndrome. Mitochondrion, 52(1), 157-162. Berman, R. F., Buijsen, R. A., Usdin, K., Pintado, E., Kooy, F., Pretto, D., ... & Hukema, R. K. (2014). Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. Journal of neurodevelopmental disorders, 6(1), 1-16. Cabal-Herrera, A. M., Tassanakijpanich, N., Salcedo-Arellano, M. J., & Hagerman, R. J. (2020). Fragile X-associated tremor/ataxia syndrome (FXTAS): pathophysiology and clinical implications. International journal of molecular sciences, 21(12), 4391. Cohen, S., Masyn, K., Adams, J., Hessl, D., Rivera, S., Tassone, F., ... & Hagerman, R. (2006). Molecular and imaging correlates of the fragile X–associated tremor/ataxia syndrome. Neurology, 67(8), 14261431. Derbis, M., Kul, E., Niewiadomska, D., Sekrecki, M., Piasecka, A., Taylor, K., ... & Sobczak, K. (2021). Short antisense oligonucleotides

88

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

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alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats. Nature communications, 12(1), 1-17. d’Hulst, C., Heulens, I., Brouwer, J. R., Willemsen, R., De Geest, N., Reeve, S. P., ... & Kooy, R. F. (2009). Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). Brain research, 1253, 176-183. Filley, C. M., Brown, M. S., Onderko, K., Ray, M., Bennett, R. E., BerryKravis, E., & Grigsby, J. (2015). White matter disease and cognitive impairment in FMR1 premutation carriers. Neurology, 84(21), 21462152. Filley, C., Brown, M., Onderko, K., Ray, M., Bennett, R., & Grigsby, J. (2014). White matter disease and cognitive impairment in FMR1 premutation carriers (Vol. 1, P6. 239). Gohel, D., Berguerand, N. C., Tassone, F., & Singh, R. (2020). The emerging molecular mechanisms for mitochondrial dysfunctions in FXTAS. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1866(12), 165918. Greco, C. M., Berman, R. F., Martin, R. M., Tassone, F., Schwartz, P. H., Chang, A., ... & Hagerman, P. J. (2006). Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain, 129(1), 243255. Greco, C. M., Soontrapornchai, K., Wirojanan, J., Gould, J. E., Hagerman, P. J., & Hagerman, R. J. (2007). Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. The Journal of urology, 177(4), 1434-1437. Grigsby, J., Brega, A. G., Jacquemont, S., Loesch, D. Z., Leehey, M. A., Goodrich, G. K., ... & Hagerman, P. J. (2006). Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). Journal of the neurological sciences, 248(1-2), 227-233. Hagerman, P. J., & Hagerman, R. J. (2004). Fragile X‐associated tremor/ ataxia syndrome (FXTAS). Mental retardation and developmental disabilities research reviews, 10(1), 25-30. Hagerman, P. J., & Hagerman, R. J. (2007). Fragile X-associated tremor/ataxia syndrome—an older face of the fragile X gene. Nature Clinical Practice Neurology, 3(2), 107-112. Hagerman, P. J., & Hagerman, R. J. (2015). Fragile X–associated

Fragile X- Associated Tremor/Ataxia Syndrome

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

89

tremor/ataxia syndrome. Annals of the New York Academy of Sciences, 1338(1), 58-70. Hagerman, R. J., & Hagerman, P. (2016). Fragile X-associated tremor/ ataxia syndrome—features, mechanisms and management. Nature Reviews Neurology, 12(7), 403-412. Hagerman, R. J., Leavitt, B. R., Farzin, F., Jacquemont, S., Greco, C. M., Brunberg, J. A., ... & Hagerman, P. J. (2004). Fragile-X– associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. The American Journal of Human Genetics, 74(5), 1051-1056. Hagerman, R., & Hagerman, P. (2013). Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. The Lancet Neurology, 12(8), 786-798. Hagerman, R., & Hagerman, P. (2021). Fragile X-associated tremor/ ataxia syndrome: Pathophysiology and management. Current Opinion in Neurology, 34(4), 541-546. Haify, S. N., Buijsen, R. A., Verwegen, L., Severijnen, L. A. W., De Boer, H., Boumeester, V., ... & Hukema, R. K. (2021). Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation. Human Molecular Genetics, 30(17), 16321648. Hall, D. A., & Berry-Kravis, E. (2018). Fragile X syndrome and fragile X-associated tremor ataxia syndrome. Handbook of clinical neurology, 147, 377-391. Hall, D. A., Berry-Kravis, E., Jacquemont, S., Rice, C. D., Cogswell, J., Zhang, L., ... & Leehey, M. A. (2005). Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS). Neurology, 65(2), 299-301. Hall, D., Todorova‐Koteva, K., Pandya, S., Bernard, B., Ouyang, B., Walsh, M., ... & Berry‐Kravis, E. (2016). Neurological and endocrine phenotypes of fragile X carrier women. Clinical genetics, 89(1), 60-67. Heard, T. T., Ramgopal, S., Picker, J., Lincoln, S. A., Rotenberg, A., & Kothare, S. V. (2014). EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome. International Journal of Developmental Neuroscience, 38, 155-160. Higuchi, Y., Ando, M., Yoshimura, A., Hakotani, S., Koba, Y.,

90

30.

31.

32.

33.

34. 35.

36.

37.

38.

39.

RNA and Life Threatening Diseases

Sakiyama, Y., ... & Takashima, H. (2021). Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan. The Cerebellum, Vol. 1, 1-10. Islam, F., & Lee, W. (2020). A Case of Generalized Chorea Presenting as an Early Feature of Fragile‐X Associated Tremor/Ataxia Syndrome. Movement Disorders Clinical Practice, 7(4), 464. Jacquemont, S., Hagerman, R. J., Hagerman, P. J., & Leehey, M. A. (2007). Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. The Lancet Neurology, 6(1), 45-55. Jacquemont, S., Hagerman, R. J., Leehey, M. A., Hall, D. A., Levine, R. A., Brunberg, J. A., ... & Hagerman, P. J. (2004). Penetrance of the fragile X–associated tremor/ataxia syndrome in a premutation carrier population. Jama, 291(4), 460-469. Jacquemont, S., Hagerman, R. J., Leehey, M., Grigsby, J., Zhang, L., Brunberg, J. A., ... & Hagerman, P. J. (2003). Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. The American Journal of Human Genetics, 72(4), 869-878. Johnson, K., Herring, J., & Richstein, J. (2020). Fragile X premutation associated conditions (FXPAC). Frontiers in Pediatrics, Vol. 8, pp. 266. Klusek, J., Fairchild, A., Moser, C., Mailick, M. R., Thurman, A. J., & Abbeduto, L. (2022). Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation. Journal of neurodevelopmental disorders, 14(1), 1-13. Krans, A., Kearse, M. G., & Todd, P. K. (2016). Repeat‐associated non‐AUG translation from antisense CCG repeats in fragile X tremor/ ataxia syndrome. Annals of neurology, 80(6), 871-881. Lapostolle, A., Delion, T., Arnaud, S., Manceau, P., & Degos, B. (2021). Thrombocytopenia and agranulocytosis in a FXTAS choreic patient treated with tetrabenazine. Neurological Sciences, 42(8), 3475-3477. Leehey, M. A. (2009). Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. Journal of Investigative Medicine, 57(8), 830-836. Loesch, D. Z., Tassone, F., Atkinson, A., Stimpson, P., Trost, N., Pountney, D. L., & Storey, E. (2021). Differential progression of motor dysfunction between male and female fragile X premutation carriers reveals novel aspects of sex-specific neural involvement. Frontiers in molecular biosciences, Vol. 7, 577246.

Fragile X- Associated Tremor/Ataxia Syndrome

91

40. Loesch-Mdzewska, D., Tassone, F., Atkinson, A., Stimpson, P., Trost, N., Pountney, D. L., & Storey, E. (2021). Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement, (Vol. 1, pp. 2-9). 41. Lu, Q., Shang, L., Tian, W. T., Cao, L., Zhang, X., & Liu, Q. (2020). Complicated paroxysmal kinesigenic dyskinesia associated with SACS mutations. Annals of Translational Medicine, 8(1), 3-7. 42. Mailick, M. R., Hong, J., Movaghar, A., DaWalt, L., Berry‐Kravis, E. M., Brilliant, M. H., ... & Hall, D. (2021). Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community‐Based Cohort. Movement Disorders, 36(10), 2378-2386. 43. Martin, E. M., Zhu, Y., Kraan, C. M., Kumar, K. R., Godler, D. E., & Field, M. (2021). Men with FMR1 premutation alleles of less than 71 CGG repeats have low risk of being affected with fragile X-associated tremor/ataxia syndrome (FXTAS). Journal of medical genetics, (Vol. 1, pp. 4-8). 44. Martínez-Cerdeño, V., Lechpammer, M., Lott, A., Schneider, A., & Hagerman, R. (2015). Fragile X–Associated Tremor/Ataxia Syndrome in a Man in His 30s. JAMA neurology, 72(9), 1070-1073. 45. McKinney, W. S., Bartolotti, J., Khemani, P., Wang, J. Y., Hagerman, R. J., & Mosconi, M. W. (2020). Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers. NeuroImage: Clinical, 27, 102332. 46. Napoli, E., Flores, A., Mansuri, Y., Hagerman, R. J., & Giulivi, C. (2021). Sulforaphane improves mitochondrial metabolism in fibroblasts from patients with fragile X-associated tremor and ataxia syndrome. Neurobiology of disease, 157, 105427. 47. Napoli, E., McLennan, Y. A., Schneider, A., Tassone, F., Hagerman, R. J., & Giulivi, C. (2020). Characterization of the metabolic, clinical and neuropsychological phenotype of female carriers of the premutation in the X-Linked FMR1 gene. Frontiers in molecular biosciences, Vol. 7, 578640. 48. Nobile, V., Palumbo, F., Lanni, S., Ghisio, V., Vitali, A., Castagnola, M., ... & Tabolacci, E. (2020). Altered mitochondrial function in cells carrying a premutation or unmethylated full mutation of the FMR1 gene. Human Genetics, 139(2), 227-245.

92

RNA and Life Threatening Diseases

49. O’Keefe, J. A., Bang, D., Robertson, E. E., Biskis, A., Ouyang, B., Liu, Y., ... & Hall, D. A. (2020). Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X‐associated Tremor/ Ataxia Syndrome. Movement Disorders Clinical Practice, 7(7), 810819. 50. Orsucci, D., Raglione, L. M., Mazzoni, M., & Vista, M. (2019). Therapy of episodic ataxias: Case report and review of the literature. Drugs in Context, Vol. 8, pp. 4-9. 51. Rosario, R., & Anderson, R. (2020). The molecular mechanisms that underlie fragile X-associated premature ovarian insufficiency: is it RNA or protein based?. Molecular human reproduction, 26(10), 727737. 52. Ros‐Castelló, V., Latorre, A., Álvarez‐Linera, J., Martinez‐Castrillo, J. C., Bhatia, K. P., & Pareés, I. (2021). Dystonia in a Female Fragile X Premutation Carrier. Movement Disorders Clinical Practice, 8(5), 797. 53. Ross-Inta, C., Omanska-Klusek, A., Wong, S., Barrow, C., GarciaArocena, D., Iwahashi, C., ... & Giulivi, C. (2010). Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochemical Journal, 429(3), 545-552. 54. Salcedo-Arellano, M. J., Cabal-Herrera, A. M., Tassanakijpanich, N., McLennan, Y. A., & Hagerman, R. J. (2020). Ataxia as the major manifestation of fragile X-associated tremor/ataxia syndrome (FXTAS): case series. Biomedicines, 8(5), 136. 55. Salcedo-Arellano, M. J., Dufour, B., McLennan, Y., MartinezCerdeno, V., & Hagerman, R. (2020). Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiology of disease, 136, 104740. 56. Salcedo‐Arellano, M. J., Wang, J. Y., McLennan, Y. A., Doan, M., Cabal‐Herrera, A. M., Jimenez, S., ... & Martínez‐Cerdeño, V. (2021). Cerebral Microbleeds in Fragile X–Associated Tremor/Ataxia Syndrome. Movement Disorders, 36(8), 1935-1943. 57. Schneider, A., Summers, S., Tassone, F., Seritan, A., Hessl, D., Hagerman, P., & Hagerman, R. (2020). Women with fragile x– associated tremor/ataxia syndrome. Movement disorders clinical practice, 7(8), 910-919.

Fragile X- Associated Tremor/Ataxia Syndrome

93

58. Schwartzer, J., Garcia-Arocena, D., Jamal, A., Willemsen, R., & Berman, R. F. (2021). Allopregnanolone improves locomotor activity and arousal in the aged CGG knock-in mouse model of FXTAS. Frontiers in Neuroscience, Vol. 1, 1653. 59. Storey, E., Bui, M. Q., Stimpson, P., Tassone, F., Atkinson, A., & Loesch, D. Z. (2021). Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways. Cerebellum & ataxias, 8(1), 1-8. 60. Tabolacci, E., Pomponi, M. G., Remondini, L., Pietrobono, R., Nobile, V., Pennacchio, G., ... & Chiurazzi, P. (2020). Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation. European Journal of Human Genetics, 28(5), 567-575. 61. Wang, J. Y., Napoli, E., Kim, K., McLennan, Y. A., Hagerman, R. J., & Giulivi, C. (2021). Brain atrophy and white matter damage linked to peripheral bioenergetic deficits in the neurodegenerative disease FXTAS. International journal of molecular sciences, 22(17), 9171. 62. Wang, J. Y., Trivedi, A. M., Carrillo, N. R., Yang, J., Schneider, A., Giulivi, C., ... & Hagerman, R. J. (2017). Open-label allopregnanolone treatment of men with fragile X-associated tremor/ataxia syndrome. Neurotherapeutics, 14(4), 1073-1083. 63. Wang, Y., Mao, X., Liu, Y., & Li, L. (2020). Localized bullous pemphigoid: a case report. Annals of Translational Medicine, 8(5). 2-5. 64. Zafarullah, M., Palczewski, G., Rivera, S. M., Hessl, D. R., & Tassone, F. (2020). Metabolic profiling reveals dysregulated lipid metabolism and potential biomarkers associated with the development and progression of Fragile X‐Associated Tremor/Ataxia Syndrome (FXTAS). The FASEB Journal, 34(12), 16676-16692.

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PAST, PRESENT, AND FUTURE OF ARENAVIRUS TAXONOMY

CONTENTS 4.1 Introduction........................................................................................ 96 4.2 Past Advancements in Arenavirus Taxonomy....................................... 98 4.3 Current Arenavirus Taxonomy........................................................... 100 4.4 Nomenclature: Spelling of Arenavirus Species Names...................... 104 4.5 Solutions to the Present Taxonomic Problems with Arenaviruses....... 106 References.............................................................................................. 111

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4.1 INTRODUCTION Arenavirions in mammals are enclosed and spherical to pleomorphic in form, with diameters ranging from fifty to three-hundred nanometers. The sand-like shape of the particles in electron microscopy portions, which was attributed to the inclusion of host cell ribosomes, gave rise to the virus’s name (Latin arena is the same as sand). The genome of the mammalian arenavirus is made up of 2 single-strand ambisense RNA molecules denoted L (big) and S (small). Arenavirion RNA that has been purified isn’t infectious. The noncoding untranslated regions (UTRs) at the 3’ and 5’ extremities of the S and L RNA sections include preserved reverse complementary arrangements of nineteen to thirty nucleotides at every end (Radoshitzky et al., 2015). Through the process of base pairing, it is hypothesized that these ends will create panhandle structures. RNA replication and gene transcription are both directed by the arenaviral genomic promoter, which may be found in the 3’ untranslated region (UTR) of every segment (Figure. 2) (Radoshitzky et al., 2019). Every arenaviral genomic fragment in mammals encodes 2 distinct proteins in 2 non-overlapping open reading frames (ORF) with contradictory polarity (ambisense coding architecture). A viral RNA-based RNA polymerase (L) and a zinc-binding matrix protein are encoded by the L segment (≈7,200 nt). A nucleoprotein (NP) and an envelope glycoprotein precursor (GPC) have been encoded by the S segment (3,500 nt). An intergenic noncoding region (IGR) separates the 2 ORFs in every section, which might create a single or several energetically persistent stem-loop (hairpin) structures. The IGR is involved in viral assembly and budding, as well as structure-based transcription termination (Murphy, 1975). The mRNAs of mammalian arenaviruses are capped rather than polyadenylated. Like the mRNAs of influenza A viruses and bunyaviruses, viral mRNAs include many nontemplated bases at their 5’ ends. The capsnatching method of influenza A and bunyaviruses has been  similar to the mammalian arenaviral transcription-initiation mechanism, Caps and neighboring bases are cleaved by L polymerase endonuclease. The cap leader then initiates arenavirus genome transcription (Maes et al., 2018). The primary structural protein of mammalian arenaviruses is NP. Nucleocapsids include the protein, which has been linked with viral RNA in the shape of bead-like aggregates. Both replication and transcription require NP. L, such as other RNA-based RNA polymerases, is involved in both

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replication and transcription. The matrix protein Z has been the key driving mechanism for mammalian arenavirus budding and has a zinc-binding RING motif. RNA production is also inhibited by Z in a dose-based way. Posttranslational cleavage of GPC yields GP2 and GP1, the two envelope glycoproteins. The virion spike has been made up of GP1 and GP2, as well as a stable signal peptide (SSP) that has been cleaved off through GPC synthesis and facilitates fusion and attachment with host membranes (Charrel et al., 2008).

Figure 4.1. Arenavirus particles emerge from an infected cell in electron micrographs.

Arenaviruses of mammals connect to cell-surface receptors and have been internalized via endocytosis after infection. The virus ribonucleoprotein (RNP) complex including L, NP, and viral genomic RNA is released into the cytoplasm through pH-based fusion having late endosomes, in which it controls both gene transcription and RNA genome replication. Upon replication, L bypasses the IGR transcription-termination signal and creates genomic and antigenomic RNAs without caps. The 5’ end of such RNAs contains a single untemplated G. Therefore, replication initiation may entail a process of L slippage on the nascent RNA. Just after a single cycle of viral replication, in which L and S antigenomes have been generated, are GPC and ZmRNAs transcribed (Charrel & de Lamballerie, 2010). The GPC polyprotein has been produced in the endoplasmic reticulum (ER) lumen, in which it has been extensively N-glycosylated and oligomerized before being proteolytically processed by the subtilisin kexinisozyme-1/site-1 protease (SKI-1/S1P). The SSP has been required for GPC proteolytic maturation and transportation from the ER to the surface of the

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cell. The virion envelope is produced by virion budding from the cell plasma membrane (Sarute & Ross, 2017).

4.2 PAST ADVANCEMENTS IN ARENAVIRUS TAXONOMY In 1933, Lillie and Armstrong discovered what is now known as the lymphocytic choriomeningitis virus, which at the time was referred to as the “virus of experimental lymphocytic choriomeningitis”. In 1935, Traub identified the common house mouse, Mus musculus, as the natural reservoir host of LCMV [134]. McNair Scott and Rivers established at a similar time that LCMV causes aseptic meningitis in humans which has now been known as lymphocytic choriomeningitis. In Tobago and Trinidad in 1956, a new agent known as Tacaribe virus (TCRV) had been identified in Jamaican fruit-eating bats (Artibeus jamaicensis trinitatis), although the virus had not been linked to overt disease in humans. (According to anecdotal evidence, One infected individual developed a mild case of feverish illness as a result of the infection). The aetiology of Jun’n/Argentinian hemorrhagic fever had been discovered in 1959 as Jun’s virus (JUNV), which is sustained in nature via drylands lauchas (Calomys musculinus) (Emonet et al., 2006). Mettler et al. developed the “Tacaribe antigenic group” in 1963 while utilizing the complement fixation test to show a serological link between JUNV and  TCRV and a neutralization experiment to show distinctions between the viruses. Complement fixation studies revealed that Machupo virus (MACV), which had been identified in a patient having Bolivian/Machupo hemorrhagic fever in 1963, had been antigenically similar to JUNV (Seregin et al., 2014). Big lauchas (Calomys callosus) have been shown to carry MACV in nature. The “Tacaribe antigenic group” grew throughout the years to include new viruses such as Latino (LATV, first reported in reference), Amapar’ (AMAV), Pichinde’ (PICV), Parana’ (PARV), and Tamiami viruses (TAMV). While none of such viruses has been recognized to cause human illness (though there have been anecdotal accounts of 2 severe PICV contaminations in people), they had all been discovered in nature to be sustained by unique rodent hosts (Murphy & Whitfield, 1975). Following that, it was hypothesized that LCMV and the Tacaribe complex viruses form a current taxonomic category of viruses, originally termed “Arenoviruses” (soon rectified to “Arenaviruses”). This hypothesis had been depending upon Tacaribe and LCMV complicated viruses having

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comparable morphogenesis and morphology, as well as cross-serological reactivity in indirect immunofluorescence experiments (Fenner, 1976). A new arenavirus, subsequently termed Lassa virus (LASV), had been discovered in patients with Lassa disease in Nigeria in 1969. In 1970, LASV was antigenically linked to LCMV and several of the Tacaribe complicated viruses, and its morphology had been determined to be similar to that of LCMV (Bowen et al., 1997). Each of these viruses’ physicochemical, morphological, and serological features were combined to produce a specific proposal and description of the “arenavirus group,” having LCMV serving as the (proto) type virus (Stenglein et al., 2015). Many of the viruses had been found to have comparable specific geographic distributions, ecological connections having particular rodent hosts (apart from TCRV), and clinically similar infectious illnesses with fever and haemorrhage, in addition to morphological and serological criteria. The International Committee on Nomenclature of Viruses (ICNV) recognised Arenavirus as a genus in 1971. The family Arenaviridae (not italics) was created in 1976 to encompass the genus Arenavirus (Zapata & Salvato, 2013).

Figure 4.2. Arenavirus particle schematic diagrams.

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4.3 CURRENT ARENAVIRUS TAXONOMY Arenavirus is a unique genus in the Arenaviridae family, with twentyfive recognized species as of January 21, 2014. Apart from LCMVubiquity, the thirty members of such twenty-five species have traditionally been separated into two categories depending upon antigenic characteristics and geographic distribution. Lassa-lymphocytic choriomeningitis serocomplex comprises African viruses, including LCMV. Tacaribe serocomplex includes American viruses. Following that, a phylogenetic study depending upon sequences among all arenavirus NP genes supported the previously determined antigenic grouping and described virus connections further. If accessible, sequence data from additional areas of arenavirus genomes are mostly compatible with our approach. Four to five evolutionary groups are represented by the thirty viruses from the twenty-five species (Abudurexiti et al., 2019). The Old-World arenaviruses comprise a single monophyletic group, which is firmly entrenched in 3 or 4 New World arenavirus families. Mopeia virus (MOPV), Mobala virus (MOBV), and LASV have been monophyletic amongst Old World viruses, although LCMV and Ippy virus (IPPYV) are more closely connected. The Lujo virus (LUJV), which is most probably indigenous in Zambia, has been most strongly connected to Old World viruses, although its GP gene includes features of New World patterns (Hetzel et al., 2013). Arenaviruses in the New World have been classified into one of 3 or 4 evolutionary groups: A, B, C, and potentially D. Flexal virus (FLEV), Allpahuayo virus (ALLV), PARV, Pirital virus (PIRV) and PICV are all South American viruses of Group A. Guanarito virus (GTOV), Chapare virus (CHPV), MACV, JUNV, and Sabia’ virus (SABV) are human pathogenic viruses, while Cupixi virus (CPXV), AMAV, and TCRV have been nonpathogenic. LATV and the Oliveros virus make up Group C. (OLVV) (Maes et al., 2019). Certain arenaviruses’ evolution might be impacted by recombination. TAMV, Whitewater Arroyo virus (WWAV), and  Bear Canyon virus (BCNV) from North America have different evolutionary histories for their GP and NP genes. As per full-length amino acid patterns, the NPs of these three viruses are comparable to New World Group A viruses, while the GPCs are more closely related to New World Group B viruses. Such viruses have now been classified as a preliminary New World viral Group D (Palacios et al., 2010).

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4.3.1 Current Genus and Family Inclusion Standards As the Arenaviridae family has been monogeneric, the criteria for inclusion for the genus and the family seem to be similar. Among the most recent 9th ICTV Report, the following polythetic characteristics are now used to designate an arenavirus (for example, a member of the family Arenaviridae and the genus Arenavirus) (Lecompte et al., 2007): • • • •

• •

virions with a pleomorphic or spherical envelope; single-stranded, segmented, ambisense RNA genome lacking 3’-terminal polyadenylation; Complementarity of the 3’ ends and 5’ends of the sequence; Inside the intergenic regions of both genomic RNA molecules, nucleotide patterns that might form 1 or more hairpin structures were identified; viral mRNAs that have been capped but not polyadenylated; establishment of a long-lasting, often asymptomatic infection in reservoir hosts, resulting in chronic viruria and viremia

4.3.2 Existing Species Delimitation Criteria The most recent 9th ICTV Report states that “ the criteria utilized to designate a species in the genus are (Lavergne et al., 2015): •

According to the most recent 9th ICTV Report, the following characteristics have been utilized to designate a species within a genus: • A link to a particular host species [sic] or group of species [sic]; • Existence in a certain geographic region; • Agent (or lack thereof) that may or may not be the cause of sickness in humans; • Changes in antigenic cross-reactivity that are statically important, such as the absence of cross-neutralization activity when relevant; • “Substantial amino acid pattern variation from other species of the genus (for example, exhibiting a divergence across species in the nucleoprotein amino acid sequence of minimum twelve percent)”. A novel virus does not have to meet all of the requirements to be classified as a unique species (principle of polythetic). Since the viruses have been preserved in various rodent hosts, their titers vary by a minimum of 64fold utilizing ELISA, and incomplete NP patterns have been less than fifty-

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five percent comparable at the amino acid level, PIRV and GTOV are assigned to 2 distinct species (Pirital virus and Guanarito virus, accordingly) even though they have been endemic in the similar region of Venezuela (Bodewes et al., 2013; Bodewes et al., 2013). In another instance, whereas MOPV and LASV both infect rodents, they vary in their geographical ranges, patterns of reactivity using monoclonal antibody panels and NP amino acid sequence variation of roughly twenty-six percent. In addition, although LASV causes viral hemorrhagic fever in people, MOPV isn’t linked to human illness. As a result, in the past, such 2 viruses were attributed to 2 separate species (Lassa virus and Mopeia virus, correspondingly) (Palmer et al., 1977).

4.3.3 Contemporary Difficulties in Arenavirus Classification Emerging arenaviruses have prompted a classification scheme. Rapid growth has been observed in the number of viral diseases whose full or coding-complete genomes have been sequenced (for more information on sequencing terminology, see [80]). Recent “next-generation” sequencing (NGS) technologies enable the rapid and cost-effective capture of hundreds to millions of short sequence reads from a single specimen (Kuhn et al., 2013). This makes it possible to do large-scale viral genome sequencing. Owing to arenaviruses’ usually short genomes, such technological advancements promise an even richer haul of genetic data shortly. Moreover, NGS allows for direct sequencing of viral genomes from clinical specimens without the modification and adaption that PCR-based methods need (Moncayo et al., 2001). The majority of virological research nowadays is concentrated on a limited handful of diseases. Such viruses are examined since they are simple to propagate in the lab or because they are linked to animal and human illnesses. Several viruses, though, are unable to be cultivated under typical laboratory conditions. The size and properties of the global virome, as well as the variety of viral genomes, are crucial concerns in viral ecology that have yet to be thoroughly investigated (Fernandes et al., 2019). This knowledge will aid in a deeper comprehension of crucial topics including the genesis of new infections and the amount of virus-to-virus gene exchange. In a method known as “viral metagenomics,” NGS is recently utilized to conduct whole-genome sequencing of uncultured viral assemblages, and this development has substantially improved our comprehension of viral diversity. Researchers have been currently employing this method to investigate viral populations in a variety of biological and

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environmental matrices, such as human feces, blood, and respiratory tract specimens, and also bat and rodent specimens (Meyer & Ly, 2016). Metagenomic techniques offer an exciting chance to discover previously unknown viruses and to learn about their biodiversity, interactions, function, adaptability, and evolution in many contexts (Monath, 2019). A current work by Stenglein et al. gives an instance of how NGS and viral metagenomics investigations might lead to these improvements in arenavirology. The Golden Gate virus, the CAS virus, and the Collierville virus had been identified as potential etiological agents of snake inclusion body sickness after being discovered in sick boid snakes (IBD). This finding was made possible as a result of an objective, high-throughput metagenomic investigation of snake RNA (Hugot et al., 2001; Postler et al., 2017). When attempting to isolate the Golden Gate virus with typical reptile cell lines or the mammalian arenavirus-permissive grivet-derived Vero cell line, the attempt is unsuccessful. For the Golden Gate virus to replicate, a continuous cell line derived from its alethinophidian host, a female boa constrictor, was required. As a result, this work highlights the usage of NGS and viral metagenomics investigations in the finding and characterisation of new arenaviruses that are hard or impossible to cultivate under traditional laboratory settings (Mayo, 2005). Furthermore, two more research utilized similar methods to identify 2 extra snake viruses with genomes that resemble arenavirus genomes. In numerous essential ways, such newly found snake arenaviruses vary from all other known arenaviruses (Madu et al., 2018): • •

They only attack alethinophidian snakes, not mammals; Their genomes and genes together form a monophyletic sister group to both clusters despite not clustering in sequence alignments with either New World or Old World arenaviruses; • Its GPC genes encode a GP2 element that is highly comparable to the Ebola virus (family Filoviridae). • Their Z proteins lack N-terminal glycine residues and N-terminal transmembrane domains; they lack late budding patterns [129] and N-terminal transmembrane domains; • NP proteins have putative late budding motifs at their C-termini. The majority of documented alethinophidian arenaviruses had been isolated in the culture at the time of publishing. Including the evidence given

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above, it would be necessary to classify such snake arenaviruses, although they may not be included in any of the existing arenavirus species in mammals. In recent years, many mammalian New and Old World arenaviruses have been identified (Pontremoli et al., 2019). Under current species delimitation standards, most unclassified mammalian arenaviruses won’t be designated as separate species. Dandenong virus is a member of the Lymphocytic choriomeningitis virus species since its NP amino acid sequence is just 3% different from LCMVs. Viruses satisfy all or most species delineation criteria. The NP amino acid sequence of the newly found Merino Walk virus differs by more than thirty-one percent from that of MOPV, the arenavirus with which it is most directly connected (Bisordi et al., 2015).

4.4 NOMENCLATURE: SPELLING OF ARENAVIRUS SPECIES NAMES Generally, arenaviral and arenavirus species names have been taken from geographic areas like rivers, regions, and towns. Because several mammalian New World arenaviruses had been identified in South America, their names have been derived from South American places spelled with the Spanish alphabet. Certain arenaviral and arenavirus species names have previously been revised by earlier ICTV Arenaviridae Study Groups by inserting proper diacritical markings. At least 2 species names, though, still include misspelled word stems (Pichinde [sic] and Amapari [sic]). To minimize misunderstanding, viral name abbreviations must be distinct to facilitate communication amongst virologists and database searches. This criterion is not met by several acronyms for recognized arenaviruses (García et al., 2011): •

• •

•

CHPV was first used as an acronym for Chandipura virus (a vesiculovirus) and chicken parvovirus, and then as an acronym for Chapare virus. Cowpox virus (an orthopoxvirus) was abbreviated as CPXV before Cupixi virus was abbreviated as CPXV. The usage of LUNV as an acronym for the newly found Luna virus precedes the utilization of LUNV as an acronym for the Lundy virus (an orbivirus). Since the initials, PARV4 and ParV-3 have been used for the unidentified parvovirus PARV4 virus and the unidentified potexvirus parsnip virus 3, correspondingly, PARV as an acronym

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for Parana’ virus is not appropriate. • The acronym PICV for the Pichinde virus isn’t optimal because it’s also used for pigeon circovirus. • Because SABV also refers to the Saboya virus (a flavivirus), using it as an acronym for the Sabia virus has been problematic. • The name TAMV for Tamiami virus isn’t perfect because TaMV has been the acronym for Tulare apple mosaic virus (an ilarvirus). Several possible acronyms for unidentified arenaviruses are likewise not distinctive: • Because BBTV has been in usage for the banana bunchy top virus (a babuvirus), it must not be utilized as an acronym for the Big Brushy Tank virus. • Because it has been in usage for citrus variegation virus (an ilarvirus), CVV must not be utilized as an acronym for the Collierville virus. • The term GGV is troublesome since GgV has been the acronym for Gaeumannomyces graminis virus (a partitivirus). • The term MPRV stands for Middle Pease River virus, whereas MpRV stands for Micromonas pusilla reovirus. • The abbreviation for the Merino Walk virus is MWV, which is problematic given that MwV is connected to an unclassified alpha-nodavirus known as the Manawatu virus. In addition, there have been no acronyms for the following unclassified arenavirus names:  Gbagroube virus, Black Mesa virus, Menekre virus, Jirandogo virus, Pinhal virus, Orogrande virus, and Real de Catorce virus (RDCV was proposed in one journal). Ultimately, the “Boa Av NL B3 virus” and several arenaviruses in North America lack correct viral names and acronyms (Fernandes et al., 2015).

Concerns with the International Code of Virus Classification and Nomenclature (ICVCN) Virus classification and nomenclature are governed by rules codified in the ICVCN. Arenavirus and arenaviral species names are now spelled similarly, except for the existence or lack of italics (for example, Jun’n virus is a member of the Junn virus species). It’s especially problematic for computerized databases, which frequently fail to distinguish between italicized and roman text. The suffixes “-virus” and “- viridae” are the only

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things that differentiate the family Arenaviridae from the genus Arenavirus, but other than that, the two names come from the same word stem (“arena”). The members of the family are referred to as arenaviruses, as are the members of the genus, which are also referred to as arenaviruses (Fernandes et al., 2018). At the moment, this lack of specificity isn’t a concern because the family only has one genus. The creation of the 2nd genus for alethinophidian arenaviruses, though, may render the name “arenavirus” confusing, since it would be unclear if it refers to all members of the family or simply those from one of the two genera. As a result, the present arenavirus taxonomy is in disagreement with ICVCN (Bodewes et al., 2014). •

•

• •

Rule 2.1: “To prevent or prohibit the usage of names which can generate mistake or misunderstanding” is one of the fundamental tenets of viral nomenclature; Rule 3.14: “New names may not be used in place of authorized names. The selection of new names must avoid being too identical to those already in use or those that have just been; Rule 3.21: A species’ name must be as short as possible while yet standing out through the names of other taxa. Rule 3.22: According to this “a species name should give a suitably clear identification of the species.”

4.5 SOLUTIONS TO THE PRESENT TAXONOMIC PROBLEMS WITH ARENAVIRUSES 4.5.1 Criteria for New Families and Taxa Inclusion We base arenavirus categorization on objective criteria depending upon coding-complete genomic section sequences in acknowledgment of the great growing variety of arenaviruses. Arenaviruses are now classified depending upon the unanimous votes of the ICTV Arenaviridae Study Group members (Fernandes et al., 2018): 1)

Though, in the absence of a culturable isolate, coding-complete genomic sequences seem to be accessible for both L and S sections; or 2) For the S section, a culturable isolate and a coding-complete genomic sequencing are also accessible.

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All arenaviruses that have been categorized must continue to be so depending upon these criteria. It is necessary to classify the viruses Boa AV NL B3, Dandenong, CAS, Lunk, Golden Gate, Middle Pease River, Merino Walk, Tonto Creek, and the University of Helsinki. Until enough information has been accessible, the following North American arenaviruses must be treated as potential members of the family: Collierville virus, Black Mesa virus, Jirandogo virus, Gbagroube virus, Ocozocoautla de Espinosa virus, Kodoko virus, Pinhal virus, Orogrande virus, Real de Catorce virus, and the unidentified North American arenaviruses (Simo Tchetgna et al., 2021). To see the distances amongst viral sequence pairs, PASC analysis generates histograms, which produce peaks that may correspond to various taxon levels. Taxon delineation criteria may be influenced by the proportions of the valleys’ lowest points (See the references for further details on PASC). Such percentage cutoffs should, preferably, be consistent with the diversity of arenaviruses inferred from previous phylogenetic analyses and not in conflict with any recognized biological traits of specific arenaviruses (Bennett et al., 2000).

Figure 4.3. Study of L section sequences using Pairwise Sequence Comparison (PASC) and analysis of NP section sequences by amino acid distance.

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These features encompass variances in host specificity and, by extension, geographic dispersion, serological cross-reactions between viral particles, and the capacity to cause human illness. If individual investigations don’t arrive at the same categorization findings, the ICTV Arenaviridae Study Group would have to address the discrepancy by weighting criteria and establishing compromises. PASC analysis and measurement of NP amino acid pairwise distances (Figure.3) had been done to examine if the various possible outputs will match the present arenavirus taxonomy and maybe accommodate additional viruses that have been believed to need the introduction of new species. Both studies demonstrate that the family Arenaviridae has a minimum of 2 genera, one for mammalian arenaviruses and the other for reptile arenaviruses (Fernandes et al., 2018). Inside the same suggested genus, paired nucleotide sequence identities for the S section have been greater than forty percent, but those from various proposed genera have been less than twenty-nine percent. Thus, the genus separation limit in PASC had been adjusted to twenty-nine to forty percent for the S segment and thirty to thirty-five for the L segment (Guterres et al., 2017). Multiple alternate sequence cutoffs for arenavirus species demarcation might be used, based on the multiple valleys-between peaks in PASC. The ICTV Arenaviridae Study Group members concurred that the most cautious approach must be used, for example, such values must be selected in a way that makes the fewest modifications and disrupts the present arenavirus categorization scheme the least. As a result, the results for arenaviruses that must correspond to the same species were eighty percent nucleotide sequence identity in the S section and seventy-six percent identity in the L section. The ICTV Arenaviridae Study Group concurred that the use of PASC or comparable approaches alone may not always support species categorization and that if practical, additional criteria must be taken into account to support or disprove study findings (Zeller et al., 2008). These standards for species taxonomy include: • • • •

connection of arenavirus with a principal host or set of sympatric hosts; spread of the arenavirus inside a particular geographic region; Considerable antigenic cross-reactivity discrepancies, such as the absence of cross-neutralization activity; substantial protein amino acid pattern variations in comparison to the homologous proteins of viruses from other species in the same

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genus (for instance, displaying a minimum of twelve percent divergence in the nucleoprotein amino acid pattern across members of various species); • relationship (or lack thereof) to human illness Arenaviruses already categorized have been reclassified, and newly identified categorized arenaviruses have also been included. The current taxonomy of mammalian arenaviruses, based on biological criteria, agrees with this classification. PASC analyses have always suggested the creation of 9 new species (Big Brushy Tank virus, Dandenong virus, Skinner Tank virus, Catarina virus, Middle Pease River virus, Merino Walk virus, Lunk virus, Tonto Creek virus, and Morogoro virus) and the division of the current species for WWAV, LCMV, MOPV, LASV, and PIRVas modifications in the new arenavirus categorization (Maes et al., 2018). The present ICTV concept of species is used by the ICTV Arenaviridae Study Group to assess the taxonomic status of certain arenaviruses. The collection of 6 polythetic criteria listed in this article is enough for classifying an arenavirus isolate according to its taxonomic position, although no one criterion alone is always adequate (Schattner et al., 2013). Phylogenetic connections and, thus, monophyly have been connected in one way or another to several species’ characteristics. Either PASC analysis or NPamino acid differences can be used to detect the genetic closeness of viruses. The genetic closeness of the GPC and NP amino acid patterns of the viruses may explain even variations in antigenic cross-reactivity. Other factors, such as the affiliation with a host, the location, and the capacity to inflict disease on humans, are connected to how the virus interacts with its surroundings (for example, the “ecological niche”) (Van Regenmortel, 2019). Even though the most conservative cutoffs have been adopted, some arenavirus species will still need to be “divided” depending only on PASC analysis, as was already indicated. Such a “split,” nevertheless, would go against the polythetic character of viral species (Contrary to the other biological demarcation parameters outlined before). Additionally, PASC analysis by itself might not always yield reliable outcomes for the L and S segments. Given that individuals of viral species continuously duplicate, change, and so create fuzzy sets having hazy boundaries, such discrepancy is not surprising (Fernandes et al., 2015). Virus species may often be thought of as a biological continuum, with members from both ends greatly varying from one another when taking into account one or more criteria, but remaining connected through several

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members having intermediary variance values. This idea is particularly true for genetic distances: two isolates may have diverged more than the cutoff value, yet they may still be connected by other intermediary isolates. The NP amino acid gap, for instance, between the Skinner Tank virus and “arenavirus AV 96010025” is 15.65 percent, which is more than the selected twelve percent requirement (Stenglein et al., 2015). They create a biological continuity with the Big Brushy Tank virus and the “North American arenavirus AV 96010151,” since their interNP distances are less than eleven percent. After discussing such topics, the ICTV Arenaviridae Study Group came to the following conclusion (Palacios et al., 2008): (i) at this time, we will not address the species splits that have been indicated by the PASC analysis and (ii) to delay the possible institution of new species for Big Brushy Tank virus, Dandenong virus, Catarina virus, Morogoro virus, Middle Pease River virus, Skinny Tank virus, and Tonto Creek virus till the additional biological data have all been evaluated and comparative sequence analyses have been conducted. As advised by PASC, the committee has agreed to generate new species for the Merino Walk virus and Lunk virus (Zeltina et al., 2017). The group considers the Morogoro virus a member of the MOPV species until further analysis, and the Big Brushy Tank, Skinner Tank, Tonto Creek, and Catarina viruses members of the WWAV species until further analysis. The team opted to wait till more biological and phylogenetic investigations have been carried out, and isolates are collected, before making any judgments regarding the taxonomic status of the Middle Pease River and Dandenong viruses. As a result, at the time of writing, these viruses have been regarded as unclassified mammalian arenaviruses. Genus and species names may be changed to reflect spelling errors and to adhere to ICVCN regulations. The genus names for Mammarenavirus, mammalian arenaviruses, and reptile arenaviruses, Reptarenavirus, were chosen by the ICTV Arenaviridae Study Group (Maes et al., 2019). Non-Latinized binomial species names have been established for species that belong to both genera of arenavirus to bring arenavirus taxonomy into conformity with the classification scheme used by the ICVCN. This was done to ensure that the arenavirus taxonomy is consistent. It is quite improbable that non-Latinized binomial species names would still be unintentionally used for viruses. This is because the majority of virologists work with real viruses, have a limited need to address species, and are accustomed to the established viral nomenclature. Additionally, “Pichinde” and “Amapari” in the species names have been changed to “Pichindé” and “Amapar,” accordingly (Emonet et al., 2009).

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REFERENCES 1.

Abudurexiti, A., Adkins, S., Alioto, D., Alkhovsky, S. V., Avšič-Županc, T., Ballinger, M. J., ... & Kuhn, J. H. (2019). Taxonomy of the order Bunyavirales: update 2019. Archives of virology, 164(7), 1949-1965. 2. Bennett, S. G., Milazzo, M. L., Webb, J. P., & Fulhorst, C. F. (2000). Arenavirus antibody in rodents indigenous to coastal southern California. The American journal of tropical medicine and hygiene, 62(5), 626-630. 3. Bisordi, I., Levis, S., Maeda, A. Y., Suzuki, A., Nagasse-Sugahara, T. K., de Souza, R. P., ... & da Fonseca, B. A. (2015). Pinhal virus, a new arenavirus isolated from Calomys tener in Brazil. Vector-Borne and Zoonotic Diseases, 15(11), 694-700. 4. Bodewes, R., Kik, M. J. L., Raj, V. S., Schapendonk, C. M. E., Haagmans, B. L., Smits, S. L., & Osterhaus, A. D. M. E. (2013). Detection of novel divergent arenaviruses in boid snakes with inclusion body disease in The Netherlands. Journal of General Virology, 94(6), 1206-1210. 5. Bodewes, R., Raj, V. S., Kik, M. J., Schapendonk, C. M., Haagmans, B. L., Smits, S. L., & Osterhaus, A. D. (2014). Updated phylogenetic analysis of arenaviruses detected in boid snakes. Journal of virology, 88(2), 1399-1400. 6. Bowen, M. D., Peters, C. J., & Nichol, S. T. (1997). Phylogenetic analysis of theArenaviridae: patterns of virus evolution and evidence for cospeciation between arenaviruses and their rodent hosts. Molecular phylogenetics and evolution, 8(3), 301-316. 7. Charrel, R. N., & de Lamballerie, X. (2010). Zoonotic aspects of arenavirus infections. Veterinary microbiology, 140(3-4), 213-220. 8. Charrel, R. N., de Lamballerie, X., & Emonet, S. (2008). Phylogeny of the genus Arenavirus. Current opinion in microbiology, 11(4), 362368. 9. Emonet, S. F., Juan, C., Domingo, E., & Sevilla, N. (2009). Arenavirus genetic diversity and its biological implications. Infection, Genetics and Evolution, 9(4), 417-429. 10. Emonet, S., Lemasson, J. J., Gonzalez, J. P., de Lamballerie, X., & Charrel, R. N. (2006). Phylogeny and evolution of old world arenaviruses. Virology, 350(2), 251-257.

112

RNA and Life Threatening Diseases

11. Fenner, F. (1976). The classification and nomenclature of viruses: summary of results of meetings of the International Committee on Taxonomy of Viruses in Madrid, September 1975. Journal of General Virology, 31(3), 463-470. 12. Fernandes, J., de Oliveira, R. C., Guterres, A., Barreto-Vieira, D. F., Terças, A. C. P., Teixeira, B. R., ... & de Lemos, E. R. S. (2018). Detection of Latino virus (Arenaviridae: Mammarenavirus) naturally infecting Calomys callidus. Acta Tropica, 179, 17-24. 13. Fernandes, J., de Oliveira, R. C., Guterres, A., de Carvalho Serra, F., Bonvicino, C. R., D’Andrea, P. S., ... & de Lemos, E. R. S. (2015). Co-circulation of Clade C New World Arenaviruses: new geographic distribution and host species. Infection, Genetics and Evolution, Vol. 33, 242-245. 14. Fernandes, J., Guterres, A., De Oliveira, R. C., Chamberlain, J., Lewandowski, K., Teixeira, B. R., ... & De Lemos, E. R. S. (2018). Xapuri virus, a novel mammarenavirus: natural reassortment and increased diversity between New World viruses. Emerging Microbes & Infections, 7(1), 1-10. 15. Fernandes, J., Guterres, A., De Oliveira, R. C., Jardim, R., Dávila, A. M. R., Hewson, R., & De Lemos, E. R. S. (2019). Aporé virus, a novel mammarenavirus (Bunyavirales: Arenaviridae) related to highly pathogenic virus from South America. Memórias do Instituto Oswaldo Cruz, Vol. 1, pp. 114. 16. Fernandes, J., Silva, T. A. C. D., Oliveira, R. C. D., Guterres, A., Oliveira, E. C. D., Terças, A. C. P., ... & Lemos, E. R. S. (2018). Silent arenavirus infection in individuals living in Colniza, Mato Grosso, Brazil, (Vol. 1, pp. 2-8). 17. García, C. C., Sepúlveda, C. S., & Damonte, E. B. (2011). Novel therapeutic targets for arenavirus hemorrhagic fevers. Future Virology, 6(1), 27-44. 18. Guterres, A., de Oliveira, R. C., Fernandes, J., de Lemos, E. R. S., & Schrago, C. G. (2017). New bunya-like viruses: Highlighting their relations. Infection, Genetics and Evolution, 49, 164-173. 19. Hetzel, U., Sironen, T., Laurinmäki, P., Liljeroos, L., Patjas, A., Henttonen, H., ... & Hepojoki, J. (2013). Isolation, identification, and characterization of novel arenaviruses, the etiological agents of boid inclusion body disease. Journal of virology, 87(20), 10918-10935.

Past, Present, and Future of Arenavirus Taxonomy

113

20. Hetzel, U., Sironen, T., Laurinmäki, P., Liljeroos, L., Patjas, A., Henttonen, H., ... & Hepojoki, J. (2014). Reply to” updated phylogenetic analysis of arenaviruses detected in boid snakes”. Journal of Virology, 88(2), 1401. 21. Hugot, J. P., Gonzalez, J. P., & Denys, C. (2001). Evolution of the Old World Arenaviridae and their rodent hosts: generalized host-transfer or association by descent?. Infection, Genetics and Evolution, 1(1), 1320. 22. Kuhn, J. H., Radoshitzky, S. R., Bavari, S., & Jahrling, P. B. (2013). The International Code of Virus Classification and Nomenclature (ICVCN): proposal for text changes for improved differentiation of viral taxa and viruses. Archives of virology, 158(7), 1621-1629. 23. Lavergne, A., de Thoisy, B., Donato, D., Guidez, A., Matheus, S., Catzeflis, F., & Lacoste, V. (2015). Patawa Virus, a new arenavirus hosted by forest rodents in French Guiana. EcoHealth, 12(2), 339-346. 24. Lecompte, E., Ter Meulen, J., Emonet, S., Daffis, S., & Charrel, R. N. (2007). Genetic identification of Kodoko virus, a novel arenavirus of the African pigmy mouse (Mus Nannomys minutoides) in West Africa. Virology, 364(1), 178-183. 25. Lozano, M. E., Posik, D. M., Albarino, C. G., Schujman, G., Ghiringhelli, P. D., Calderon, G., ... & Romanowski, V. (1997). Characterization of arenaviruses using a family-specific primer set for RT-PCR amplification and RFLP analysis: its potential use for detection of uncharacterized arenaviruses. Virus research, 49(1), 79-89. 26. Madu, I. G., Files, M., Gharaibeh, D. N., Moore, A. L., Jung, K. H., Gowen, B. B., ... & Amberg, S. M. (2018). A potent Lassa virus antiviral targets an arenavirus virulence determinant. PLoS Pathogens, 14(12), e1007439. 27. Maes, P., Adkins, S., Alkhovsky, S. V., Avšič-Županc, T., Ballinger, M. J., Bente, D. A., ... & Kuhn, J. H. (2019). Taxonomy of the order Bunyavirales: second update 2018. Archives of virology, 164(3), 927941. 28. Maes, P., Alkhovsky, S. V., Bào, Y., Beer, M., Birkhead, M., Briese, T., ... & Kuhn, J. H. (2018). Taxonomy of the family Arenaviridae and the order Bunyavirales: update 2018. Archives of virology, 163(8), 22952310.

114

RNA and Life Threatening Diseases

29. Mayo, M. A. (2005). Changes to virus taxonomy 2004. Archives of virology, 150(1), 189. 30. Meyer, B., & Ly, H. (2016). Inhibition of innate immune responses is key to pathogenesis by arenaviruses. Journal of virology, 90(8), 38103818. 31. Monath, T. P. (2019). A short history of Lassa fever: The first 10–15 years after discovery. Current Opinion in Virology, 37, 77-83. 32. Moncayo, A. C., Hice, C. L., Watts, D. M., De Rosa, A. P. T., Guzman, H., Russell, K. L., ... & Tesh, R. B. (2001). Allpahuayo virus: a newly recognized arenavirus (Arenaviridae) from arboreal rice rats (Oecomys bicolor and Oecomys paricola) in northeastern Peru. Virology, 284(2), 277-286. 33. Murphy, F. A. (1975). Arenavirus taxonomy: a review. Bulletin of the World Health Organization, 52(4-6), 387. 34. Murphy, F. A., & Whitfield, S. G. (1975). Morphology and morphogenesis of arenaviruses. Bulletin of the World Health Organization, 52(4-6), 409. 35. Palacios, G., Druce, J., Du, L., Tran, T., Birch, C., Briese, T., ... & Lipkin, W. I. (2008). A new arenavirus in a cluster of fatal transplantassociated diseases. New England journal of medicine, 358(10), 991998. 36. Palacios, G., Savji, N., Hui, J., Da Rosa, A. T., Popov, V., Briese, T., ... & Lipkin, W. I. (2010). Genomic and phylogenetic characterization of Merino Walk virus, a novel arenavirus isolated in South Africa. The Journal of general virology, 91(Pt 5), 1315. 37. Palmer, E. L., Obijeski, J. F., Webb, P. A., & Johnson, K. M. (1977). The Circular, Segmented Nucleocaspid of an Arenavirus-Tacaribe Virus. Journal of General Virology, 36(3), 541-545. 38. Pontremoli, C., Forni, D., & Sironi, M. (2019). Arenavirus genomics: novel insights into viral diversity, origin, and evolution. Current Opinion in Virology, Vol. 34, 18-28. 39. Postler, T. S., Clawson, A. N., Amarasinghe, G. K., Basler, C. F., Bavari, S., Benkő, M., ... & Kuhn, J. H. (2017). Possibility and challenges of conversion of current virus species names to Linnaean binomials. Systematic Biology, 66(3), 463-473.

Past, Present, and Future of Arenavirus Taxonomy

115

40. Radoshitzky, S. R., Bào, Y., Buchmeier, M. J., Charrel, R. N., Clawson, A. N., Clegg, C. S., ... & de la Torre, J. C. (2015). Past, present, and future of arenavirus taxonomy. 41. Radoshitzky, S. R., Buchmeier, M. J., Charrel, R. N., Clegg, J. C. S., Gonzalez, J. P. J., Günther, S., ... & de la Torre, J. C. (2019). ICTV virus taxonomy profile: Arenaviridae. Journal of General Virology, 100(8), 1200-1201. 42. Sarute, N., & Ross, S. R. (2017). New World arenavirus biology. Annual review of virology, 4(1), 141. 43. Schattner, M., Rivadeneyra, L., Pozner, R. G., & Gómez, R. M. (2013). Pathogenic mechanisms involved in the hematological alterations of arenavirus-induced hemorrhagic fevers. Viruses, 5(1), 340-351. 44. Seregin, A., Yun, N., & Paessler, S. (2014). Lymphocytic Choriomeningitis, Lassa Fever, and the South American Hemorrhagic Fevers (Arenaviruses). In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases (Vol. 1, pp. 2031-2037). Elsevier Inc.. 45. Simo Tchetgna, H., Descorps-Declère, S., Selekon, B., Kwasiborski, A., Vandenbogaert, M., Manuguerra, J. C., ... & Berthet, N. (2021). Molecular characterization of a new highly divergent Mobala related arenavirus isolated from Praomys sp. rodents. Scientific Reports, 11(1), 1-11. 46. Stenglein, M. D., Jacobson, E. R., Chang, L. W., Sanders, C., Hawkins, M. G., Guzman, D. S., ... & DeRisi, J. L. (2015). Widespread recombination, reassortment, and transmission of unbalanced compound viral genotypes in natural arenavirus infections. PLoS pathogens, 11(5), e1004900. 47. Van Regenmortel, M. H. (2019). Solving the species problem in viral taxonomy: recommendations on non-Latinized binomial species names and on abandoning attempts to assign metagenomic viral sequences to species taxa. Archives of virology, 164(9), 2223-2229. 48. Zapata, J. C., & Salvato, M. S. (2013). Arenavirus variations due to host-specific adaptation. Viruses, 5(1), 241-278. 49. Zeller, H., Leitmeyer, K., Santos, C. V., & Coulombier, D. (2008). Unknown disease in South Africa identified as arenavirus infection. Eurosurveillance, 13(42), 19008.

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50. Zeltina, A., Krumm, S. A., Sahin, M., Struwe, W. B., Harlos, K., Nunberg, J. H., ... & Bowden, T. A. (2017). Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization. Proceedings of the National Academy of Sciences, 114(27), 7031-7036.

CHAPTER

5

CARDIOVASCULAR DISEASE

CONTENTS 5.1 Introduction...................................................................................... 118 5.2 Topology of Disease.......................................................................... 118 5.3 Disease Burden................................................................................. 121 5.4 Future of Disease.............................................................................. 129 5.5 Cardiovascular Research................................................................... 130 5.6 Typology of Research........................................................................ 133 5.7 High Profile Research....................................................................... 136 5.8 Future Research Agenda................................................................... 137 References.............................................................................................. 139

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5.1 INTRODUCTION The term “cardiovascular disease” (also known as “heart disease”) belongs to a collection of conditions that cause the heart muscle, specifically the heart’s blood vessels. The above disease can affect a single portion of one’s heart or multiple portions of someone’s heart as well as your circulatory system. An individual may exhibit symptoms of a disease but may not exhibit any symptoms at all depending on their condition (not feeling everything at all) (Nabel, 2003). Problems with the heart’s arteries of various categories are included in the category of heart problems (Verhaar et al., 2002): • • •

Irregular heartbeats. Valve dysfunction of the cardiac. Plaque narrows blood channels inside the cardiac, different organs, and throughout the body. • Heart constricting and difficulty relaxing. • You were born having cardiovascular system vascular issues. • Difficulties with the outer lining of your heart. Cardiovascular disease (CVD) is indeed the leading cause of mortality around the globe, and this is a life-threatening situation in all of its manifestations. CVD is a group of illnesses and traumas that impact the cardiovascular, rather than a single condition (the heart and blood vessels). These are the most prevalent related to heart illnesses inside the brain and heart. generally, they afflict individuals later on in life (having incidence dramatically increasing just after the 30-44 age group), yet, as per a famous cardiologist, many persons who will develop a type of CVD will have the disease start even by age of 35 (Anderson et al., 1991).

5.2 TOPOLOGY OF DISEASE CVD is a term that refers to a group of disorders that affect heart health. Coronary artery disease, angina, strokes, myocarditis, congenital heart defects, peripheral artery disease, aortic aneurysms and dissections, and thromboembolism, as well as other, less prevalent cardiovascular disorders are among them (Lee et al., 2008).

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5.2.1 Coronary Heart Disease Heart disease also recognized as cardiovascular disease (CAD), and atheromatous heart problems, is caused by the development of atherosclerotic lesions within the arterial walls that supply the heart muscle (the muscle of the heart). The majority of the population with cardiovascular disease don’t show any symptoms for years, although the disease progresses, before the first signs, which seem to be generally a “rapid” heart problem, appear. This is because the clinical signs of cardiovascular disease are generally only noticed in the delayed stages of illness. Placed above a white month of expansion, the majority of such atherosclerotic lesions could fracture, decreasing the blood flow to a heart muscle (including the stimulation of the clotting factor system). The main reason for unplanned deaths is disease (Shirley & Rushton, 2005).

5.2.2 Angina Angina is a type of pain linked with highly severe CHD that often manifests as a feeling of pressure inside the thorax, shoulder pain, jaw pain, or other types of irritation. Because the type and degree of angina vary greatly across people, and also most individuals do not regard angina as being painful until it is serious, the term discomfort is favored so over term pain to describe the feeling. Angina is simply a heart muscle spasm (Matsuzawa, 2008).

5.2.3 Stroke A stroke is a kind of severe neurological damage in which the blood circulation to a region of the brain gets cut off, either due to an arterial dissection or a ruptured artery (hemorrhage). Because the brains innervated by such blocked or ruptured arteries could no longer get oxygen from the blood, they are injured or dead (becoming necrotic), affecting the functions of that portion of the brain. When a stroke is not recognized and treated swiftly, it may result in irreversible disability or even death (Dorman & Corcoran, 2009). Ischemic and hemorrhagic strokes are the two main types of strokes. Thrombus (clotting), embolization (clot or obstruction away in the organism), or global hypoperfusion may all cause ischemia (decrease of the blood movement to all portions of the body). Intracranial hemorrhage and intracranial hemorrhage are two types of hemorrhaging. Ischemia is responsible for 80% of attacks (Wasserheit & Aral, 1996).

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5.2.4 Rheumatic Heart Disease Rheumatic heart disease is a disorder in which rheumatic fever produced by staphylococcus infection damages the heart valves. Rheumatic fever is indeed an inflammation illness that affects the structural body tissues, particularly those from the heart, joints, brains, and epidermis. Acute rheumatic fever may affect anybody, although it is most common in children aged five to fifteen. The rheumatic heart disease which develops as a consequence may be fatal. At least a handful of every 1,000 newborns originating in the United Kingdom each year have such a cardiac abnormality. Approximately 50% of these newborns have such a minor abnormality and would not need care, while the other half will require medical attention or surgery (Pachauri et al., 2011).

5.2.5 Congenital heart disease Congenital heart disease is just a wide phrase that refers to a variety of cardiac abnormalities, all of which are structural and functional irregularities of a cardiac caused by defective or disorganized heart growth before birth. Some conditions, such as aortic coarctation, may well not manifest for several years, while others, including a minor ventricular septal defect (VSD), might not ever create any issues and be consistent with physical activity and just an ordinary life span. Many congenital cardiac problems may be managed with medicine alone, while others necessitate surgery. In the United States, the risk of mortality after congenital heart problem surgery has decreased from over 30% in the 1970s to the less than 5% like in most instances today (Marceau et al., 2010).

5.2.6 Peripheral Arterial Disease The arteries that provide blood to the legs become constricted or entirely clogged in atherosclerotic disease. The arterial narrowing generally happens within the upper region of the leg. A progressive creation of fatty substances inside the arterial walls causes the illness (atherosclerosis). A thrombus (or thrombosis) may develop within the setting of thrombus formation, totally closing the arterial. Different arteries inside the body are prone to narrow in individuals with atherosclerotic disease. Angina or cardiac arrest may be caused by constriction of the arteries that feed blood back to the heart. If somehow the arteries inside the neck are clogged, the blood supply to the brain is disrupted, which may lead to a stroke (Bompadre & Andrey, 2019).

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5.2.7 Deep Vein Thrombosis A deep vein thrombosis (DVT) is just a thrombus (blood clot) which forms in a blood vessel in the brain, commonly within the lower leg. Venous thrombosis is a condition that causes leg discomfort and may progress to problems. In the United Kingdom, around 1-3 persons per 1000 developed DVT each year. A DVT generally occurs in a large vein within the leg, although it may also happen in the arm (Belchi et al., 2018). Deep veins run down the middle of both legs and thus are encircled by muscle. Blood clots that develop in a distinct group of veins under the skin (called superficial veins) are not the same as DVTs. Such clots are known as shallow thrombophlebitis but are not as dangerous as deep thrombophlebitis. Although it is unusual for DVT to induce complications, Pulmonary Embolism (PE) and comment syndrome are two possible outcomes. PE occurs when a portion of a blood clot breaks off and travels through the circulation to settle in the lungs, obstructing blood flow (Meschi et al., 2021). This might happen minutes, hours, or perhaps even days after a clot forms in the leg veins. Chest discomfort and loss of breath are possible side effects. Post-thrombotic syndrome occurs when a DVT destroys the vein’s valves, causing blood to pool in the upper thigh instead of moving upwards. This may lead to leg discomfort, edema, and ulceration. Heart tumors, vascular tumors of the brain, heart muscle abnormalities (heart disease), heart valve illnesses, and heart lining disorders are all possibilities (Olde Dubbelink et al., 2014).

5.3 DISEASE BURDEN The disease is famously difficult to quantify in a community since it explains those who do not seek medical attention and those who remain misdiagnosed. This endeavor is almost hard in terms of world CVD frequency because there are several nations reporting incidence in somewhat various ways and just several distinct conditions that make up CVD that may be construed in various ways. Because the United States has elevated amounts of CVD and very well statistical records, it is often cited as an example of the global burden of disease study data in this section. As part of an overall suite of publications, the numbers for Retrosight research nations will be provided in regionally-based reports (Pereira et al., 2016). However, the overall number of incidents with CVD in the United States was projected to be 71.3 million in 2003, which is more than one in every four Americans. About 13.2 million instances of cardiovascular disease

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including 5.5 million incidences of stroke were among the 71.3 million new cases. In the nation apply to particular papers, prevalence estimates for the research countries that participated in Mission Retrosight are presented (Pereira et al., 2015).

5.3.1 Change Over Time Every year, 17 million deaths worldwide from cardiovascular disease (CVD) over the globe. In affluent nations, CVD mortality has decreased in the previous 10-15 years owing to advances in therapy. However, difficulties persist in poor nations, and several concerns are expected to afflict wealthy countries in the future years. Diabetes and obesity, two main associated with an increased risk of CVD, are likely to rise in prevalence throughout the globe (by 7 billion people by 2015 and roughly 140 million persons by 2025, accordingly), due to an increase in CVD occurrences (Harrington et al., 2015).

5.3.2 Geographic Spread Despite data pointing to an increase in CVD in developed nations including the United States and the United Kingdom owing to overweight, poor nutrition, and lack of physical activity, this is not exclusively a problem of advanced economies. CVD is a greater hazard to people in underdeveloped nations than it is to those in industrialized ones. Over 60% of the worldwide burden of CHD, for instance, is carried by poor nations. CHD is the leading cause of mortality in  China, India , and Russia, with Lithuania and Bhutan all reporting high rates (Forrest, 2009). The data for stroke are similar, with the same three nations having the highest number of fatalities per year. Only Mongolian and Kazakhstan have DALYs (Lived With Disability Years) dropped due to strokes over 20 every 1000 inhabitants. This indicates that CVD has a particularly significant effect on Mongolian and Kyrgyz people. Altogether, these numbers suggest that now the developing world is dealing with a serious CVD issue, one that is expected to worsen as prevention and management improve in the industrialized nations (Morillo et la., 2003). This isn’t to say that cardiovascular disease isn’t an issue in industrialized nations; far from being. CVD accounts for 18% of all DALYs lost in elevated nations, and only 10% of DALYs are wasted in low- and middle-income nations. Stroke, for example, is the leading cause of serious impairment in the United Kingdom (Ramadan et al., 2016).

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5.3.3 Mortality and Morbidity In terms of worldwide fatality, CVD is indeed the leading cause of 57 million deaths occurring to the World Health Organization in 2002. Cardiovascular disease kills more people worldwide than cancer and Aids combination (Figure 1). In today’s terms, CVD kills almost 100 times so many more people each year than conflict (Lopez & Murray, 1998).

Figure 5.1. In 2002, the main causes of death were the leading causes of death worldwide (millions). Source: https://www.researchgate.net/figure/Evolution-of-leading-causes-ofglobal-under-5-deaths-from-1990-to-2016-and-in-the-2040_fig3_328327345

Because CVD is a broad word that refers to a variety of illnesses, it’s critical to understand the specific sources of the burden of disease in terms of deaths and disability. The WHO Navigator of Heart Attacks and Strokes (2004) divides the 16.7 million fatalities worldwide attributable to CVD into deaths from coronary heart disease, strokes, rheumatic fever, inflammation of heart disease, hypertension, and other types of cardiovascular disease (Figure 5.2) (Murray & Lopez, 2013).

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Figure 5.2. CVD was the leading cause of mortality worldwide in 2002. (millions). Source: https://www.ahajournals.org/doi/10.1161/circulationaha.105.591792

Global morbidity is measured in DALYs lost in the process of an illness. And including HIV and melancholy, CVD is a major contributor to the overall number of DALYs lost worldwide (bipolar disorders) (Herder & Roden, 2022). Figure 3 provides WHO data for illness-related DALYs lost worldwide, with CVD impacts broken down into cardiovascular diseases. It also separates the numbers by gender, indicating that cardiovascular disease is the second and third leading cause of DALYs lost among men (the leading cause when grouped as CVD), correspondingly, but heart diseases are the 3rd and 4th leading causes of DALYs lost within women (even though again, shared as CVD they would be the major single source) (Michaud et al., 2013).

Figure 5.3. In 2002, the top four illnesses in terms of worldwide DALYs lost were: Disease-related DALYs account for % of worldwide DALYs lost. Source: https://www.researchgate.net/figure/Change-in-rank-order-of-DALYsfor-the-10-leading-causes-of-the-global-burden-of-disease_tbl2_237554619

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The utilization of global statistics to assess the relevance of CVD in terms of fatalities and disability is beneficial. Furthermore, since there are significant disparities between rich and developing nations, it is critical to understand the morbidity and mortality statistics in Retrosight nations as well as in other nations. Figure 4 depicts the quantity of DALYs lost every 1000 populations in a range of countries, contrasting those lost in wealthy countries to those wasted in developing ones (Lv & Zhang, 2019).

Figure 5.4. In certain nations, the number of DALYs lost per 1000 people has decreased (2003 or nearest data). Source: https://www.researchgate.net/figure/Median-annual-DALYsper-100-000-population-for-selected-infectious-diseases-EU-EEA_ fig3_324615405

5.3.4 Economic and Socio-economic Costs The financial effect of CVD involves more than just the healthcare costs related to the condition; it also includes lost productivity as a result of CVD and overall health costs to the economy. Because CVD is so common, the economic impact may be significant, particularly in nations with greater CHD and stroke mortality. The American Heart Association and Blood Institute and Lung estimate the expense of CVD in the United States to just be over USD 400 billion in 2006. 20 That cost is likely to climb, with the WHO forecasting that now the cost of healthcare for persons aged 50-65 in the United States would rise from 15% in 2010 to 25% in 2030 (Must et al., 1999).

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5.3.5 Risk Factors CVD is a complicated group of disorders, thus there are a variety of hazard factors to consider. The reality that several of the risk variables for CVD interplay with each other adds to the complexity. Diabetes and obesity, for instance, are both substantial risk variables for CVD, but being overweight is indeed a health risk for type-2 Diabetes. As just a result, producing a cumulative equation for forecasting CVD based on the risk factors is difficult; all that can be said is that possessing and over one potential risk increases your probability of developing one kind of CVD. The key risk factors for CVD are explored in further depth below (Mensah & Brown, 2007).

Smoking Smoking raises the risk of coronary artery disease by two to four times. Smoking is a significant independent predictor for sudden heart mortality in people with coronary artery disease, having smokers having nearly double the rates of non. Even non-smokers are now at risk of developing heart disease when they are exposed to certain other people’s smoking; the British Heart Foundation believes that frequent exposure to secondary smoke may raise the risk for CHD by up to 25%. 23 When smoking cigarettes is combined with some other risk variables, the risk of coronary heart disease skyrockets (Mathers et al., 2001). The processes through which smoking raises the risk of heart disease (CVD) are fairly well recognized. The biggest danger is that smokers have a higher risk of thrombosis, which may lead to myocardial injury. Increased atherosclerotic, blood pressure, pulse rate, myocardial contractility, and myocardial blood flow are among the other processes. Smoking also raises carbon monoxide levels in the blood, which attaches to the hemoglobin and reduces oxygen delivery to bodily tissues. In 2000, the amount of cigarette consumption was predicted to be 5,500 billion, a figure that has continued to rise as the world’s largest population has grown. Daily smokers are estimated to number roughly 1 billion males and 250 million women globally (Ezzati et al., 2002).

Obesity Even though no additional hazards are identified, being overweight, especially extra fat from around the waist, increases the risk of developing CHD. Extra weight puts a burden on just one heart, elevates heart rate, raises cholesterol

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and triglycerides in the blood, and reduces HDL cholesterol points. Every one of these things might raise your chances of getting atherosclerotic and thrombolytic emboli. It also raises the likelihood of type 2 diabetes, which is another CVD health risk. According to the WHO, about a billion people everywhere in the world were overweight in 2005, with 400 million heavy (Gwatkin et al., 1999).

Diabetes Diabetes is a condition that impairs a person’s capacity to maintain a healthy blood sugar level. Type 1 and Type 2 diabetes are the two types of diabetes. Insulin-dependent diabetes often referred to as category I diabetes, is characterized either by the body’s inability to produce insulin. Kind II diabetes is the most prevalent type of diabetes, so it happens whenever the system does not create sufficient insulin and when the insulin is just not adequately processed by the cells (Raskob et al., 2014). Elevated blood cholesterol levels, hypotension, and atherosclerotic may all increase the risks of CVD in both types. Insulin resistance is linked to coronary heart disease. According to WHO projections, about 180 million individuals globally have diabetes, and so this figure is expected to more than quadruple by 2030. Diabetes claimed the lives of an estimated 1.1 million individuals globally in 2005. 31 According to a 1986 assessment of mortality in the United States, 60–75 percent of diabetics died from heart disease (Bradshaw et al., 2003).

High blood pressure High blood pressure (hypertension) is significantly associated with cardiovascular disorders. Hypertension causes the heart to harden and stiffness as it continues to work to pump more blood, which may result in heart problems. Stress upon the walls of the vascular causes embolisms and strokes inside the vasculature (Lopez et al., 2006). High blood pressure would be a widespread disease in industrialized nations, with approximately one in every four persons in the United States being diagnosed having hypertension, even though this is a decrease from the 1980s when the incidence was about one in every two. Worldwide hypertension statistics are predicted to climb within the next 20 years, surpassing 1.5 billion individuals, up from 14 percent of the worldwide people (Jones et al., 2012).

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High LDL cholesterol LDL cholesterol (low-density lipoproteins cholesterol) raises the risk of cardiovascular disease by accumulating buildup of plaque in coronary arteries, which leads to atherosclerotic. LDL cholesterol triggers endothelial cells to produce integrins which speed up the progression of atherosclerosis, according to a recent study (Lopez et al., 2006). In 2004, a WHO study looked just at the frequency of high cholesterol in a variety of countries and found that “non-optimal lipoprotein” was responsible for 4.4 million deaths and more than 40 million DALYs globally. 36 About 8% of fatalities and 3% of DALYs occur as a result of these conditions. Total cholesterol has already been growing worldwide, and estimates show that this trend will continue until 2030. (although fascinatingly, North America and Western Europe are predictable to have a droplet in the fat stages) (Afilalo et al., 2011).

Socio-economic risks Low socioeconomic status is linked to cardiovascular disease mortality. CVD rates are up to six times greater in emerging nations like Ukraine as well as India than those in industrialized ones like Canada, Australia, and also the United Kingdom (see Figure 4). This risk is closely linked to several many other risk variables, including food, physical exercise, and obesity rates. Even smoking is linked to a worse socioeconomic position in the UK’s South Asian community (Mathers & Loncar, 2006).

Other risk factors Several additional risk factors have a role in the development of CVD. Associated with obesity, for instance, is regarded as a significant risk factor. Physical exercise may lower cholesterol levels, prevent obesity, and make the cardiac and muscular work even harder to circulate blood throughout the body (Prince et al., 2015). Alcohol use is indeed a health risk, but it’s a complicated one since moderate alcohol levels may lower the risk of cardiovascular disease (by slowing the degradation of Cholesterol levels with antioxidant polyphenols), but excessive amounts of alcohol consumption raise the risk of CHD including stroke (by swelling blood pressure). A bad diet has a direct influence on fat concentrations inside the body (raising the risk of heart problems and overweight), sugar blood glucose levels (raising the chance of developing type II diabetes), and sodium levels in the body

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(rising the accidental of emerging type 2 diabetes mellitus) (cumulative blood pressure and the risk of stroke) (Lopez & Mathers, 2006).

5.4 FUTURE OF DISEASE Based on available data and examination of pertinent data, the WHO has generated forecasts for the development of CVD up to 2030. According to their estimates, worldwide yearly CVD deaths would increase to 18.1 million in 2010, 20.5 million in 2020, and 24.2 million by 2030. These three groups account for 30.8 percent, 31.5 percent, and 32.5 percent of all fatalities worldwide, correspondingly (Plass et al., 2014). CHD-related fatalities are expected to increase from 13.1 percent of all adult deaths in 2010 to 14.9 percent in 2030. Surprisingly, the same figure forecasts a decrease in CHD mortality for women, from 13.6 percent in 2010 to 13.1 percent in 2030. Equally men and women are expected to die from strokes in the future (from 9.2 percent to 10.4 percent for men, and from 11.5 percent to 11.8 percent for women) (Mathers et al., 2000). The quantity of DALYs, as well as the percent of all DALYs covered by CVD, are on the rise, according to morbidity forecasts (all in DALYs) (see Table 1). Stroke is anticipated to become the fourth leading cause of DALYs lost worldwide by 2020 (Rehm et al., 2003). Table 5.1. Worldwide CVD morbidity projections in the future By 2010

By 2020

By 2030

CVD DALYs (milions)

153

'69

187

Burden of CVD (% of all DALYs)

10.4

11.0

11.6

CVD Rankings glcbally

34 CHD

3d CHD

3rd CHD

5 Stroke

4 Stroke

4th Stroke

th

th

Major CVD health issues are also expected to increase by 2030, with the smoking rate expected to climb by 34 percent. Over the same timeframe, the incidence of diabetes cases also is expected to rise considerably. Even though both of these numbers are moderated by a projected increase in the global population, a genuine rise in smoking and diabetic cases is forecast through 2030 (Table) (Stewart et al., 2014).

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Table 5.2. Prediction of main CVD risk variables By 2010 Smokers Diabetes World population"

By 2020

By 2030

Number (upper estimate) 1.4 billion

1.6 billion

1.8 billion

%World population

20.6

21.3

22.2

Number (>20 years old)

221 million

300 million 366 million

%World population

3.3

4.0

4.5

Number (billions)

6.79

7.50

8.11

Obesity would be the second main CVD-related concern that has reached pandemic proportions. Obesity has become a major issue in the industrialized world, but it is increasingly becoming a concern in undeveloped nations, as noted in the main risk section. Overweight and obesity become more common among children all around the globe. According to the latest figures from the “Global Overweight Special task force,” an estimated 155 million school-aged children worldwide are considered overweight or obese (Miller et al., 2020). Obese children represent 30-45 million of the world’s largest kids ages 5 to 17, representing 2-3 percent of the world’s youngsters. According to prior IOTF worldwide projections based on Who statistics for under-fives, another 22 million young kids also are impacted. 44 Similarly, the WHO estimates that 2.3 billion people would be overweight in 2015, with over 700 million being obese. This is concerning information since CVD-related mortality is rising in wealthy nations. It’s especially concerning since juvenile overweight is connected to the development of diabetes, and some other Cardiovascular disease risk components and the World Health Organization predicts that diabetes mortality will rise by 50% within the next ten years (Prüss-Üstün & Corvalán, 2007).

5.5 CARDIOVASCULAR RESEARCH The significance of CVD as just a global illness is represented in a worldwide research program aimed at lowering both the death rate (mortality) as well as the disease’s incidence (morbidity). CVD research spans a broad variety of issues, from public health initiatives like smoking cessation programs to intrusive surgical methods like a microscopic heart transplant (Molinari et al., 2007). The discipline of cardiovascular science goes back to China’s Qing Huang Ti in the 26th centuries Bc when he discovered that blood poured via a circulation system of the body regulated either by the heart.

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Throughout time, progress has been made, with Leonardo Da Vinci defining atherosclerotic (albeit not inventing the name) in the 15th century. When cholesterol became identified, atherosclerosis plaque became characterized, as well as the electric pulses linked with the heartbeat became identified in the 19th century, cardiovascular research has taken off (Rehm et al., 2010). In current times, the main cardiologist achievements of the twentieth century constitute the foundations of a modern medical cardiologist. The relevance of electrics in cardiologists was discovered, including both terms of cardiac electrical impulses and the insertion of electric implantable devices (Forrest, 2009). The photography of heart rate, first by echocardiogram and subsequently through MRI, CT, and MRA methods, went hand in hand only with electric surveillance of cardiac activity. At the turn of the century, soviet Russia saw the creation of a lipid theory of atherosclerotic, which laid the groundwork for an investigation into cholesterol and the therapeutic alleviation of atherosclerosis by angioplasty (including catheterization with balloons, and stents) (Prüss et al., 2002). Additional surgical advancements which have been useful in the care of CVD include heart surgery as well as microscopic surgery, which also has come a long way since the very first heart surgery in the 1950s. Drug therapies have advanced significantly during the twentieth century, with the adoption of aspirin to avoid heart attacks in the 1970s as well as the continued advancement of thrombolytic therapy medications like streptokinase (developed in 1945) among the most notable examples (Balakrishnan et al., 2019). Additional surgical advancements that have been useful in the care of CVD include heart surgery as well as microscopic surgery, which also has come a long way since the very first heart surgery in the 1950s. Drug therapies have advanced significantly during the twentieth century, with the adoption of aspirin to avoid heart attacks in the 1970s as well as the continued advancement of thrombolytic therapy medications like streptokinase (discovered in 1945) among the most notable examples (Heidenreich et al., 2011). Figures 5 and 6 depict the chronology of significant events in CVD testing and therapy, albeit, as previously said, providing a detailed description of significant research is almost difficult due to CVD’s vast scope and lengthy history of accomplishment (Oliver-Williams et al., 2013).

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Figure 5.5. CVD research timeline: 1860s to 1970s. Source: ease

https://timelines.issarice.com/wiki/Timeline_of_cardiovascular_dis-

Figure 5.6. From the 1980s until the present, researchers have been studying cardiovascular disease. Source:https://www.researchgate.net/figure/The-timeline-of-let-7-discovery-incardiovascular-diseases_fig5_258957930

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5.6 TYPOLOGY OF RESEARCH Given that heart disease spans a wide spectrum of clinical disorders, it’s no surprise that there are numerous study domains dedicated to meeting CVD’s clinical demands. Throughout this chapter, we divide the CVD study into four categories (electrics, surgery, mechanical, and other study topics) to highlight the major research threads that are now impacting clinical practice (Hauspurg et al., 2018). CVD is a useful umbrella term for a broad variety of clinical disorders, which necessitates research into a broad variety of clinical and biological therapies. In line with all of this, the structure of clinical trials, which seeks many solutions or therapies for a single ailment, leads to an even broader range of CVD-related study subjects and domains. In this section, we’ve divided CVD research into categories based on the study approach rather than the disease being studied. Surgery, for instance, is a field of study that touches on a variety of elements of CVD, from arterial vascularization to congenital cardiac abnormalities. Because many surgical advancements are relevant to both kinds of treatments, it makes sense to combine surgical advancements (Hennekens, 1998). CVD is a useful umbrella term for a broad variety of clinical disorders, which necessitates research into a broad variety of clinical and biological therapies. In line with all of this, the structure of clinical trials, which seeks many solutions or therapies for a single ailment, leads to an even broader range of CVD-related study subjects and domains. In just this section, we’ve divided CVD research into categories based on the study approach rather than the disease being studied. Surgery, for instance, is a field of study that touches on a variety of elements of CVD, from arterial vascularization to congenital cardiac abnormalities. Because many surgical advancements are relevant to both kinds of treatments, it makes sense to combine surgical advancements (Berends et al., 2008). • • • •

Pacemakers, defibrillators, and other electrical devices Surgery – Open cardiac surgery, endoscopic surgery, transplantation, and other procedures are available. Stents, balloons, and other mechanical devices Other advances – Drugs to avoid transplanted tissue rejections, lifestyle studies for CVD causes, preventative studies, screening tools, and so on are among them.

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We will examine the study subfields within all of these domains, using some recent developments as illustrations. We’ll also talk about how the regions don’t always exist in isolation. For instance, improvements in drug treatment to avoid the rejecting of a transplanted organ are a clear example of a field wherein surgery could develop without improvements in areas like drug treatment quality or efficient genotyping of transplantation donors (Solomon et al., 2002).

5.6.1 Electrics The heartbeat, which was invented in the 1950s, was the first big innovation in electrics. Electrically powered research today includes efforts examining a wide range of cardiac disorders that may be addressed using electronic items. However, one field is implanted cardiac miniaturization, which eliminates the need for bulky rechargeable batteries. Another option is to employ implanted devices to track and reset the cardiac rhythm in the event of turbulence. Heart electrics advancements are now heavily reliant on advancements in power electronics and computational technologies (Magnusson et al., 2013).

5.6.2 Surgery Heart surgery is the most well-known surgical procedure connected with CVD, as well as the introduction of the Bypass Surgery system in the 1960s rendered open heart surgery simpler. These days, surgical method research is divided into two categories. To begin, development into heart transplant continues, with a focus on aortic valve replacement and the development of human heads. Secondly, a key field of study involves surgery on other sections of the heart and lungs. Breakthroughs in angiography and the insertion of electrical equipment during surgical operations are two examples (Lefkowitz & Willerson 2001).

5.6.3 Mechanics (Stents, balloons, catheterization) Though biomechanical in cardiovascular research frequently relates to the continuum flow of the circulatory system, the term “physics” in clinical medicine has a somewhat different meaning. The term “mechanics” is used in this article to refer to therapies that modify the cardiovascular physically. Cents, for instance, are wire mesh cylinders that have been used to physically keep arteries open (Chae et al., 2003). This permits blood to circulate more freely to all of the internal tissues. After catheterization, stents are frequently

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used to maintain arteries wide so that they may mend without constricting and limiting blood flow. Stents may now be coated with slow-release medication coatings that prevent the artery from closing (sclerosis) following surgery. These are known as “drug-eluting stents,” and they are quickly becoming the preferred option for cardiovascular surgeons (Hughes, 1986). Surgery or catheterization are both necessary for stent insertion. When utilizing a catheter, it is sometimes essential to start with a stent that has a smaller starting size than just the arterial it is intended to remain open to implant the stent. Balloon angioplasty is a method used to do this. The catheter used in this method has a gelatinous blob attached to the end. A mesh stent encircles this balloon. The balloon once the stent is in place in the artery, expands its diameter and moves it there. The balloon is inflated and withdrawn with both the catheter after the artery has been opened and is keeping the stents in position (Ho et al., 2013). Involved in this process would be a more complicated technique of catheterization that may eliminate atherosclerosis plaques. Polishing the plaque, stealing away sections of a plaque, employing a rotating device which the ability to control the plaque (similar to a rotating sander) and even lasers atherectomy utilizing modified catheters are all options for atherectomy (Deb et al., 2016).

5.6.4 Other fields of CVD research The aforementioned disciplines are on the medical edge of the CVD study range. Study into arteriosclerosis as well as the science underneath atherosclerotic plaques; pharmaceutical research into relieving inflammation of CVD (including such statin drugs investigation and anti-thrombotic research); image analysis methods that enable a more accurate view of the brain’s actions in vivo; involved in research through into biological causes of CVD; and stem cell into regenerating compromised cardiomyocytes are all examples of basic science research. There’s also a lot of study on CVD screening methods (including phenotypical screening), CVD risk factor detection and mitigation, delivering services research, and CVD policy analysis (Levy & Moskowitz, 1982). Cardiovascular disease seems to be a vast arena upon which to conduct research, and most of the fundamental scientific research pertinent to CVD comes from other disciplines. The deciphering of the genetic code is an excellent illustration of this. Each year, the American Heart Association produces a list of the “Top 10 Scientific Developments in CVD,” and the

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genetic code was indeed the top breakthrough in 2000, even though it had nothing to do with CVD research. This demonstrates how difficult it is to describe CVD research, and also that the examples provided above are just a sampling of the fields in which CVD research is conducted (Jaganathan et al., 2014).

5.7 HIGH PROFILE RESEARCH One method to identify what comprises advanced scientific research is to examine publications and references that come from certain articles. It’s been argued in the past that researchers and doctors are biased against pragmatic medical science since their patterns of inquiry are constantly changing in comparison to fundamental researchers. The initial Project Retrosight effort will include a bibliometric evaluation of the cardiovascular research field with an emphasis on studies from genuine case countries. The remainder of this section gives an overview of the different types of data that were utilized in previous bibliometric assessments of CVD studies, but the current citation study would provide a more thorough review (Buck et al., 2019). The Wellcome Trust examined biomedical scientific publications including their dissemination in 1998. 56 This involved examining how publications within Science Citation (SCI) were distributed among various research topics, nations, and donors. Cardiology publications accounted for 11% of all papers published in biomedical. The bulk of both the cardiology publications was written by researchers in the United States. The United Kingdom contributed 9% of the total, Canada 5%, and Australia 2%. (statistics for New Zealand are not comprised in the Wellcome education). Even if only looking at clinical studies on cardiovascular disease, there is now more research into CVD issues than any other, from who data57 (Figure 5.7) (Kasprowicz et al., 1990). The journal “The Scientist” presented a bibliometric study of the top publications (depending on citation) released throughout all science from 2003 to 2005, 1995 to 2005, as well as all-time in 2005. CVD studies were characterized by two publications in the last two years, and by two documents in the last 10 years; nevertheless, this was not mentioned in an all-list (though the mainstream of papers in the all-time list was operational) (Blakely et al., 2017).

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Figure 5.7. The number of worldwide clinical studies in chosen biomedical topics that have been reported in Medline. Source: https://www.mdpi.com/2076-393X/8/3/474/htm

5.8 FUTURE RESEARCH AGENDA Researchers often talk about the direction of CVD studies. Several articles and talks on the future course of CVD studies were especially prevalent around the turn of the last century (Morillo et al., 2003). In 1997, the Shattuck Lecture examined the state of cardiology just at the start of the millennium and outlined potential areas for future research advances in identifying potential risk factors (such as estrogen insufficiency in postmenopausal women); improving cardiac imagery; comprehending the molecular mechanism of CVD; transgenesis experimenting for CVD investigation; and gene delivery (Ricciardi et al., 2020). Claude Lenfant, a retired administrator of the Nationwide Heart, Lung, and Blood Research centre in the US, discussed several of the fundamental biological technological developments that will help cardiovascular investigations (in specific heart problems) in the long term in an opinion piece published in Circulation Investigation in the the 2001. Naturally, heredity, molecular genetics, and genomes are mentioned as potentially significant fields for CVD future research. Nevertheless, Lenfant contends that comprehending pathogenic mechanisms just at the cell level will depend

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on the next step after deciphering the genome: determining the structure of human proteomics (Hughes et al., 2018). He further discussed how improvements in experimental therapeutics and molecular genetics might assist transplantation therapy by lowering the likelihood of immune response rejection by the host (for instance, in the context of cellular therapy inside a CVD patient). This may even imply somatic embryogenesis at its most severe. Additionally, imaging is referenced, albeit in a more hypothetical way. Lenfant speaks about the potential for cellular imaging, particularly concerning the use of PET visualization to spot gene activity in cardiomyocytes (Herder & Roden, 2022). The 2001 book “Prospects for Cardiac Study” by Lefkowitz and Willerson echoes these research themes. 64 They point to increased risk as the primary problem, contending that they would only contribute to about half of all instances of heart disease. They utilize the fundamental biological advancements determined by Lenfant to identify future CVD research topics, although their suggestions are much more clinical than either Lenfant. The application of molecular genetics innovations to comprehend the cellular mechanisms behind plaque development in atherosclerosis is one instance of this. This future of healthcare, however, is mostly driven by researchers rather than by diseases. It will be more crucial than ever to design research topics to address issues specific to poor nations, where the bulk of CVD happens (Dickson et al., 2008). The WHO’s predictions for CVD studies in their Atlas of Heart Disease are arguably the most exciting ones. The WHO identifies possible improvements in Research and innovation and care in this document (which will rely on R&D advances). For instance, they forecast that by 2020, a vaccination that shuts off nicotine receptors was perhaps created (cutting the physical addictiveness of cigarettes) (Buck et al., 2013). Additionally, they state that by 2020, a variety of specific genes will be used for cardiovascular disease security checks, transgenic organisms (the organ removes of organ transplants into living beings) will be feasible due to advances in our knowledge of tissue rejection, and nanomaterials will enable the the the intra-artery cardiovascular disease repair (Bruk-Lee et al., 2013).

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REFERENCES 1.

Afilalo, J., Therrien, J., Pilote, L., Ionescu-Ittu, R., Martucci, G., & Marelli, A. J. (2011). Geriatric congenital heart disease: burden of disease and predictors of mortality. Journal of the American College of Cardiology, 58(14), 1509-1515. 2. Anderson, K. M., Odell, P. M., Wilson, P. W., & Kannel, W. B. (1991). Cardiovascular disease risk profiles. American heart journal,  121(1), 293-298. 3. Balakrishnan, K., Dey, S., Gupta, T., Dhaliwal, R. S., Brauer, M., Cohen, A. J., ... & Dandona, L. (2019). The impact of air pollution on deaths, disease burden, and life expectancy across the states of India: the Global Burden of Disease Study 2017. The Lancet Planetary Health, 3(1), e26-e39. 4. Belchi, F., Pirashvili, M., Conway, J., Bennett, M., Djukanovic, R., & Brodzki, J. (2018). Lung topology characteristics in patients with chronic obstructive pulmonary disease. Scientific reports, 8(1), 1-12. 5. Berends, A. L., de Groot, C. J., Sijbrands, E. J., Sie, M. P., Benneheij, S. H., Pal, R., ... & Steegers, E. A. (2008). Shared constitutional risks for maternal vascular-related pregnancy complications and future cardiovascular disease. Hypertension, 51(4), 1034-1041. 6. Blakely, T., Disney, G., Atkinson, J., Teng, A., & Mackenbach, J. P. (2017). A typology for charting socioeconomic mortality gradients. Epidemiology, 28(4), 594-603. 7. Bompadre, O., & Andrey, G. (2019). Chromatin topology in development and disease. Current opinion in genetics & development, 55, 32-38. 8. Bradshaw, D., Groenewald, P., Laubscher, R., Nannan, N., Nojilana, B., Norman, R., ... & Johnson, L. (2003). Initial burden of disease estimates for South Africa, 2000. South African Medical Journal, 93(9), 682-688. 9. Bruk-Lee, V., Nixon, A. E., & Spector, P. E. (2013). An expanded typology of conflict at work: Task, relationship and non-task organizational conflict as social stressors. Work & Stress, 27(4), 339350. 10. Buck, H. G., Hupcey, J., Juárez-Vela, R., Vellone, E., & Riegel, B. (2019). Heart failure care dyadic typology: initial conceptualization, advances in thinking, and future directions of a clinically relevant

140

11.

12.

13.

14.

15. 16.

17. 18. 19.

20.

21.

RNA and Life Threatening Diseases

classification system.  The Journal of cardiovascular nursing,  34(2), 159. Buck, H. G., Kitko, L., & Hupcey, J. E. (2013). Dyadic heart failure care types: qualitative evidence for a novel typology. The Journal of cardiovascular nursing, 28(6), E37. Chae, H., Lyoo, I. K., Lee, S. J., Cho, S., Bae, H., Hong, M., & Shin, M. (2003). An alternative way to individualized medicine: psychological and physical traits of Sasang typology. The Journal of Alternative & Complementary Medicine, 9(4), 519-528. Deb, S., Austin, P. C., Tu, J. V., Ko, D. T., Mazer, C. D., Kiss, A., & Fremes, S. E. (2016). A review of propensity-score methods and their use in cardiovascular research. Canadian Journal of Cardiology, 32(2), 259-265. Dickson, V. V., Deatrick, J. A., & Riegel, B. (2008). A typology of heart failure self-care management in non-elders. European Journal of Cardiovascular Nursing, 7(3), 171-181. Dorman, C. J., & Corcoran, C. P. (2009). Bacterial DNA topology and infectious disease. Nucleic Acids Research, 37(3), 672-678. Ezzati, M., Lopez, A. D., Rodgers, A., Vander Hoorn, S., Murray, C. J., & Comparative Risk Assessment Collaborating Group. (2002). Selected major risk factors and global and regional burden of disease. the lancet, 360(9343), 1347-1360. Forrest, C. B. (2009). A typology of specialists’ clinical roles. Arch Intern Med, 169(11), 1062-1068. Gwatkin, D. R., Guillot, M., & Heuveline, P. (1999). The burden of disease among the global poor. The Lancet, 354(9178), 586-589. Harrington, D. L., Rubinov, M., Durgerian, S., Mourany, L., Reece, C., Koenig, K., ... & Rao, S. M. (2015). Network topology and functional connectivity disturbances precede the onset of Huntington’s disease. Brain, 138(8), 2332-2346. Hauspurg, A., Ying, W., Hubel, C. A., Michos, E. D., & Ouyang, P. (2018). Adverse pregnancy outcomes and future maternal cardiovascular disease. Clinical cardiology, 41(2), 239-246. Heidenreich, P. A., Trogdon, J. G., Khavjou, O. A., Butler, J., Dracup, K., Ezekowitz, M. D., ... & Woo, Y. J. (2011). Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation, 123(8), 933-944.

Cardiovascular Disease

141

22. Hennekens, C. H. (1998). Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation, 97(11), 1095-1102. 23. Herder, C., & Roden, M. (2022). A novel diabetes typology: Towards precision diabetology from pathogenesis to treatment. Diabetologia, 1-13. 24. Ho, E., Galougahi, K. K., Liu, C. C., Bhindi, R., & Figtree, G. A. (2013). Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox biology, 1(1), 483-491. 25. Hughes, B. M., Lü, W., & Howard, S. (2018). Cardiovascular stress-response adaptation: Conceptual basis, empirical findings, and implications for disease processes. International Journal of Psychophysiology, 131, 4-12. 26. Hughes, H. C. (1986). Swine in cardiovascular research. Laboratory animal science, 36(4), 348-350. 27. Jaganathan, S. K., Supriyanto, E., Murugesan, S., Balaji, A., & Asokan, M. K. (2014). Biomaterials in cardiovascular research: applications and clinical implications. BioMed research international, 2014, (Vol. 1, pp. 4-8). 28. Jones, D. S., Podolsky, S. H., & Greene, J. A. (2012). The burden of disease and the changing task of medicine. New England Journal of Medicine, 366(25), 2333-2338. 29. Kasprowicz, A. L., Manuck, S. B., Malkoff, S. B., & Krantz, D. S. (1990). Individual differences in behaviorally evoked cardiovascular response: Temporal stability and hemodynamic patterning. Psychophysiology, 27(6), 605-619. 30. Lee, D. S., Park, J., Kay, K. A., Christakis, N. A., Oltvai, Z. N., & Barabási, A. L. (2008). The implications of human metabolic network topology for disease comorbidity. Proceedings of the National Academy of Sciences, 105(29), 9880-9885. 31. Lefkowitz, R. J., & Willerson, J. T. (2001). Prospects for cardiovascular research. Jama, 285(5), 581-587. 32. Levy, R. I., & Moskowitz, J. (1982). Cardiovascular research: decades of progress, a decade of promise. Science, 217(4555), 121-129. 33. Lopez, A. D., & Mathers, C. D. (2006). Measuring the global burden of disease and epidemiological transitions: 2002–2030. Annals of Tropical Medicine & Parasitology, 100(5-6), 481-499.

142

RNA and Life Threatening Diseases

34. Lopez, A. D., & Murray, C. C. (1998). The global burden of disease, 1990–2020. Nature medicine, 4(11), 1241-1243. 35. Lopez, A. D., Mathers, C. D., Ezzati, M., Jamison, D. T., & Murray, C. J. (2006). Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. The lancet, 367(9524), 1747-1757. 36. Lopez, A. D., Mathers, C. D., Ezzati, M., Jamison, D. T., & Murray, C. J. (2006). Measuring the global burden of disease and risk factors, 1990–2001. Global burden of disease and risk factors, 1, 1-14. 37. Lv, J. C., & Zhang, L. X. (2019). Prevalence and disease burden of chronic kidney disease. Renal Fibrosis: Mechanisms and Therapies, Vol. 1, 3-15. 38. Magnusson, M., Lewis, G. D., Ericson, U., Orho-Melander, M., Hedblad, B., Engström, G., ... & Melander, O. (2013). A diabetes-predictive amino acid score and future cardiovascular disease. European heart journal, 34(26), 1982-1989. 39. Marceau, V., Noël, P. A., Hébert-Dufresne, L., Allard, A., & Dubé, L. J. (2010). Adaptive networks: Coevolution of disease and topology. Physical Review E, 82(3), 036116. 40. Mathers, C. D., & Loncar, D. (2006). Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine, 3(11), e442. 41. Mathers, C. D., Stevenson, C. E., Vos, E. T., & Begg, S. J. (2000). The Australian Burden of Disease Study: measuring the loss of health from diseases, injuries and risk factors. Medical Journal of Australia, 172(12), 592-596. 42. Mathers, C. D., Vos, E. T., Stevenson, C. E., & Begg, S. J. (2001). The burden of disease and injury in Australia. Bulletin of the World Health Organization, 79, 1076-1084. 43. Matsuzawa, Y. (2008). The role of fat topology in the risk of disease. International journal of obesity, 32(7), S83-S92. 44. Mensah, G. A., & Brown, D. W. (2007). An overview of cardiovascular disease burden in the United States. Health affairs, 26(1), 38-48. 45. Meschi, S. S., Farghadan, A., & Arzani, A. (2021). Flow topology and targeted drug delivery in cardiovascular disease. Journal of Biomechanics, 119, 110307. 46. Michaud, C. M., Murray, C. J., & Bloom, B. R. (2001). Burden of disease—implications for future research. Jama, 285(5), 535-539.

Cardiovascular Disease

143

47. Miller, I. F., Becker, A. D., Grenfell, B. T., & Metcalf, C. J. E. (2020). Disease and healthcare burden of COVID-19 in the United States. Nature Medicine, 26(8), 1212-1217. 48. Molinari, N. A. M., Ortega-Sanchez, I. R., Messonnier, M. L., Thompson, W. W., Wortley, P. M., Weintraub, E., & Bridges, C. B. (2007). The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine, 25(27), 5086-5096. 49. Morillo, F., Bordons, M., & Gómez, I. (2003). Interdisciplinarity in science: A tentative typology of disciplines and research areas. Journal of the American Society for Information Science and technology, 54(13), 1237-1249. 50. Morillo, F., Bordons, M., & Gómez, I. (2003). Interdisciplinarity in science: A tentative typology of disciplines and research areas. Journal of the American Society for Information Science and technology, 54(13), 1237-1249. 51. Murray, C. J., & Lopez, A. D. (2013). Measuring the global burden of disease. New England Journal of Medicine, 369(5), 448-457. 52. Must, A., Spadano, J., Coakley, E. H., Field, A. E., Colditz, G., & Dietz, W. H. (1999). The disease burden associated with overweight and obesity. Jama, 282(16), 1523-1529. 53. Nabel, E. G. (2003). Cardiovascular disease. New England Journal of Medicine, 349(1), 60-72. 54. Olde Dubbelink, K. T., Hillebrand, A., Stoffers, D., Deijen, J. B., Twisk, J. W., Stam, C. J., & Berendse, H. W. (2014). Disrupted brain network topology in Parkinson’s disease: a longitudinal magnetoencephalography study. Brain, 137(1), 197-207. 55. Oliver-Williams, C. T., Heydon, E. E., Smith, G. C., & Wood, A. M. (2013). Miscarriage and future maternal cardiovascular disease: a systematic review and meta-analysis. Heart, 99(22), 1636-1644. 56. Pachauri, D., Hinrichs, C., Chung, M. K., Johnson, S. C., & Singh, V. (2011). Topology-based kernels with application to inference problems in Alzheimer’s disease. IEEE transactions on medical imaging, 30(10), 1760-1770. 57. Pereira, J. B., Aarsland, D., Ginestet, C. E., Lebedev, A. V., Wahlund, L. O., Simmons, A., ... & Westman, E. (2015). Aberrant cerebral network topology and mild cognitive impairment in early Parkinson’s disease. Human brain mapping, 36(8), 2980-2995.

144

RNA and Life Threatening Diseases

58. Pereira, J. B., Mijalkov, M., Kakaei, E., Mecocci, P., Vellas, B., Tsolaki, M., ... & Westman, E. (2016). Disrupted network topology in patients with stable and progressive mild cognitive impairment and Alzheimer’s disease. Cerebral Cortex, 26(8), 3476-3493. 59. Plass, D., Vos, T., Hornberg, C., Scheidt-Nave, C., Zeeb, H., & Krämer, A. (2014). Trends in disease burden in Germany: results, implications and limitations of the Global Burden of Disease study. Deutsches Ärzteblatt International, 111(38), 629. 60. Prince, M. J., Wu, F., Guo, Y., Robledo, L. M. G., O’Donnell, M., Sullivan, R., & Yusuf, S. (2015). The burden of disease in older people and implications for health policy and practice. The Lancet, 385(9967), 549-562. 61. Prüss, A., Kay, D., Fewtrell, L., & Bartram, J. (2002). Estimating the burden of disease from water, sanitation, and hygiene at a global level. Environmental health perspectives, 110(5), 537-542. 62. Prüss-Üstün, A., & Corvalán, C. (2007). How much disease burden can be prevented by environmental interventions?. Epidemiology, 18(1), 167-178. 63. Ramadan, E., Alinsaif, S., & Hassan, M. R. (2016). Network topology measures for identifying disease-gene association in breast cancer. BMC bioinformatics, 17(7), 473-480. 64. Raskob, G. E., Angchaisuksiri, P., Blanco, A. N., Buller, H., Gallus, A., Hunt, B. J., ... & Weitz, J. I. (2014). Thrombosis: a major contributor to global disease burden. Arteriosclerosis, thrombosis, and vascular biology, 34(11), 2363-2371. 65. Rehm, J., Baliunas, D., Borges, G. L., Graham, K., Irving, H., Kehoe, T., ... & Taylor, B. (2010). The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction, 105(5), 817-843. 66. Rehm, J., Room, R., Monteiro, M., Gmel, G., Graham, K., Rehn, N., ... & Jernigan, D. (2003). Alcohol as a risk factor for global burden of disease. European addiction research, 9(4), 157-164. 67. Ricciardi, C., Edmunds, K. J., Recenti, M., Sigurdsson, S., Gudnason, V., Carraro, U., & Gargiulo, P. (2020). Assessing cardiovascular risks from a mid-thigh CT image: a tree-based machine learning approach using radiodensitometric distributions. Scientific reports, 10(1), 1-13.

Cardiovascular Disease

145

68. Shirley, M. D., & Rushton, S. P. (2005). The impacts of network topology on disease spread. Ecological Complexity, 2(3), 287-299. 69. Solomon, C. G., Hu, F. B., Dunaif, A., Rich-Edwards, J. E., Stampfer, M. J., Willett, W. C., ... & Manson, J. E. (2002). Menstrual cycle irregularity and risk for future cardiovascular disease. The Journal of Clinical Endocrinology & Metabolism, 87(5), 2013-2017. 70. Stewart, B. W. K. P., Khanduri, P., McCord, C., Ohene-Yeboah, M., Uranues, S., Vega Rivera, F., & Mock, C. (2014). Global disease burden of conditions requiring emergency surgery. Journal of British Surgery, 101(1), e9-e22. 71. Verhaar, M. C., Stroes, E., & Rabelink, T. J. (2002). Folates and cardiovascular disease. Arteriosclerosis, thrombosis, and vascular biology, 22(1), 6-13. 72. Wasserheit, J. N., & Aral, S. O. (1996). The dynamic topology of sexually transmitted disease epidemics: implications for prevention strategies. Journal of Infectious Diseases, 174(Supplement_2), S201-S213, (Vol. 1, pp. 4-6).

CHAPTER

6

NEUROLOGICAL DISORDERS

CONTENTS 6.1 Introduction...................................................................................... 148 6.2 A Disease of Alzheimer and Other Dementias.................................. 150 6.3 Epilepsy............................................................................................ 155 References.............................................................................................. 160

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6.1 INTRODUCTION Based on which nations and institutions have started a program of disease control, mortality figures have traditionally been considered the primary indicator of the severity of diseases by policymakers and academics. Nonetheless, relying solely on mortality data understates the pain brought on by illnesses that may not be fatal but significantly impair life. This area includes a wide variety of neurological and psychiatric disorders. Long-term carelessness of neurological illnesses has been exacerbated by the omission of certain of them from lists of the top causes of mortality. Numerous neurological disorders show up as the major reasons for suffering globally when the comparative importance of diseases is judged by time spent with impairment instead of by mortality (Rajkumar et al., 1997).

Figure 6.1. METHODS and associations regarding neurological disorders. Source: https://www.intechopen.com/chapters/766045

According to WHO data, brain and mental illnesses establish a significant and growing source of morbidity. The size and weight of psychiatric, neurological, and behavioral problems are enormous, affecting about 451 million people worldwide. As per the Global Burden of Disease Report, neurological and mental illnesses account for 32.8 percent of years spent with disability and 12.9 percent of DALYs (disability-adjusted life years), accounting for 4 of the 6 top reasons for years spent with disability (Mathers et al., 2003).

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Figure 6.2. Cataloging of neurological disorders. Source: https://www.researchgate.net/figure/Classification-of-neurologicaldisorders_fig1_3248233635

Sadly, the prevalence of these illnesses in developing nations is usually ignored. In addition, the consequence imposed by these chronic neurological disorders is likely to be especially catastrophic in disadvantaged communities. It is anticipated that the main indicators of the influence on the poor, such as the failure of decent jobs and the resulting loss of family earnings, the need for providing care, with additional possible salary loss, the expense of medications, and the necessity for other health services, will be pretty devastating for those with limited funds. Human rights abuses, ostracization, and inequality are regularly experienced by persons afflicted with these disorders, in addition to the associated medical expenses. Stigmatization and inequality further restrict the access of patients to therapy (Coleman et al., 2004). Thus, emerging nations must pay particular attention to these illnesses. This chapter discusses epilepsy, dementias like Alzheimer’s, and various types of dementia. According to high prevalence, sizable numbers of untreated patients, and the provision of free yet efficient therapies that may be used on a wide scale via primary care, these disorders are existing or emergent public health challenges in developing nations. Regrettably, there are very little trustworthy population-centered data on the prevalence of these and other neurological illnesses from underdeveloped nations. Due to challenges in proposing evidence-based therapies in underdeveloped

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nations, some additional significant neurological diseases with substantial morbidity, like headache, aren’t mentioned.

6.2 A DISEASE OF ALZHEIMER AND OTHER DEMENTIAS Dementia is defined as a deterioration in mental functioning and other brain abilities serious enough to hinder  social or vocational functioning. AD is the most frequent reason for dementia amongst adults aged 66 and older globally, trailed by vascular dementia, mixed dementia (AD plus vascular dementia), and dementia triggered by basic medical problems (Podcasy & Epperson, 2022; Villemagne et al., 2011). Even though differentiating Alzheimer’s disease from other types of dementia is critical for therapy with acetylcholinesterase signals, the impact of all dementias is identical. Though this chapter focuses mostly on Alzheimer’s disease, the significance of curable dementias in developing nations is critical because they can minimize the burden on families (Ou et al., 2012; ).

Figure 6.3. Disease of Alzheimer. Source: https://en.wikipedia.org/wiki/File:Brain-ALZH.png

6.2.1 Occurrence and Rate of Incidence Over one hundred occurrence of researches of AD, as well as other dementias, have indeed been identified globally. Typically, the occurrence of dementia doubles with each 5-year advancing age, from 3 % at age 71 to 20-30%  at

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age 84 (Jorm et al., 2000). According to studies conducted in developing nations, the occurrence of dementia ranges from 0.84-3.60 % (Chandra et al., 1998; Hendrie et al., 1995)Multiple types of research have stated the prevalence of Alzheimer’s disease as well as other dementias in the US and Europe (Jorm & Jolley, 1998). Extremely low age-particular incidence rates of AD, as well as other dementias, have been observed in poor nations in comparison to occurrence in industrialized countries ( Hendrie et al., 2001; Chandra et al., 2001). A contrast of data between advanced and developing nations highlights several significant issues. The stated variations in AD as well as  other dementia occurrence among nations may be partially attributable to methodological discrepancies or may represent real differences brought on by real changes in diet, schooling, mortality rates, sociocultural variables, and some other risks. The low incidence recorded in India, and Nigeria, suggests that environmental factors or relationships between genes and the environment may play a role in the development of AD. In China, however, multi-infarct dementia is much more prevalent than basic degenerative dementia, which further demonstrates that risks differ between nations.

6.2.2 Hazard and Defensive Factors and Survivorship Three distinct genes (PS1, PS2, and APP) have been related to early-onset, familial Alzheimer’s disease. One more gene (APO E4) is linked to lateonset, non-familial instances (Jorm et al., 2000). Various genes have been suggested but not proven in major research. Other risks described in the texts comprise growing age, a positive family background of dementia, female gender (though this factor is debatable), a lower education level, a variety of medical disorders, and exposure to environmental variables like AL (aluminum) and organic solvents. Literature-reported protective variables comprise a greater education level, a particular gene (APO E2), the consumption of antioxidants, and the utilization of certain anti-inflammatory drugs (Jorm and Henderson 2000). The usage of estrogen pills was thought to be a protective measure against Alzheimer’s disease (Henderson, 1997). A new study of women taking a mixture of estrogen and progesterone revealed that they had twice the chances of contracting dementia compared to women receiving a placebo (Shumaker et al., 2003). The median lifespan after the beginning of dementia symptoms has been observed in studies from wealthy nations to range from 5.1 years

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to 9.2 years (Walsh et al., 1990). For all demented people and those with AD, the observed median survival in underdeveloped nations was 3.2 and 2.6 years (Chandra et al., 1998).

6.2.3 Burden of Disease Predictions of the disease burden of Alzheimer’s disease and some other dementias comprise vascular dementia, nonspecific dementias, and perhaps other unclassified degenerative nervous system illnesses. Mathers and colleagues (2003) suggest that DALYs for all dementias total 17,109,000, with females bearing nearly double the burden (11,017,000) as males (6,092,000). Since dementia is a disease of the elderly, the incidence of dementia is often substantially greater in high-income nations, where the average lifespan is higher, identification is improved, and special healthcare leads to extended longevity. Nonetheless, take note of the comparatively high burden in South Asia, the Pacific, and East Asia in comparison to their rate of economic growth (table 6.1). In developing nations, the majority of dementia care is given at home by family members, with spouses (35 percent) and children (43 percent) serving as the primary caregivers. Typically, women are the primary caretakers in both industrialized and developing nations (Pham et al., 2000). According to studies conducted in industrialized nations, the psychological health of caregivers is a crucial determinant in individuals’ admittance to nursing homes or inhabited care facilities (Levin et al., 1994). When calculating the total expense of dementia care, it is important to underline the value of minimizing the load on caregivers. Social segregation, mental stress, and a high level of depression can all be brought on by providing care (Buck et al., 1997). Yet, it is necessary to standardize the methods for calculating the expenses of informal care.

6.2.4 Interventions Although there is currently no treatment for AD, several interventions can help patients and caregivers with their symptoms. Population-oriented Interventions. There is no significant proof that every type of population-oriented intervention may avoid AD or slow the trajectory of cognitive deterioration in an old life.

17,108

6,223

2,325

72,024

Epilepsy

PD

Cerebrovascular disease

Both sexes

Global total

AD and other dementias

Condition

1,202

2,922

11,016

Females

35,482 36,542

1,124

3,301

6,092

Males

25,832

435

1,303

4,110

East Asia and the Pacific

12,616

228

354

1,612

3,936

90

737

1215

1,948

81

248

292

13,184

303

1,741

1,955

Europe and Latin America Middle East South Central Asia and the and Asia Caribbean North Africa

Table 6.1. Disability-Accustomed Life Span by Region and Cause, 2001

5,125

100

1,373

450

SubSaharan Africa

9,354

1,086

464

7,468

Highincome countries

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Conversely, accumulating inference data recommends that decreasing the hazard of brain trauma in childhood, for instance, by regulating the usage of seat belts and crash helmets, might help avoid dementia in later years (Gentleman et al., 1993). Personal Interventions. Patients with Alzheimer’s disease have decreased amounts of the neurotransmitter acetylcholine in the brain. Inhibitors of acetylcholinesterase, the essential enzyme for metabolizing acetylcholine, raise acetylcholine levels in the brain. Experimental trials have proven that acetylcholinesterase inhibitors provide cognitive performance advantages, as a minimum in the near term, for people with mild to moderate AD (Foster & Viswanathan, 1996). Despite this advantage for patients, the practical advantages of acetylcholinesterase inhibitor therapy are primarily due to the reduced strain on caregivers. Acetylcholinesterase inhibitors haven’t yet been demonstrated to be effective for treating other dementias. Family members who are caring for patients can experience significant stress due to the behavioral and cognitive signs of dementia. It has been demonstrated that educating family caregivers in interactive management strategies, such as problem-solving, cognitive training, and reality orientation, lowers dementia patients’ levels of restlessness and anxiety (Brodaty & Gresham, 1989; Haupt et al., 2000). Caregiver anxiety has been demonstrated to decrease with the use of modest dosages of antipsychotic drugs, which relax the patient and lessen symptoms like hostility and roaming, but these gains haven’t been measured (Melzer et al., 2004). Caregiver teaching, coaching and encouragement for caregivers, and behavioral and cognitive family therapies have all demonstrated positive outcomes in combating stress and anxiety among caregivers (Datta et al., 2000). The need for professional training, which makes such tactics less appropriate for underdeveloped nations, is one of the constraints to their execution. The difficulty for poor countries is to create culturally acceptable therapies that can be implemented using current resources, like assisting families in their roles as carers. The treatment of the underlying condition and cardiovascular disease risk indicators can aid in the prevention of chronic cerebrovascular disease that might contribute to multi-infarct dementia. Other disorders, like hypothyroidism or vitamin B12 insufficiency, that may cause or exacerbate dementia are easily treatable, and the expenses of therapy are significantly less compared to expenditures of dementia care.

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In Western nations, competent, long-term institutional care is the standard of care for people with mild to severe dementia. These long-term care facilities don’t exist in poor nations, and even if they did, they would be very costly and out of the price range of the majority of patients and family members. As a result, home care must be the foundation of the care model in emerging economies, combined with assistance and coaching for family carers. Interventions that must be avoided include the utilization of various drugs, which can be harmful in older groups, especially untested medications like cerebral activators and neurotropic agents. Furthermore, in several underdeveloped nations, dementia is still associated with madness, and patients are occasionally referred to traditional practitioners. Community education can help to eliminate these practices.

6.3 EPILEPSY Epilepsy is a chronic brain illness defined by at least 2 unprovoked convulsions. Seizures are distinct events resulting from transitory, aberrant, hypersynchronous neural activity. Seizures can happen in nearby temporal conjunction with a range of acute medical and neurological conditions, like acute stroke, sepsis, and alcohol abstinence. Conversely, the great majority of seizures don’t have an obvious cause.

Figure 6.4. Kinds of epilepsy. Source: https://epilepsyqueensland.com.au/about-epilepsy-epilepsyqueensland/seizure-types/what-are-the-different-kinds-of-seizures/

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Generally, there are 3 kinds of epilepsy: cryptogenic epilepsy, for which there is unclear proof of an etiological factor, symptomatic epilepsy, and idiopathic epilepsy, which is considered to have a genetic basis (for instance, primary generalized childhood-onset exclusion epilepsy). Symptomatic epilepsy is influenced by a recognized central nervous system injuries or illness, like infection, traumatic brain injury, stroke, or cerebral dysgenesis. About 71 % of instances of epilepsy are idiopathic and cryptogenic, with the rest 29 % being symptomatic.

6.3.1 Occurrence, Rate of Incidence, Remission, and Death The worldwide recognized approximation of the occurrence of active epilepsy is 5-8 per one thousand population, however, African and Latin American researchers claim at least double the occurrence reported elsewhere (Leonardi & Ustun, 2002). Epilepsy affects roughly 42 out of every 100 thousand people in advanced nations (Kotsopoulos and others 2002). Epilepsy incidence rates are greater in poorer nations, with a median of 70 cases per 100 thousand people (Kotsopoulos et al., 2002). Cockerell and colleagues (1997) state that after 9 years of follow-up of patients treated by health personnel in U.K, 86 % of epilepsy patients had accomplished a 3-year remission, and 68 % had obtained a 5-year remission. Therefore, data from affluent countries imply that most individuals treated for seizures have a positive prognosis. Though many persons with newonset seizures don’t receive therapy in poor nations, some individuals go into impulsive remission through without therapy (Mani, 1993). Consequently, population-centered studies haven’t yet been able to capture the real remission rate in poor nations. Epilepsy sufferers face a 2 to 3 times greater chance of dying before their time as compared to the general public. Further mortality comes from accidents and suicide moreover to unexpected mysterious death, which affects up to one in a hundred people with serious refractory epilepsy. In most instances, the precise reason for the elevated risk is unknown.

6.3.2 Risk Factors A detailed history of epilepsy has been identified as the factor for idiopathic epilepsy. Prenatal or perinatal reasons have been identified as risk factors for symptomatic epilepsy (obstetric problems, prematurity, low weight at birth, neonatal asphyxia). According to new research, the impact of obstetric

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problems or neonatal hypoxia might have been overstated. Premature birth, low weight at birth, and neonatal convulsions might be risk factors on their own along with indicators of underlying illness. Brain trauma, central nervous system diseases, cerebrovascular illness, brain cancer, and neurodegenerative diseases are some of the other causes. Developmental disabilities aren’t in and of themselves a health risk for epilepsy, but they might be connected with neurological conditions (Casetta et al., 2002; Leone et al., 2002).

6.3.3 Treatment Gap Around fifty million individuals globally suffer from epilepsy, and 80% of them reside in poor nations (WHO 2000). The term treatment gap refers to the discrepancy between the proportion of people with severe epilepsy and those receiving adequate care in a community at a given period. Meinardi et al.(2001) said that 90 % of epilepsy patients in developing nations receive insufficient care. The anxiety of stigmatization, cultural mores, ignorance of the medical aspect of epilepsy, ignorance, economic problems, proximity to medical facilities, a lack of antiepileptic medicines (AEDs), and a lack of prioritizing by health officials are all potential causes of the increased treatment gap (Wang et al., 2003). Patients who reside in remote rural areas, inner-city slums, or who are separated from the majority due to cultural factors might very well experience a treatment gap even in the advanced world.

6.3.4 Faith Healers Many patients with epilepsy seek therapy from spiritualists, to whom they devote enormous quantities of money or in kind for therapy that has no medical benefits. Researchers discover that in Silivri, Turkey, 65 % of 48 patients with epilepsy consulted religious leaders at the beginning or even during the ailment. According to research conducted in rural India, 44 % of children with epilepsy got therapy from traditional healers, while around 32.9 % percent received treatment from both certified and traditional therapists (Pal et al., 2002). Native Americans continue to seek ancient healing rites for epilepsy rather than or in parallel to Western medication.

6.3.5 Patient Compliance Only 56.9% of epileptic patients in research in rural Thailand adhered to their therapy completely, probably as a result of misinterpretation of the

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instructions (47%) forgetfulness (15%), and financial constraints (15%). (Asawavichienjinda et al., 2003). Medical professionals visited a rural African village every 6 months and gave the long-term provision of pharmaceuticals in a struggle to boost compliance; by twenty months, this effort had significantly increased adherence (Kaiser et al., 1998). Desai and others (1998) show how in India access to free care is necessary for compliance. Poor communication between medical professionals and patients has a negative impact on compliance (Gopinath & Becker, 2000).

6.3.6 Burden of Disease The figures for BOD for epilepsy comprise both epilepsy and status epilepticus. Mathers et al(2003) assess the DALYs associated with epilepsy to be 6,222,000, with somewhat greater percentages for males (3,301,000) as compared to females (2,921,000). Numerous risk indicators for epilepsy are associated with a lower degree of economic growth; hence, South Asia and Sub-Saharan Africa bear the greatest burden (Table 6.1). Notable is the allegedly low weight in North Africa and the Middle East, despite the region’s comparatively underdeveloped regions. Epilepsy places a significant financial burden on individuals and their families. It also puts a hidden weight of harassment and discrimination on patients and family members in society, employment, school, and home. The misery of epileptic patients is exacerbated by social exclusion, emotional discomfort, reliance on family, inadequate employment options, and bodily damage.

6.3.7 Interventions There are presently no treatments to avoid idiopathic or cryptogenic epilepsy, although there are several ways to stop secondary seizures.

Population-centered Interventions Better perinatal care provided by skilled birth attendants (especially in rural areas) and measures to prevent serious head injuries (including mandating helmet use for motorcyclists and banning drunk driving) are examples of health policies that can alter health risks for epilepsy and subsequently lower the occurrence and prevalence of the condition. Such infections can be avoided by implementing neurocysticercosis control measures, like installing latrines in rural regions. Though a campaign in Ecuador showed success, mass retreatment for neurocysticercosis hasn’t been proven to be long-lastingly efficacious (Pal et al., 2000).

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According to statistics, 70-80 % of people in the third world live in rural or isolated areas with little access to expert medical care. Approaches must be proposed that include training community-oriented health care clinicians who work in these settings to detect and treat patients with epilepsy. Policies are necessary to guarantee that all epilepsy patients have continued access to affordable and effective drugs like phenobarbital. Campaigns to teach populations about the medical basis of epilepsy and debunk misapprehensions about epilepsy may lessen discrimination and motivate sufferers to seek medical care.

Personal Interventions Researchers, mainly in high-income nations, have examined the efficacy of these AEDs when used alone or in a mixture, as well as the effectiveness of newer and older AEDs in decreasing the occurrence of seizures. These AEDs include lamotrigine, topiramate, and oxcarbazepine. Certain novel AEDs, though not all, might be more well-tolerated in monotherapy and suffer from fewer long-term side effects. Unfortunately, no research has demonstrated a difference in effectiveness between the more recent and older drugs (Aldenkamp et al., 2003). More costly and nearly difficult to obtain for most people living in developing nations are newer drugs. Furthermore, even more, dated AEDs aren’t always accessible, and once they are, the supply is erratic in certain low-income nations. For patients with relapsed epilepsy who are currently using AEDs, novel AEDs are typically advised as supplemental or adjunctive medications for improved seizure control. About 50% of individuals treated with the 1st AED will no longer experience seizures. With a higher than 50% reduction in seizure frequency, between 20-40% of patients who don›t respond to the 1st AED might respond to the addition of a 2nd AED (Schapel et al., 1993).

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REFERENCES 1.

Aldenkamp, A. P., Krom, M. D., & Reijs, R. (2003). Newer antiepileptic drugs and cognitive issues. Epilepsia, 44, 21-29. 2. Asawavichienjinda, T., Sitthi-Amorn, C., & Tanyanont, W. (2003). Compliance with treatment of adult epileptics in a rural district of Thailand. Journal of the medical Association of Thailand= Chotmaihet Thangphaet, 86(1), 46-51. 3. Brodaty, H., & Gresham, M. (1989). Effect of a training programme to reduce stress in carers of patients with dementia. British Medical Journal, 299(6712), 1375-1379. 4. Buck, D., Jacoby, A., Baker, G. A., & Chadwick, D. W. (1997). Factors influencing compliance with antiepileptic drug regimes. Seizure, 6(2), 87-93. 5. Casetta, I., Granieri, E., Fallica, E., la Cecilia, O., Paolino, E., & Manfredini, R. (2002). Patient demographic and clinical features and circadian variation in onset of ischemic stroke. Archives of neurology, 59(1), 48-53. 6. Chandra, R., Dagum, L., Kohr, D., Menon, R., Maydan, D., & McDonald, J. (2001). Parallel programming in OpenMP. Morgan kaufmann, 35(1), 112-130. 7. Chandra, V., Ganguli, M., Pandav, R., Johnston, J., Belle, S., & DeKosky, S. T. (1998). Prevalence of Alzheimer’s disease and other dementias in rural India: the Indo-US study. Neurology, 51(4), 10001008. 8. Coleman, P., Federoff, H., & Kurlan, R. (2004). A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology, 63(7), 1155-1162. 9. Datta, D., Tassou, S. A., & Marriott, D. (2000). Application of neural networks for the prediction of the energy consumption in a supermarket. In Proceedings of the international conference CLIMA (pp. 98-107). 10. Foster, F. D., & Viswanathan, S. (1996). Strategic trading when agents forecast the forecasts of others. The Journal of Finance, 51(4), 14371478. 11. Gentleman, S. M., Graham, D. I., & Roberts, G. W. (1993). Molecular pathology of head trauma: altered βAPP metabolism and the aetiology of Alzheimer’s disease. Progress in brain research, 96, 237-246.

Neurological Disorders

161

12. Gopinath, C., & Becker, T. E. (2000). Communication, procedural justice, and employee attitudes: Relationships under conditions of divestiture. Journal of management, 26(1), 63-83. 13. Haupt, M., Karger, A., & Jänner, M. (2000). Improvement of agitation and anxiety in demented patients after psychoeducative group intervention with their caregivers. International journal of geriatric psychiatry, 15(12), 1125-1129. 14. Henderson, V. (1997). Externalities and industrial development. Journal of urban economics, 42(3), 449-470. 15. Hendrie, H. C., Hall, K. S., Hui, S., Unverzagt, F. W., Yu, C. E., Lahiri, D. K., ... & Schellenberg, G. D. (1995). Apolipoprotein E genotypes and Alzheimer’s disease in a community study of elderly African Americans.  Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 37(1), 118120. 16. Hendrie, H. C., Ogunniyi, A., Hall, K. S., Baiyewu, O., Unverzagt, F. W., Gureje, O., ... & Hui, S. L. (2001). Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. Jama, 285(6), 739-747. 17. Jorm, A. F., & Jolley, D. (1998). The incidence of dementia: a metaanalysis. Neurology, 51(3), 728-733. 18. Jorm, A. F., Christensen, H., Henderson, A. S., Jacomb, P. A., Korten, A. E., & Rodgers, B. (2000). Predicting anxiety and depression from personality: Is there a synergistic effect of neuroticism and extraversion?. Journal of abnormal psychology, 109(1), 145. 19. Kaiser, M. J., Edwards, D. B., Armstrong, P. J., Radford, K., Lough, N. E. L., Flatt, R. P., & Jones, H. D. (1998). Changes in megafaunal benthic communities in different habitats after trawling disturbance. ICES Journal of Marine Science, 55(3), 353-361. 20. Kotsopoulos, I. A., Van Merode, T., Kessels, F. G., De Krom, M. C., & Knottnerus, J. A. (2002). Systematic review and meta‐analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia, 43(11), 1402-1409. 21. Leonardi, M., & Ustun, T. B. (2002). The global burden of epilepsy. Epilepsia, 43, 21-25.

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RNA and Life Threatening Diseases

22. Leone, G., Teofili, L., Voso, M. T., & Lubbert, M. (2002). DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. haematologica, 87(12), 1324-1341. 23. Levin, E., Moriarty, J., Gorbach, P., & Seed, P. (1994). Better for the Break. Ageing and Society, 14(4), 65-478. 24. Mani, M. K. (1993). Chronic renal failure in India. Nephrology Dialysis Transplantation, 8(8), 684-689. 25. Mathers, C. D., Bernard, C., Iburg, K. M., Inoue, M., Ma Fat, D., Shibuya, K., ... & Xu, H. (2003). Global burden of disease in 2002: data sources, methods and results. Geneva: World Health Organization, 54. 26. Meinardi, H., Scott, R. A., Reis, R., & On Behalf Of The Ilae Commission on the Developing World, J. S. (2001). The treatment gap in epilepsy: the current situation and ways forward. Epilepsia, 42(1), 136-149. 27. Melzer, K., Kayser, B., & Pichard, C. (2004). Physical activity: the health benefits outweigh the risks.  Current Opinion in Clinical Nutrition & Metabolic Care, 7(6), 641-647. 28. Ou, Y., Grossman, D. S., Lee, P. P., & Sloan, F. A. (2012). Glaucoma, Alzheimer disease and other dementia: a longitudinal analysis. Ophthalmic epidemiology, 19(5), 285-292. 29. Pal, D. K., Carpio, A., & Sander, J. W. (2000). Neurocysticercosis and epilepsy in developing countries. Journal of Neurology, Neurosurgery & Psychiatry, 68(2), 137-143. 30. Pal, S. K., Talwar, V., & Mitra, P. (2002). Web mining in soft computing framework: Relevance, state of the art and future directions. IEEE transactions on neural networks, 13(5), 1163-1177. 31. Pham, D. L., Xu, C., & Prince, J. L. (2000). A survey of current methods in medical image segmentation. Annual review of biomedical engineering, 2(3), 315-337. 32. Podcasy, J. L., & Epperson, C. N. (2022). Considering sex and gender in Alzheimer disease and other dementias. Dialogues in clinical neuroscience. 33. Rajkumar, S., Kumar, S., & Thara, R. (1997). Prevalence of dementia in a rural setting: a report from India. International Journal of Geriatric Psychiatry, 12(7), 702-707.

Neurological Disorders

163

34. Schapel, G. J., Beran, R. G., Vajda, F. J., Berkovic, S. F., Mashford, M. L., Dunagan, F. M., ... & Davies, G. (1993). Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures.  Journal of Neurology, Neurosurgery & Psychiatry,  56(5), 448-453. 35. Shumaker, D. K., Kuczmarski, E. R., & Goldman, R. D. (2003). The nucleoskeleton: lamins and actin are major players in essential nuclear functions. Current opinion in cell biology, 15(3), 358-366. 36. Villemagne, V. L., Ong, K., Mulligan, R. S., Holl, G., Pejoska, S., Jones, G., ... & Rowe, C. C. (2011). Amyloid imaging with 18F-florbetaben in Alzheimer disease and other dementias. Journal of Nuclear Medicine, 52(8), 1210-1217. 37. Walsh, J. S., Welch, H. G., & Larson, E. B. (1990). Survival of outpatients with Alzheimer-type dementia. Annals of internal medicine,  113(6), 429-434. 38. Wang, H., Ding, Y., Li, X., Yang, L., Zhang, W., & Kang, W. (2003). Fatal aspergillosis in a patient with SARS who was treated with corticosteroids. New England Journal of Medicine, 349(5), 507-508.

CHAPTER

7

DIABETES AND CANCER

CONTENTS 7.1 Introduction...................................................................................... 166 7.2 Cancer Risk is Increased in Diabetic Patients.................................... 167 7.3 Incidence of Liver and Pancreatic Cancer is Increased in Diabetes........................................................................................ 168 7.4 The Role of Hyperinsulinemia .......................................................... 178 7.5 Anti-Diabetic Drugs that May Influence Cancer Risk in Diabetic Patients........................................................................... 183 7.6 Other Factors that May Influence the Risk of Cancer in Diabetes...... 185 References.............................................................................................. 188

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7.1 INTRODUCTION Diabetes mellitus (DM) is a major and developing global health concern linked with serious acute and long-term- term consequences that have a detrimental impact on both the standard of living and lifespan of those afflicted. This number is predicted to increase to 380 million during the next 20 years, from its current level of 250 million (Suh & Kim, 2011). If diabetes is connected with even a slightly enhanced danger of cancer, it might have significant population-level repercussions.

Figure 7.1. Illustration of diabetes and cancer. Source: https://www.aicr.org/resources/blog/many-unaware-diabetes-ups-cancer-risk-how-lifestyle-can-help/

The relationship between diabetes and heart disease has been studied extensively, with the majority of studies, but not all, concluding that DM is linked with an improved incidence of many forms of cancer (Vigneri et al., 2009). Since DM is not a singular illness, but instead a spectrum of metabolic diseases defined by hyperglycemia, most data collected must be reinterpreted (Lee & Chan, 2015). Throughout this scenario, other hormonal and metabolic problems that impact diabetic patients differ based on the form of diabetes. Thus, it is incorrect to see diabetes individuals as a homogenous group. Moreover, many possible confounders connected straight to the illness (obesity, metabolic control, treating medications, food, etc.) and

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exist in diabetic patients may impact the connection between diseases and diabetes (Yeo et al., 2014). Throughout this study, we would examine the existing information about the link between diseases and diabetes, the many features of diabetes that may impact that connection, and the potential procedures related.

Figure 7.2. The defining characteristics of diabetes and cancer, as well as the impacted biological systems. Source: https://www.researchgate.net/figure/Hallmarks-of-diabetes-and-cancer-Representing-the-major-affected-biological-processes_fig1_348624033

7.2 CANCER RISK IS INCREASED IN DIABETIC PATIENTS New studies, as well as meta-analyses, as well as meta-analyses, demonstrate that diabetes people have an increased risk for various solid as well as hematologic malignancies (especially the liver, pancreatic, colon, and kidney, bladder, endometrial, and breast cancers and non-lymphoma). Hodgkin’s (Table 7.1). There is no relationship found between diabetes and other malignancies, however, diabetic persons had a lower risk of prostate cancer (Table 7.1). Taking into account that disease is more prevalent in DM, the favorable link between diabetes as well as disease risk may be slightly understated (Shikata et al., 2013).

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In actuality, diabetes is an undiagnosed condition (3–5% of the population aged has undetected diabetes; Harris et al., 1998), and so the regulator group very generally holds people with diabetes, which will raise the risk of developing cancer in the ‘normal’ group (Noto et al., 2102; DeCensi et al., 2010). Cancer in diabetic people might be promoted by: •

generic processes that enhance cancer start or advancement in either organ since they are attributable to changes (e.g., hyperglycemia, hyperinsulinemia, or medications) that impact all organs; and ii) site-certain methods that influence cancerogenesis in a specific part of the body.

Figure 7.3. Diabetes and disease risk in the traditional paradigm of how diabetes promotes cancer progression. Source: https://www.researchgate.net/figure/Diabetes-and-cancer-risk-In-theclassical-model-of-how-diabetes-propels-cancer-left_fig2_224924912

7.3 INCIDENCE OF LIVER AND PANCREATIC CANCER IS INCREASED IN DIABETES Many meta-analyses show that the biggest link between diabetes as well as elevated risk is really with pancreatic as well as liver failure (Table 7.1), two major organs implicated in the metabolic abnormalities common in diabetes (Eibl et al., 2108). Because of the general portal vein, liver cells are

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subjected to increased insulin levels than other tissues, which is worsened in insulin-resistant hyperinsulinemic type 2 diabetics but not in insulindeficient patients with type 1 diabetes managed with insulin injections (see Fig. 7.1). Because liver function cells are biologically subjected to greater insulin levels than other tissues, it is unclear that insulin’s mitogenic effect is directly implicated in the higher occurrence of liver cancer in diabetes people (Lee et al., 2011). Furthermore, in diabetes individuals who get exogenous insulin injections, the liver is subjected to similar insulin levels as the other tissues. Because most epidemiologic studies show a two- to threefold rise in hepatocellular carcinomas (HCC) in diabetes individuals, additional liverspecific factors must enhance liver cancerogenesis in diabetic patients (Wideroff et al., 1997). Diabetes has been interrogated as a primary potential cause for liver cancer, or if diabetes-related liver disorders are also occupied. Similarly, in diabetic individuals, steatosis as well as cirrhosis, both well-known signs and symptoms of HCC, are more common. Similarly, nonalcoholic fatty liver disease (NAFLD) is quite prevalent in both overweight and hypertension, and it is much more prevalent among older individuals, affecting more than 80% of type 2 diabetic patients. Hepatitis B and C virus (HBV and HCV) infections, which are both common in diabetic people relative to the non-diabetic population, may also encourage HCC in DM (Davila et al., 2005). Table 7.1. Meta-analyses on the relative risk (RR) of cancer in different organs of diabetic patients

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Figure 7.4. (A) Mammary tumor development in four equal groups of mice fed whether a regular diet or a food supplemented with oral glucose, insulin injections, or both (big variations: *P0.05; **P0.01; ***P0.0005(Heuson et al, 1972). (B) Mammary tumor regression after alloxan diabetes induction in 2 categories of matching rats. 6 weeks of observation; P0.001 (Heuson & Legros, 1972). Source: https://erc.bioscientifica.com/view/journals/erc/16/4/1103.xml

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In summary, the increased prevalence of liver cancer in diabetes is widely recognized, and while the specific processes behind this link remain unknown, liver inflammation, hepatocyte damage, and repair are believed to be implicated in the often of HCC amongst diabetic individuals. Most previous research studying the link between diabetes, as well as pancreatic cancer, is likely to be deceptive since they fail to discriminate between or before diabetes (which may promote exocrine stomach cancer) and new-onset diabetes (a possible symptom of pancreatic functional repair due to a still undiagnosed pancreatic cancer (Noy & Bilezikian, 1994). The second circumstance is so common that hyperglycemia and diabetes beyond the age of 45–50 years in a slim person with no high prevalence of diabetes are regarded as adequate to warrant pancreatic screening services (Noy & Bilezikian, 1994). Likewise, elderly persons with new-onset diabetes had a roughly eightfold increased risk of pancreatic cancer over three years than non-diabetic individuals of comparable age and gender (Chari et al., 2005). Diabetes induced by colon cancer seems to be induced by cytokines released by the tumor rather than related to endocrine pancreatic tissue invasion as well as destruction, according to research and clinical findings (Basso et al., 2002; Pannala et al., 2009). This finding is further reinforced by the data that hyperglycemia starts today in pancreatic cancer and is unrelated to tumor volume or phase (Chari et al., 2008; Pannala et al., 2008). Observational data in people who had diabetes at least a year before being diagnosed with or dying from pancreatic cancer found a relative risk (RR) of 2.1 (95 percent confidence interval (CI)Z1.6–2.8). The RR for pancreatic cancer was comparable whenever a similar analysis was performed on just individuals with 5 years of pre-diagnosed diabetes (RRZ2.0; Everhart & Wright 1995). Because all of such data eliminate diabetes caused by pancreatic tumors, the published results support the idea that diabetes is a significant predictor of pancreatic cancer. Pre-diabetes should be regarded as a potential cause of pancreatic cancer. A greater RR with greater glucose tolerance impairment was found in a study that looked at the relationship between post-load glucose levels as well as pancreatic cancers in 35 658 people. After controlling for age, race, smoking cigarettes, as well as body mass index (BMI), the risk climbed from healthy to those with changed slightly glycemia (RRZ1.65) and now to diabetes (RRZ2.15; Gapstur et al., 2000). Whenever individuals who passed away from cancer within the first 5 years following the examination of postload sugar levels were removed, the findings were unchanged, indicating

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that hyperglycemia, as well as diabetes, are possible causes of pancreatic cancer. The biochemical processes behind the diabetes-pancreatic cancer link are unknown. Due to a similar blood supply with nearby insulin-secreting islets, exocrine pancreatic cells, that give birth to the majority of pancreatic tumors, are subject to very increased insulin levels (Williams & Goldfine, 1985). High insulin might serve as a tumor growth promoter in a range of methods (covered later). Furthermore, this method does not explain the increase of pancreatic cancer in insulin-treated diabetic individuals or type 1 diabetes wherein pancreatic cells are not subjected to greater insulin quantities than other tissues (Stevens et al., 2007; Green & Jensen, 1985). Moreover, the analysis in these studies is complicated by an inadequate number of instances collected owing to the form of diabetes (type 1 diabetes represents 10% of all Patients with DM) and age of the patient (pancreatic cancer is rare before age 40).

7.3.1 Increased Incidence of Other Cancers in Diabetes Other organ malignancies are more common in diabetic individuals, which has been attributed to a range of general and local reasons. The number of studies in these instances is lower than in liver and pancreatic cancers, and the improvements in RR are not quite as statistically meaningful ((Yuan et al., 1998). Although, given the frequency of the two illnesses in the general population, the higher risk is functionally significant in many cases. The increasing prevalence and death rates for kidney cancer in diabetic patients have been thought to be due to both possible devices (hyperinsulinemia and fatness) and individual characteristics, primarily hypertension and the common kidney diseases occurring in diabetic patients (Lindblad & Adami, 2002; Chow et al., 2000). Diabetes patients also have a slightly increased risk of bladder cancer. In this scenario, moreover to normal causes such as hyperinsulinemia, an increment incidence of urinary infections is believed to be at work (Zucchetto et al., 2007). Diabetes also increases the chance of malignancies of the female reproductive organs. Diabetes increases the risk of both mammary and endometrial cancer, and so this risk is unrelated to obesity (a very well-known risk for cancer) since it continues even after adjusting epidemiological evidence for this condition. Many biochemical factors, most notably sex hormone imbalances, may be at work. Hyperinsulinemia

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may raise bioactive levels of estrogen by lowering the level of circulating sex hormone-binding globulin but it may also promote androgen production in the ovarian stroma (Kaaks, 1996). Other potential reasons involve delayed menarche, which is more common in type 1 diabetic women, who seem to have a greater prevalence of nulliparity, irregular menstruation, and reproductive issues. Most, though not all, studies link to type 2 diabetes to a higher risk of colorectal adenomas as well as carcinomas (Elwing et al., 2006; Limburg et al., 2006). Either men or women are at higher risk of colon and rectal disease (Larsson et al., 2005). Aside from hyperinsulinemia, postulated reasons involve delayed colon travel time and the higher fecal bile acid levels often reported in diabetes (Stadler et al., 1988). Large prospective cohort studies, as well as case-control studies, have presented a slight rise in non-lymphoma Hodgkin’s in diabetic patients, which might be attributed to immunological dysfunction caused by reduced neutrophil action and anomalies in humoral and cellular defense in diabetes (Mitri et al., 2008).

7.3.2 Decreased Incidence of Prostate Cancer in Diabetes Contrary to the enhanced danger of several kinds of neoplasia, the majority of research indicates that men with diabetes have a decreased risk of prostate cancer. The latest meta-analysis comprising 14 research performed in the pre-PSA era (i.e., before the widespread utilization of prostate antigenspecific testing for prostate; and five extra research performed in the PSA age (and thus, regarding cancer cases previous and lesser cancers) discovered a decreased significantly danger in diabetic patients (Table 7.1) (Kasper & Giovannucci, 2006; Bonovas et al., 2004). The lower levels of testosterone in diabetes individuals are likely responsible for the reduced risk of getting prostate cancer by an average of 16 percent (Barrett-Connor, 1992, Betancourt-Albrecht & Cunningham, 2003). Other hormonal and metabolic variables, like modified insulin and leptin densities, the widespread usage of medications like statins as well as metformin, and diet changes and way of life to regulate diabetes also have been postulated as potential contributors to the opposite relationship between diabetes and prostate cancer (Kasper & Giovannucci, 2006). In summary, the epidemiological data referenced previous section might well be partly distorted by relevant heterogeneity leading to variations in study designs (ready to call), inadequate characterization of DM,

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and failure to account for possible confounders (obesity, history of diabetes, and hospitalization), and also a differentially known control population. Therefore, the significantly greater risk of developing multiple forms of cancer in diabetes people has to be regarded as well-documented. Diabetes is associated with a little to a considerable rise in the number of cancers of the pancreas, liver, breast, gastrointestinal tract, urinary system, and female reproductive organs, and a slight decrease in the prostate cancer risk.

7.3.3 Cancer Mortality is Increased in Diabetic Patients Compared to statistics on cancer rates, information on cancer death in diabetes people are less common and less uniform. Three out of five findings suggest a correlation between breast cancer incidence as well as diabetes, with a pooling RR from the 5 studies of 1.24 (95 percent CIZ0.951.62). After accounting for age, race, BMI, physical activity, tobacco, as well as alcohol in the biggest research (cohort number 588 321, with 4346 deaths from cancer), diabetes women’s risk ratio (RR) was 1.27 (1.11–1.45) whenever contrasted to the nondiabetic female people. As with most cohorts, no stratification was done for the various types of diabetes and therapies (Chow et al., 1995). Additionally, there was no record of menopausal status. In the latest studies looking at how diabetes might influence breast cancer prognosis, the death rate for breast cancer was higher in women with diabetes after an implied follow-up of 5 years (potential danger ratio 1.39; 95 percent CIZ1.22-1.59, P! 0.0001), indicating that initial preservation after breast cancer was lowered in women with diabetes (Wang et al., 2020; Sitotaw et al., 2022). This decreased lifespan may be brought on by comorbidities associated with diabetes as well as more aggressive breast cancer. In reality, since the reason for death was not noted within this research, it is possible that diabetes, instead of breast cancer, was the primary factor raising mortality. This is because diabetic women lacking breast cancer had a higher risk of death equivalent to those diabetic women with breast cancer (Boschetti et al., 2021). Deaths from colorectal cancer were also strongly correlated with diabetes. Three out of six investigations revealed a statistically significant correlation, while a fourth one indicated a non - significant positive relationship (Shahid et al., 2021). A favorable correlation between diabetes and colorectal cancer death was found in the pooled data from the six trials (RRZ1.26; 95 percent CIZ1.05-1.50), however, the findings’ significance is somewhat hampered by heterogeneity concerns. The two prospective studies that looked at

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the case fatality ratio in these six papers both found a link between DM and colorectal cancer death. Even so, just one investigation found that diabetes individuals had significantly higher colorectal cancer death. Diabetes has a detrimental impact on colon cancer patients’ chances of survival, according to research that examined the impact of the disease on the lasting outcomes of patients who had their colons surgically removed (3759 patients, 287 of whom had diabetes) (Malberti et al., 2020). Age, gender, race, clinical status, TNM (tumor, node, metastasis classification) category, Dukes stage, location of the primary tumor, and grade of differentiation were all taken into account as predictors of colon cancer outcome in the analysis, and the results showed that diabetic patients had significantly lower diseasefree survival (DFS) and overall survival (OS) at 5 years (DFSZ48 vs 59 percent in nondiabetics; OSZ57 vs 66 percent Diabetes patients’ median survival was 6.0 years, compared to 11.3 years for non-diabetic participants (Dubourg et al., 2022). Although cancer recurrence was also greater in diabetic patients (recurrence-free mortality 56 vs. 64 percent in nondiabetics, P0.012), the influence of DM comorbidities throughout this section (that could negatively impact mortality rate amongst cancer patients due to unfavorable medical problems) was probably modest. In two investigations, a positive relationship between diabetes and endometrial cancer risk was also discovered, albeit only one of the studies showed it to be statistical significance (RRZ2.38; 95 percent CIZ1.05-5.37. It’s noteworthy to note that while men with diabetes have a lower chance of developing prostate cancer, once an insulin-resistant, overweight man has prostate cancer, his risk of passing away from the condition rises (Hohneck et al., 2020). The danger ratio for death in tumor patients with diabetes relative to cancer non-diabetic subjects was calculated to be 1.41 (95 percent CIZ1.281.55) in the latest studies on the comprehensive evaluation of long-term, allcause death in people with cancer with or without diabetes. Breast cancer, endometrial, colon, as well as rectum all have extremely high death. Lung, stomach, liver, pancreatic, and prostate cancers did not substantially increase the risk of death in this research ((Malberti et al., 2020). Ultimately, the data’s importance is hampered, at least in part, by the heterogeneity of the research that was examined and the duration of the observation time (1969–2008, a period in both which cancer and diabetes therapy underwent significant change).

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The higher chance of cancer mortality in DM may be explained by several different scenarios. For example, it is still unknown if diabetes, via a variety of pathways, increases cancer’s aggressiveness or if the host body is less resistive to the course of the disease. Additionally, diabetic people may have various cancer treatments (i.e. oncologists can pay lower chemotherapy doses in diabetic patients, worried about their overall health and their heart, liver, and kidney occupation). It also is conceivable that persons with diabetes may react to chemotherapy less favorably than those without the disease (Wang et al., 2020). In summary, epidemiologic research shows that diabetes individuals have a slightly higher cancer death risk. It is yet unknown if this is a result of high blood sugar and high insulin levels (which have a growth-promoting influence on cancer cells), the poor health circumstances brought on by diabetes’ comorbidities or a mixture of the two.

7.3.4 Type 1 and Type 2 Diabetes and Cancer Risk Diabetes mellitus is a category of metabolic illnesses marked by hyperglycemia. Both hormonal and metabolic aspects distinguish the two most common subgroups of DM: in type 1 diabetic patients (5–10% of all diabetics), hyperglycemia is linked with an extreme insufficiency of endogenous insulin production and an absolute necessity for exogenous insulin administration (Ding et al., 2013). Due to insulin resistance in peripheral tissues, hyperglycemia and hyperinsulinemia occur for an extended period in type 2 diabetes. Endogenous insulin shortage will only need the administration of insulin after the b-cell activity has entirely failed. Despite these substantial pathogenetic as well as clinical distinctions, several research on the link between diseases and diabetes was conducted without distinguishing between the two types of diabetes (Asmat et al., 2016). Most research on the relationship between diabetes and heart disease has been conducted on individuals with type 2 diabetes for apparent epidemiological reasons (90 percent of all diabetic patients). As these individuals, apart from those with type 1 diabetes, exhibit endogenous hyperinsulinemia as well as insulin resistance, it is dubious if such findings can be immediately applied to people with type 1 diabetes. This worry is especially pertinent for earlier studies wherein diabetes evaluation was dependent on self-reported hyperglycemia and there were no criteria to differentiate type 1 from type 2 diabetes. Even though more current research was based on medical records, the difference between type 1 and

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type 2 diabetes was primarily dependent on surrogate indications of diabetes type, such as young patient age or insulin therapy (assumed to be type 1) vs insulin-independent diabetes (assumed as type 2) (Bigby et al., 2020). This difference does not account for a variety of distinct situations, such as type 2 diabetic patients who are handled with insulin even though oral hypoglycemic agents (OHA) aren’t any longer useful (secondary inability to OHA), type 1 diabetes of the individual (w5% of adult subjects officially identified as type 2 diabetes and other less common conditions (Wright & Aroda, 2020). It is plausible to believe that the large bulk of tumors reported in people with diabetes developed in type 2 diabetics, given the 10:1 ratio across type 2 as well as type 1 diabetes and the fact that cancer is mostly a disease of the elderly (when type 1 diabetes is a little less common) (Lawrence et al., 2021). The large bulk of malignancies detected in type 2 diabetic individuals has likely disguised any particular traits associated with type 1 diabetes and cancer. Even those research examining the prevalence of cancer in type 1 diabetic individuals have inadequate diabetes type evaluation. A recent cohort study to assess the rate of cancer in nearly 30,000 Swedish type 1 diabetic patient given a diagnosis between 1965 and 1999 recognized 355 cancer deaths (incidence rate ratio (SIR)Z1.2; 95 percent confidence interval (CI) CIZ1.0–1.3, relative to the overall Swedish population). In comparison to type 2 diabetes individuals, this group was not associated with an elevated chance of breast, pancreatic, colorectal, or kidney cancer. Patients with type 1 diabetes exhibited a higher RR for gastrointestinal (SIRZ2.3; 95% CIZ1.1–4.1), endometrial (SIRZ2.7; 95% CIZ1.4–4.7), and cervical cancer (1.6; 1.1–2.2). Such a significant correlation is associated with the high predominance of Helicobacter pylori infection or pernicious anemia (for gastric carcinomas) and the increased prevalence of nulliparity, irregular menstrual cycles, and ovulation abnormalities in type 1 diabetic women (for uterine malignancies) (Lawrence et al., 2021; Wright & Aroda, 2020). Contrary a recent metaanalysis comprised of three cohort studies as well as six case-control studies indicated that the relative risk (RR) for pancreatic cancer was twice in type 1 diabetes individuals as well as young-onset diabetics compared to nondiabetics). The vast bulk of epidemiologic studies on cancer rates and death has been collected from people with type 2 diabetes. Due to the biological differences

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in the two categories of diabetes, such results cannot be extrapolated to type 1 diabetes.

7.4 THE ROLE OF HYPERINSULINEMIA Animal studies were the first to discover that insulin plays a large part in cancer growth. In control and treated animals, rats and mice decided to make diabetic with streptozotocin or alloxan (thus hyperglycemic and insulin insufficient) creating less assertive tumor cells with an extended time gap for tumor progression, fewer tumors, shorter tumor growth, and relatively small the last tumor volume (Fig. 1). Such impacts were reversed by insulin treatment (Kuusisto et al., 1993). Such findings support the well-known mitogenic action of insulin, which has been studied extensively in both Vivo studies. Often these type 1 and type 2 diabetic patients are linked to greater insulin concentrations for centuries, even though every person with diabetes has very various physiologic and therapeutic situations. Due to progressive degeneration of one‘s pancreatic b-cells, type 1 diabetics are not able to generate endogenous insulin and must rely solely on exogenous insulin. Insulin administration could not mimic physiologic insulin secretion in such patient populations, not just in aspects of sequence as well as hormone serum concentrations, but in aspects of chamber distribution (Verma et al., 2001). Admittedly, pancreasderived insulin is first transported to the liver (first passage insulin), where a significant aliquot (up to 80%; is maintained and deteriorated. The surviving hormone is carried to the adipose tissue via systemic circulation. All through insulin secretion bursts, the liver/peripheral tissue glucose proportion varies from 3:1 to 9:1. Exogenously administered insulin, on the other hand, will reach peripheral tissues and the liver at a time similar and concentration (Verma et al., 2001; Drazninetal., 1988). Exogenous insulin-induced peripheral tissue hyperinsulinemia (plasma concentrations could peak two to fivefold higher than usual endogenous stages, depending on the dose implanted as well as the method of insulin or analog utilized) and the resulting relative liver hyperinsulinemia are thus a frequent cause in type 1 diabetic patients (Fig. 2). On the opposite, hyperglycemia is linked with endogenous hyperinsulinemia in the majority of type 2 diabetic patients, a corrective state affected by insulin sensitivity. This situation frequently lasts for several decades (decades when comprising the pre-diabetes era before clinically

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apparent diabetes is diagnosed) (Freude et al., 2005; Suga et al., 1999). As a result, the liver/peripheral tissue insulin concentration ratio in such patients is higher than in patients without diabetes. Although, unlike in healthy people, higher insulin release in diabetes patients lacks to replenish body fuel stores in proportion to meals due to insulin resistance. As a result, abundant unneeded substrates (such as glucose) coexist with hyperinsulinemia in such individuals. This aberrant condition is associated with several additional disorders affecting other hormones like glucagon, incretins, leptin, and so on. As DM continues for several decades, this picture is often prone to change, with many of these type 2 diabetes patients gradually exhibiting lower insulin release after b-cell failure, due to higher apoptosis levels that are not compensated by neogenesis (Weyer et al., 2001). Patients with type 2 diabetes may be at risk at this point and may become like type 1 diabetics, with endogenous hypoinsulinemia and an exogenous insulin demand.

Figure 7.5. The distribution of endogenous insulin using a three-chamber model: Insulin is generated by pancreatic b-cells and travels to the liver, where it is mostly utilized and destroyed; hence, peripheral tissues get 1/3–1/10 of the quantity acquired by the liver. Exogenous insulin is dispersed using a single compartment approach, which means once that infused, all tissues get a similar dosage. Source: https://www.researchgate.net/figure/Endogenous-insulin-is-distributed-according-to-a-three-compartment-model-A-produced-by_fig1_26683934

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Diabetes duration, as well as insulin demand, might consequently alter tissue exposure to insulin in varying methods while examining type 2 diabetic individuals. If hyperinsulinemia plays an important role in cancer development and/or progression, such factors should be addressed whenever estimating a diabetic patient’s unique risk of developing cancer. Most investigations on diabetes–cancer link ignored these many physiologic circumstances ((Freude et al., 2005; Draznin et al., 1988). Finally, diabetes is defined by hyperglycemia and hyperinsulinemia, which are frequently associated with a diminished metabolic action of insulin (insulin resistance) in adipose tissue. Chronic hyperinsulinemia, on the other hand, maybe a factor encouraging cancer development and/or development in diabetic individuals owing to insulin’s mitogenic impact. The variability and complexity of diverse tissues’ sensitivity to hyperinsulinemia in diabetic persons precludes measurement of insulin’s function in raising disease risk in distinct diabetic patients’ organs One instance is the newly released inhaled insulin, which may raise the risk of lung cancer in diabetic people. This kind of therapy’s longterm consequences is unclear. Even though short-term animal research has indicated no significant effect on cell division index values, the increased insulin ability to focus at alveolar as well as bronchiolar epithelial (given the detail that only 10–25 percent of inhaled insulin is sucked up) has brought up safe work doubts in the minds of promoting lung cancer (Draznin et al., 1988). Long-term monitoring data revealed that 6 out of 4740 (0.13 percent) diabetic patients managed with inhaled insulin had lung cancer, whereas only 1 out of 4292 comparator-treated individuals (0.02 percent) acquired lung cancer. Insulin’s mitogenic actions are thought to be caused by several complicated processes. Initially, while insulin numbers increased (as in the postprandial surge in insulin-resistant individuals or just after an insulin injection), insulin might very well connect to and generate the linked insulinlike protein called (IGF-I) signaling pathway, which happens to share 80% homology only with insulin receptor (IR) but has an extra potent mitogenic as well as converting action. Furthermore, insulin reduces IGF-I-binding proteins (IGF-BP1 and maybe IGF-BP2; resulting in more free IGF-I, the physiologically active version of the cofactor. Furthermore, several cancer cells have an elevated IR level (Papa et al. 1990; Fig. 3A) (Papa et al. 1990; Fig. 3A). Splicing of the IR gene transcript might result in the production of two distinct isoforms, A and B. In malignant

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cells, the A variant (IR-A) is predominantly expressed; Fig. 3B), as well as its activity, unlike that of the IR-B isoform, induces greater mitogenic than metabolism (Suga et al.,1999; Draznin et al., 1988). By interacting with the upregulation of IR-A, insulin might enhance the course of cancer and the development of tumors that might have stayed purely descriptive for an indeterminate period without insulin. Lastly, insulin mitogenic action may be increased at the molecular level by post-receptor molecular pathways, such as insulin (or its synthetic analogs) residency duration on the sensor and the intracellular upregulation of the insulin mitogenic route. However unlike the insulin biochemical route, this route, according to experimental evidence, might not even be diminished in the situation of insulin resistance characteristic of diabetes (Fig. 4). The AMPK-mTOR-insulin signaling network.

Figure 7.6. Total IR concentration and IR isoform transcription in matched healthy and malignant human breast, lung, and colon tissues. Cancer, as well as healthy tissue samples, were taken from the same people, and IR concentration was measured by ELISA. Source: https://erc.bioscientifica.com/view/journals/erc/16/4/1103.xml

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Figure 7.7. The ‘paradox’ of insulin resistance is seen. Source: https://erc.bioscientifica.com/view/journals/erc/16/4/1103.xml

constitute three interdependent elements of a complex process regulating cellular functions to availability of food, and their dysregulation may promote malignant cell growth in reaction to hyperinsulinemia. In summary, circumstantial data shows that endogenous hyperinsulinemia, as well as exogenous insulin or synthetic analogs, have a part in encouraging the

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development of cancer in diabetic individuals (Weyer et al., 2001). Though, the clinical significance of this insulin-induced pro-cancer impact on diabetes individuals keeps uncertain.

7.5 ANTI-DIABETIC DRUGS THAT MAY INFLUENCE CANCER RISK IN DIABETIC PATIENTS Many diabetes patients are made with a combination of medicines for decades or even centuries (Table 7.2). The possible impact of such medications on cancer promotion is unidentified, though it is most probable modest if any. Data are inconclusive since the vast common of diabetes patients change medicine dose and/or category for numerous periods throughout the condition. Furthermore, some patients are given over one medication (Bora & Patel, 2021). As a result, epidemiological research on this topic is difficult to understand and often ambiguous. The three primary oral anti-diabetic medication groups (sulphonylureas, biguanides, and thiazolidinediones) all work oppositely. Sulphonylureas enhance endogenous insulin production, whereas the other two types of chemicals are insulin sensitizers, meaning they become tissues more receptive to insulin and, as a result, reduce hyperinsulinemia (Choi et al., 2010). If hyperinsulinemia increases the risk of developing cancer and development in people with diabetes, it is logical to predict that such medications would have a different impact on the diabetes-cancer relationship. The biguanide metformin, which has been extensively used for over 30 years and is now recommended as first-line treatment in type 2 diabetes patients, has now been shown to lower the risk of developing cancer (odds ratioZ0.86) while comparison to untreated individuals. Aside from decreasing the quantity of circulating insulin, another probable method for metformin’s anti-cancer impact is the activation of AMPK (an enzyme that induces glucose absorption by muscles) and its higher regulator LKB1, a well-known tumor suppressor genes protein (Hagberg et al., 2014). Since they diminish insulin (and IGF-I) signaling downstream of the receptor and thereby limit insulin-stimulated proliferation, AMPK activators operate as antiproliferative drugs (McCarty 2004, Ruderman & Prentki 2004) (Laskar et al 2018; Bora & Patel, 2021). As a result, this dual process may describe metformin’s anti-cancer impact. In vitro metformin suppressed cell proliferation, decreased colony formation, and produced a partial cell cycle in breast cancer cell lines

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MCF-7, BT-474, and SKBR-3. Such results were duplicated in erbB2overexpressing cells and then were primarily caused by MAPK, AKT, and mTOR suppression. A clinical experiment for testing metformin’s effect on breast cancer cell proliferation (Ki67 index) in 100 cancer patients is now underway, based on both epidemiologic studies and also in vitro research. The information on the second insulin-sensitizing medication (thiazolidinediones) is more debatable. A favorable, neutral, and even harmful. Table 7.2. Oral hypoglycemic medications for treating type 2 diabetes mellitus are listed

The impact has been documented on several forms of cancer. Such chemicals’ biological function is to stimulate PPARg receptors, which has demonstrated a possible anticancer impact in numerous in vitro experimental settings. This mechanism, in addition to decreasing hyperinsulinemia, may underlie glitazones’ anti-cancer impact (Laskar et al., 2018). In any event, the usage of these drugs is too new and too restricted to trust the current scant epidemiologic evidence. The third class of medicines (sulphonylureas) act as secretagogues, causing hyperinsulinemia via increasing insulin secretion. As predicted, they have indeed been linked to a higher chance of cancer. Varying sulphonylureas might well have various impacts, with gliclazide being more harmful than glyburide. Although their influence on cancer incidence is linked to the patients’ prolonged hyperinsulinemia, a positive impact on cancer (positive or negative) could not be ruled out (Golder et al., 2021).

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In conclusion, some evidence shows that the biguanide metformin might lower disease hazards in diabetic people, although the impact of diabetes medications on cancer risk is not thoroughly explored, and data is poor, indirect, and contentious.

7.6 OTHER FACTORS THAT MAY INFLUENCE THE RISK OF CANCER IN DIABETES 7.6.1 Obesity Over 80 percent of people with type 2 diabetes are obese. Obesity is connected with increased cancer rates and death. Furthermore, the mortality rate rises dramatically with rising BMI. The distribution of fat inside the body is also significant: centralized (arms and shoulders or android) obesity is more dangerous than gynoid obesity in regards to cancer risk and severity (Miulescu et al., 2012). Considering such data, it is obvious that the high incidence of obesity among DM patients influences investigations on the link between diabetes and cancer (Miulescu et al., 2012). Given that both diabetes and obesity are defined by hyperinsulinemia and a greater risk of cancer, it is hard to determine the relative impact of every illness. Hyperinsulinemia (which is characteristic of central obesity), food and dietary variables generating a higher level of efficiency, and other hormone imbalances have been implicated as causes (Marengo et al., 2106). Obesity, circulating levels of estrogen, and higher breast cancer risk are tightly correlated, particularly in postmenopausal women. Estrone as well as estradiol levels are often elevated in obese postmenopausal women, a probable result of enhanced aromatase activity in fatty tissue (Shai et al., 2006). Given the increasing incidence of obesity as well as diabetes in both developing and industrialized countries, such findings may help to explain the increase in estrogen receptor-positive breast tumors. The greater prevalence of breast cancer in obese (and obese diabetic) premenopausal and postmenopausal women may be attributable to many additional molecular changes linked to obesity. Preclinical data shows that leptin, an adipocytederived cytokine that is upregulated in obese subjects, encourages breast cancer cell proliferation (Avgerinos et al., 2019). However, this analysis has not yet been revealed in the clinical setting, as no correlation between serum concentrations and breast cancer output has been established. Adiponectin, an adipokine generated by adipose tissue that is negatively linked with

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body fat, may exhibit a protective impact on breast epithelial cells, as its introduction to several breast cancer cell lines suppressed proliferation and increased apoptosis.

7.6.2 Free Fatty Acids Deregulation of fatty acid synthase (FASN) activity, which acts as a catalyst for the biosynthesis of de novo fatty acids, may also have a role in the pathophysiology of insulin resistance, diabetes, as well as cancer. FASN function is essential for de novo fatty acid biosynthesis in the liver, and a low-fat, high-carbohydrate food stimulates. FASN production is elevated in insulin-resistant/ hyperinsulinemic individuals, and its elevated action worsens insulin resistance and might even cause NAFLD, which is related to an enhanced danger of hepatocarcinoma. FASN action is also elevated in cancer cells, in which de novo fatty acid generation is essential for membrane remodeling throughout cell proliferation and migration and lipid-based post-translational changes of intracellular proteins in rapidly proliferating cellular components (i.e. myristylation of RAS). The hypothesis that FASN is directly engaged in altering tumor growth is supported by other research including the FASN inhibitor cerulenin. Furthermore, this inhibitor has cytostatic, cytotoxic, and apoptotic impacts on cells in vitro and inhibits tumor development in xenograft models ((Avgerinos et al., 2019; Sowah et al., 2020). FASN activity and fatty acid synthesis are thus another potential connection between diabetes and cancer, as suggested by the concept that insulin-resistant diseases such as obesity, type 2 diabetes, and cancer are promoted by a FASN-driven ‘lipogenic state’ .

7.6.3 Chronic Inflammation and Oxidative Stress The metabolic anomalies that define diabetes, particularly in the presence of poor metabolic control, enhance oxidative stress and result in a persistent pro-inflammatory state. This prolonged pro-inflammatory state (which endures for years or decades) lowers intracellular anti-oxidant capability, making vulnerable cells more prone to malignant transformation. In reality, large concentrations of various free radicals and oxidants form a powerful ROS that may damage cell DNA by direct oxidation or by interfering with DNA repair systems. ROS may also react with proteins and lipids, creating derivatives that may affect intracellular homeostasis

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and promote the accumulation of mutations, which in turn contribute to the multistep carcinogenesis process (Amirani et al., 2020). A potential additional mechanism is associated with mitochondrial dysfunction, a well-known anomaly of diabetes. DNA repair is an extremely energy-intensive process that requires increased mitochondrial activity. Stimulating dysfunctional mitochondria not only results in a deficient energy supply but also increases ROS generation (Gutiérrez-Cuevas et al., 2021). Additionally, the pro-inflammatory cytokine tumor necrosis factor-a (TNFa) generated by adipose tissue is linked with insulin resistance. Many of TNFa’s pro-tumorigenic actions are mediated by nuclear factor-kappa B (NF-kB), which is substantially activated by TNFa (Avgerinos et al., 2019) In conclusion, DM, via mechanisms both unique to diabetes and shared with other chronic degenerative illnesses, may hasten the aging biological processes that promote cancerogenesis.

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REFERENCES 1.

Amirani, E., Milajerdi, A., Mirzaei, H., Jamilian, H., Mansournia, M. A., Hallajzadeh, J., & Ghaderi, A. (2020). The effects of probiotic supplementation on mental health, biomarkers of inflammation and oxidative stress in patients with psychiatric disorders: A systematic review and meta-analysis of randomized controlled trials. Complementary therapies in medicine, 49, 102361. 2. Asmat, U., Abad, K., & Ismail, K. (2016). Diabetes mellitus and oxidative stress—A concise review. Saudi pharmaceutical journal, 24(5), 547-553. 3. Avgerinos, K. I., Spyrou, N.s, Mantzoros, C. S., & Dalamaga, M. (2019). Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism, 92, 121-135. 4. Barrett-Connor, E. (1992). Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Annals of internal medicine, 117(10), 807-811. 5. Basso, D., Valerio, A., Seraglia, R., Mazza, S., Piva, M. G., Greco, E., ... & Plebani, M. (2002). Putative pancreatic cancer-associated diabetogenic factor: 2030 MW peptide. Pancreas, 24(1), 8-14. 6. Betancourt-Albrecht, M., & Cunningham, G. R. (2003). Hypogonadism and diabetes. International journal of impotence research,  15(4), S14-S20. 7. Bigby, S. M., Tin Tin, S., Eva, L. J., Shirley, P., Dempster‐Rivett, K., & Elwood, M. (2020). Increasing incidence of endometrial carcinoma in a high‐risk New Zealand community. Australian and New Zealand Journal of Obstetrics and Gynaecology, 60(2), 250-257. 8. Bonovas, S., Filioussi, K., & Tsantes, A. (2004). Diabetes mellitus and risk of prostate cancer: a meta-analysis. Diabetologia,  47(6), 10711078. 9. Bora, V., & Patel, B. M. (2021). Investigation into the role of antidiabetic agents in cachexia associated with metastatic cancer. Life Sciences, 274, 119329. 10. Boschetti, G., Sgarabotto, D., Meloni, M., Bruseghin, M., Whisstock, C., Marin, M., ... & Brocco, E. (2021). Antimicrobial resistance patterns in diabetic foot infections, an epidemiological study in Northeastern Italy. Antibiotics, 10(10), 1241.

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11. Chari, S. T., Leibson, C. L., Rabe, K. G., Ransom, J., De Andrade, M., & Petersen, G. M. (2005). Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology, 129(2), 504-511. 12. Chari, S. T., Leibson, C. L., Rabe, K. G., Timmons, L. J., Ransom, J., De Andrade, M., & Petersen, G. M. (2008). Pancreatic cancer– associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology, 134(1), 95-101. 13. Choi, J. H., Banks, A. S., Estall, J. L., Kajimura, S., Boström, P., Laznik, D., ... & Spiegelman, B. M. (2010). Anti-diabetic drugs inhibit obesitylinked phosphorylation of PPARγ by Cdk5. Nature, 466(7305), 451456. 14. Chow, W. H., Gridley, G., Fraumeni Jr, J. F., & Järvholm, B. (2000). Obesity, hypertension, and the risk of kidney cancer in men. New England Journal of Medicine, 343(18), 1305-1311. 15. Chow, W. H., Gridley, G., Mellemkjær, L., McLaughlin, J. K., Olsen, J. H., & Fraumeni, J. F. (1995). Cancer risk following polymyositis and dermatomyositis: a nationwide cohort study in Denmark. Cancer Causes & Control, 6(1), 9-13. 16. Davila, J. A., Morgan, R. O., Shaib, Y., McGlynn, K. A., & El-Serag, H. B. (2005). Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut, 54(4), 533-539. 17. DeCensi, A., Puntoni, M., Goodwin, P., Cazzaniga, M., Gennari, A., Bonanni, B., & Gandini, S. (2010). Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysisMetformin and Cancer Incidence in Diabetic Patients. Cancer prevention research, 3(11), 1451-1461. 18. Ding, J., Tang, J., Chen, X., Men, H. T., Luo, W. X., Du, Y., ... & Liu, J. Y. (2013). Expression characteristics of proteins of the insulinlike growth factor axis in non-small cell lung cancer patients with preexisting type 2 diabetes mellitus. Asian Pacific Journal of Cancer Prevention, 14(10), 5675-5680. 19. Draznin, B., Sussman, K. E., Eckel, R. H., Kao, M., Yost, T., & Sherman, N. A. (1988). Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. The Journal of clinical investigation, 82(6), 1848-1852.

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RNA and Life Threatening Diseases

20. Dubourg, J., Fouqueray, P., Quinslot, D., Grouin, J. M., & Kaku, K. (2022). Long‐term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52‐week, open‐label, multicentre phase 3 trial. Diabetes, Obesity and Metabolism, 24(4), 609-619. 21. Elwing, J. E., Lustman, P. J., Wang, H. L., & Clouse, R. E. (2006). Depression, anxiety, and nonalcoholic steatohepatitis. Psychosomatic medicine, 68(4), 563-569. 22. Freude, S., Plum, L., Schnitker, J., Leeser, U., Udelhoven, M., Krone, W., ... & Schubert, M. (2005). Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes, 54(12), 3343-3348. 23. Gapstur, S. M., Gann, P. H., Lowe, W., Liu, K., Colangelo, L., & Dyer, A. (2000). Abnormal glucose metabolism and pancreatic cancer mortality. Jama, 283(19), 2552-2558. 24. Golder, S., Bach, M., O’Connor, K., Gross, R., Hennessy, S., & Hernandez, G. G. (2021). Public perspectives on anti-diabetic drugs: Exploratory analysis of Twitter posts. JMIR diabetes, 6(1), e24681. 25. Green, A., & Jensen, O. M. (1985). Frequency of cancer among insulintreated diabetic patients in Denmark. Diabetologia, 28(3), 128-130. 26. Gutiérrez-Cuevas, J., Santos, A., & Armendariz-Borunda, J. (2021). Pathophysiological molecular mechanisms of obesity: A link between MAFLD and NASH with cardiovascular diseases. International Journal of Molecular Sciences, 22(21), 11629. 27. Hagberg, K. W., McGlynn, K. A., Sahasrabuddhe, V. V., & Jick, S. (2014). Anti-diabetic medications and risk of primary liver cancer in persons with type II diabetes. British journal of cancer, 111(9), 17101717. 28. Heuson, J. C., & Legros, N. (1972). Influence of insulin deprivation on growth of the 7, 12-dimethylbenz (a) anthracene-induced mammary carcinoma in rats subjected to alloxan diabetes and food restriction. Cancer research, 32(2), 226-232. 29. Hohneck, A., Shchetynska-Marinova, T., Ruemenapf, G., Pancheva, M., Hofheinz, R., Boda-Heggemann, J., ... & Sigl, M. (2020). Coprevalence and incidence of lung cancer in patients screened for abdominal aortic aneurysm. Anticancer Research, 40(7), 4137-4145. 30. Kaaks, R. (1996). Nutrition, hormones, and breast cancer: is insulin the missing link?. Cancer Causes & Control, 7(6), 605-625.

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191

31. Kasper, J. S., & Giovannucci, E. (2006). A meta-analysis of diabetes mellitus and the risk of prostate cancer. Cancer Epidemiology Biomarkers & Prevention, 15(11), 2056-2062. 32. Kuusisto, J., Koivisto, K., Mykkänen, L., Helkala, E. L., Vanhanen, M., Hänninen, T., ... & Laakso, M. (1993). Essential hypertension and cognitive function. The role of hyperinsulinemia. Hypertension, 22(5), 771-779. 33. Larsson, S. C., Orsini, N., & Wolk, A. (2005). Diabetes mellitus and risk of colorectal cancer: a meta-analysis. Journal of the National Cancer Institute, 97(22), 1679-1687. 34. Laskar, J., Bhattacharjee, K., Sengupta, M., & Choudhury, Y. (2018). Anti-diabetic drugs: cure or risk factors for cancer?. Pathology & Oncology Research, 24(4), 745-755. 35. Lawrence, J. M., Reynolds, K., Saydah, S. H., Mottl, A., Pihoker, C., Dabelea, D., ... & Wagenknecht, L. (2021). Demographic Correlates of Short-Term Mortality Among Youth and Young Adults With YouthOnset Diabetes Diagnosed From 2002 to 2015: The SEARCH for Diabetes in Youth Study. Diabetes Care, 44(12), 2691-2698. 36. Lee, M. S., Hsu, C. C., Wahlqvist, M. L., Tsai, H. N., Chang, Y. H., & Huang, Y. C. (2011). Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC cancer, 11(1), 1-10. 37. Lee, S. C., & Chan, J. C. (2015). Evidence for DNA damage as a biological link between diabetes and cancer. Chinese medical journal, 128(11), 1543-1548. 38. Limburg, P. J., Vierkant, R. A., Fredericksen, Z. S., Leibson, C. L., Rizza, R. A., Gupta, A. K., ... & Cerhan, J. R. (2006). Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Official journal of the American College of Gastroenterology| ACG, 101(8), 1872-1879. 39. Lindblad, P., & Adami, H. O. (2002). Kidney cancer. Textbook of cancer epidemiology. New York: Oxford University Press, vol.1, pp. 467-85 40. Malberti, F., Pecchini, P., Marchi, G., & Foramitti, M. (2020). When a nephrology ward becomes a COVID-19 ward: the Cremona experience. Journal of nephrology, 33(4), 625-628.

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41. Marengo, A., Rosso, C., & Bugianesi, E. (2016). Liver cancer: connections with obesity, fatty liver, and cirrhosis, vol.1, pp. 1-30 42. Mitri, J., Castillo, J., & Pittas, A. G. (2008). Diabetes and risk of Non-Hodgkin’s lymphoma: a meta-analysis of observational studies. Diabetes care, 31(12), 2391-2397. 43. Miulescu, R. D., Danoiu, S., Purcarea, V., & Ionescu-Tîrgovişe, C. (2012). Factors that may influence the risk of cancer in diabetes. Farmacia, 60(5), 602-614. 44. Miulescu, R. D., Danoiu, S., Purcarea, V., & Ionescu-Tîrgovişe, C. (2012). Factors that may influence the risk of cancer in diabetes. Farmacia, 60(5), 602-614. 45. Noto, H., Goto, A., Tsujimoto, T., & Noda, M. (2012). Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PloS one, 7(3), e33411. 46. Noy, A., & Bilezikian, J. P. (1994). Clinical review 63: Diabetes and pancreatic cancer: clues to the early diagnosis of pancreatic malignancy. The Journal of Clinical Endocrinology & Metabolism, 79(5), 1223-1231. 47. Pannala, R., Basu, A., Petersen, G. M., & Chari, S. T. (2009). Newonset diabetes: a potential clue to the early diagnosis of pancreatic cancer. The lancet oncology, 10(1), 88-95. 48. Pannala, R., Leirness, J. B., Bamlet, W. R., Basu, A., Petersen, G. M., & Chari, S. T. (2008). Prevalence and clinical profile of pancreatic cancer–associated diabetes mellitus. Gastroenterology,  134(4), 981987. 49. Shahid, R. K., Ahmed, S., Le, D., & Yadav, S. (2021). Diabetes and cancer: risk, challenges, management and outcomes. Cancers, 13(22), 5735. 50. Shai, I., Jiang, R., Manson, J. E., Stampfer, M. J., Willett, W. C., Colditz, G. A., & Hu, F. B. (2006). Ethnicity, obesity, and risk of type 2 diabetes in women: a 20-year follow-up study. Diabetes care, 29(7), 1585-1590. 51. Shikata, K., Ninomiya, T., & Kiyohara, Y. (2013). Diabetes mellitus and cancer risk: review of the epidemiological evidence. Cancer science, 104(1), 9-14. 52. Sitotaw, E., Sitotaw, A., Aleka, Y., & Lemma, M. (2022). Prevalence of Intestinal Helminths among Cancer Patients Who Are under

Diabetes and Cancer

53.

54.

55.

56.

57. 58.

59. 60.

61.

193

Chemotherapy at the University of Gondar Comprehensive Specialized Hospital Oncology Clinic, Northwest Ethiopia. Journal of Cancer Epidemiology, 2022, 104(1), 9-14 Sowah, S. A., Hirche, F., Milanese, A., Johnson, T. S., Grafetstätter, M., Schübel, R., ... & Stangl, G. I. (2020). Changes in plasma shortchain fatty acid levels after dietary weight loss among overweight and obese adults over 50 weeks. Nutrients, 12(2), 452. Stadler, J. O. N. A., Stern, H. S., Yeung, K. S., McGuire, V. A. L. E. R. I. E., Furrer, R. U. D. O. L. F., Marcon, N. O. R. M. A. N., & Bruce, W. R. (1988). Effect of high fat consumption on cell proliferation activity of colorectal mucosa and on soluble faecal bile acids. Gut,  29(10), 1326-1331. Stevens, M. (2007). Predator perception and the interrelation between different forms of protective coloration. Proceedings of the Royal Society B: Biological Sciences, 274(1617), 1457-1464. Suga, A., Hirano, T., Kageyama, H., Kashiba, M., Oka, J., Osaka, T., ... & Inoue, S. (1999). Rapid increase in circulating leptin in ventromedial hypothalamus-lesioned rats: role of hyperinsulinemia and implication for upregulation mechanism. Diabetes, 48(10), 2034-2038. Suh, S., & Kim, K. W. (2011). Diabetes and cancer: is diabetes causally related to cancer?. Diabetes & metabolism journal, 35(3), 193-198. Verma, S., Leung, Y. M., Yao, L., Battell, M., Dumont, A. S., & McNeill, J. H. (2001). Hyperinsulinemia superimposed on insulin resistance does not elevate blood pressure. American journal of hypertension, 14(5), 429-432. Vigneri, P., Frasca, F., Sciacca, L., Pandini, G., & Vigneri, R. (2009). Diabetes and cancer. Endocrine-related cancer, 16(4), 1103-1123. Wang, Z., Du, Z., & Zhu, F. (2020). Glycosylated hemoglobin is associated with systemic inflammation, hypercoagulability, and prognosis of COVID-19 patients. Diabetes research and clinical practice, 164, 108214. Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R. E., & Tataranni, P. A. (2001). Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. The Journal of Clinical Endocrinology & Metabolism, 86(5), 1930-1935.

194

RNA and Life Threatening Diseases

62. Wideroff, L., Gridley, G., Chow, W. H., Linet, M., Mellemkjaer, L., Olsen, J. H., ... & Borch-Johnsen, K. (1997). Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. Journal of the National Cancer Institute, 89(18), 13601365. 63. Williams, J. A., & Goldfine, I. D. (1985). The insulin-pancreatic acinar axis. Diabetes, 34(10), 980-986. 64. Wright Jr, E. E., & Aroda, V. R. (2020). Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes considered for injectable GLP-1 receptor agonist therapy or currently on insulin therapy. Postgraduate medicine, 132(sup2), 26-36. 65. Yeo, Y., Ma, S. H., Hwang, Y., Horn-Ross, P. L., Hsing, A., Lee, K. E., ... & Park, S. K. (2014). Diabetes mellitus and risk of thyroid cancer: a meta-analysis. PloS one, 9(6), e98135. 66. Yuan, J. M., Castelao, J. E., Gago-Dominguez, M., Ross, R. K., & Yu, M. C. (1998). Hypertension, obesity and their medications in relation to renal cell carcinoma. British journal of cancer, 77(9), 1508-1513. 67. Zucchetto, A., Dal Maso, L., Tavani, A., Montella, M., Ramazzotti, V., Talamini, R., ... & La Vecchia, C. (2007). History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Annals of Oncology, 18(3), 596-600.

CHAPTER

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BLOOD DISEASES

CONTENTS 8.1 Introduction...................................................................................... 196 8.2 Anemia............................................................................................. 196 8.3 Leukocytosis..................................................................................... 202 8.4 Polycythemia Vera............................................................................ 203 8.5 Sickle Cell Disease........................................................................... 206 8.6 Thalassemia...................................................................................... 208 8.7 Von Willebrand Disease.................................................................... 211 8.8 Effects of Blood Disorders................................................................. 213 8.9 Diagnosis and Tests........................................................................... 215 References.............................................................................................. 221

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8.1 INTRODUCTION Disorders of the blood occur when anything in the blood stops it from performing its normal functions. Although certain blood problems are inherited from one’s parents, others may be brought upon by conditions, certain drugs, or a deficiency of certain nutrients in one’s diet (Carmeliet, 2003). Several distinct kinds of illnesses may affect the blood. Some conditions are entirely cured by treatment, while others do not manifest themselves clinically and have no impact on total longevity (they are benign). Some conditions are permanent and chronic, yet they do not influence how long a person lives overall. Other types of blood diseases, such as sickle cell anemia and blood malignancies, are also potentially lethal. Included in the list of blood disorders are (Hunter et al., 2002): • • • • • • •

Anemia. Hemophilia. Leukocytosis. Polycythemia vera. Sickle cell disease. Thalassemia. Von Willebrand disease.

8.2 ANEMIA Red blood cell deficiency, or anemia, is a condition. Iron as well as hemoglobin, one protein that aids in transporting oxygen via circulation to various organs throughout the body, are carried by the cells as they move around the body. An individual is referred to just be “anemic” whenever they acquire anemia. When someone’s skin appears overly pale, then maybe anemic if you have unusually high levels of fatigue or cold. It is a result of your systems not getting the oxygenation that needs to function. Once they go to give blood, some individuals learn that they are deficient in iron (Stevens et al., 2001).

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Figure 8.1. Red blood cell counts that are unusually low are known as anemia. Source: https://www.drugs.com/health-guide/anemia.html

8.2.1 Types of Anemia A decrease in the number of red blood cells circulating is a common symptom of all various kinds of anemia. A few of the systems function for low red blood cell counts are (Weiss & Goodnough, 2005): •

Hemoglobin production by the human body is insufficient (low hemoglobin). • Hemoglobin is produced by the human body, however, it doesn’t function properly. • Red blood cell production by the human body is insufficient. • Red blood cells are broken down very fast by the human organism. Iron deficiency anemia, as well as sickle cell anemia, are two examples of anemia (Gonzalez-Casas et al., 2009). Over 2 billion individuals, or even more than 30% of both the world’s population, suffer from anemia. Although it is more prevalent in nations with little resources, this also affects a large number of individuals inside the industrial nations. Anemia is perhaps the most prevalent blood disorder in the United States. 3 million Americans are said to suffer from the condition (Faux et al., 2014).

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8.2.2 Effects of anemia In addition to making people feel chilly or weary, anemia may have additional impacts on human health. You may also have hair loss and fragile or spoonshaped fingernails if you are iron deficient. You could notice feeling your perception of tasting has altered and that your ears are buzzing. Various anemias might result in more severe issues. Lung and heart problems are frequent in individuals having sickle cell disease (Socié et al., 2000). Untreated anemia may cause cardiac arrhythmias (irregular heartbeats), enlarged hearts, and heart failure. Additionally, you have a higher chance of contracting illnesses and developing depression. You may have a hearing about iron deficiency and eating ice are related, and that’s true. Ice chewing is just a symptom of pica, a disorder that also involves consuming non-food items like chalked or dirt. Pica is just a symptom of iron insufficiency, thus. Kids suffering from anemia frequently experience it (Miller, 2013). Kids must get enough iron as well as other minerals in their meals to avoid anemia and its associated issues including attention deficit disorder, impaired motor skill growth, including learning difficulties. Anemia symptoms throughout physical growth, as well as menstrual periods, should be watched out for in older kids. Anemia may contribute much more to disorientation or sadness in elderly persons. Walking might be more challenging if you’re weak. If you are elderly and have anemia, this could reduce your lifetime if not addressed (Ferguson et al., 1992). Lack of iron could also contribute to weight problems. According to studies, addressing low iron levels in the blood may help overweight persons lose weight. When you also have other illnesses like cancer, you could unintentionally lose weight in addition to having anemia. Due to vitamin/ mineral shortages, individuals who have undergone weight reduction surgery may develop anemia. Premature delivery is one of the issues that may arise from iron shortage throughout pregnancy. Research has shown that infants delivered to mothers with decreased iron levels after the delivery are more likely to experience low body mass and issues with their actual personal iron stages (McCullough, 2003). Iron deficiency anemia is more prone to occur during pregnancy. You are the only source of iron as well as other minerals for your unborn child. To avoid anemia, most pregnant women consume iron supplements. Consume well-balanced diets that contain iron-rich products and meals that give B12 as well as B9 vitamins to ensure that have adequate iron for you and your

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unborn child. Take vitamins that add iron to your diet as directed by your healthcare practitioner. The discovery of your anemia is only the start. The best course of action will depend on what caused the anemia (Prakash, 2012).

8.2.3 Causes of Anemia Low bodily iron stores are the most typical causes of anemia. Iron deficiency anemia is the name given to this kind of anemia. To create hemoglobin, the molecule that transports oxygen around the body, your body requires a certain quantity of iron. Iron deficiency anemia is only one form, however. Different kinds are brought on by (Chulilla et al., 2009): • •

• • •

•

B12 deficiency in the diet or inability to utilize or absorb B12 (like malicious anemia). Diets deficient in folic acid, commonly known as folate, or improper folic acid utilization by your system (like folatedeficiency anemia). genetic blood conditions (similar to sickle cell anemia or thalassemia). circumstances that speed up the deterioration of red blood cells (similar to hemolytic anemia). Chronic illnesses prevent your body from producing enough chemicals to form red blood cells. Which include lupus, severe renal disease, hypothyroidism, hyperthyroidism, as well as other chronic illnesses. Loss of blood brought on by various medical disorders including gastric, ulceration, or hemorrhoid.

8.2.4 Haemophilia Blood rarely clots properly just at the area of a cut or damage in people with hemophilia, a rare genetic bleeding illness. Because specific blood coagulation components are either absent or function improperly, the disease develops. A cut and wound might result in significant bleeding whereas a clot doesn’t form. Exterior bleeding is what this is. Internal injuries, sometimes known as internal hemorrhage, may also happen, particularly in joints and muscles like the knees and hips. There are a few instances in which a girl might be impacted with hemophilia, which mostly affects men (Zadrazil & Horak, 2015).

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Figure 8.2. A bleeding ailment called hemophilia impairs the blood coagulation mechanism. Source: https://medlineplus.gov/genetics/condition/hemophilia/

Hereditary hemophilia comes in two primary forms (Gomollón & Gisbert, 2013): •

A most prevalent variety, Category A, is brought on by a lack of feature VIII, one of the proteins necessary for blood clotting. The term “classical hemophilia” refers to this kind. • Type B hemophilia is caused by a deficiency of factor IX. This type is also called Christmas disease. The illness may also be developed later on in life if indeed the body starts to create antibodies that target as well as damage coagulation factors because bleeding is often identified at birth. The acquired form of hemophilia is extremely uncommon. Autoimmunity hemophilia, and inherited hemophilia A, are other names for developed hemophilia (AHA) (Poggiali et al., 2014). An uncommon condition is hemophilia. Every ethnic and racial group is susceptible to it. One in 5,000 to 10,000 men have hemophilia A. One in 25,000 to 30,000 guys have hemophilia B, a less prevalent condition. The extreme type of hemophilia A affects 60 to 70 percent of patients, whereas the intermediate form affects just approximately 15 percent. Mild hemophilia affects others (Elstrott et al., 2020).

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8.2.5 Causes of hemophilia Just one X chromosome contains the genes responsible for the synthesis of factors VIII as well as IX. Factor VIII and factor IX genetic abnormalities on the X - linked are the primary causes of bleeding (Van Vulpen et al., 2018). Women have two sets of chromosomes and because one of them has the defective gene on it, she would be carriers of hemophilia rather than having the disease herself. This implies that she may carry the hemophilia gene onto her offspring. Anyone of her boys who inherited the genes and are born with hemophilia has a 50% probability of doing so. Additionally, there seems to be a 50% probability that some of her children who do not already have bleeding will become particular genetic carriers (Mazurier, 1992). It is very rare for a girl to be born with hemophilia, but it can happen if the father has hemophilia and the mother carries the gene for hemophilia. The daughter will then have the abnormal gene on both of her X chromosomes. In about 20% of all cases of hemophilia, the disorder is caused by a spontaneous gene mutation. In such cases, there is no family history of abnormal bleeding (Knobe & Berntorp, 2011).

8.2.6 Symptoms of Hemophilia The primary symptom is bleeding, which may be visible bleeding that lasts for a long time or bruising that occurs after little trauma and for no apparent cause. According to whether a person does have the moderate, medium, or serious type of the illness, different symptoms apply (Dou et al., 2020): •

Gratuitous (impulsive) hemorrhage events are frequent in people with Spartan bleeding. • Chronic bleeding usually happens in mild hemophilia following a bigger wound. • An individual with moderate hemophilia may have extraordinary hemorrhaging, but only following serious trauma, operation, or infection. Internal injuries may take any form in hemophiliacs, although knees, elbows, hips, shoulders, and ankles joints and muscles are most often affected. If such bleeding persists, the joints might be warm to the touch, swelling, and difficult to move, although there may initially be no discomfort (Song et al., 2020).

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With time, persistent hemorrhage toward the links and strengths may result in lasting harm, such as limited mobility with joint deformities (Bi et al., 1995). For people with impaired immune systems, brain hemorrhage is a very dangerous issue. It may endanger your safety. If you experience any bleeding symptoms, including but not limited to (Gater et al., 2011): • • • • • • •

Variations in performance. Unnecessary drowsiness. Headaches that resolve not to go away. Neckline pain. Dual vision. Vomiting. Spasms or annexations.

8.3 LEUKOCYTOSIS A high white blood cell concentration is referred to as leukocytosis. You thus have a higher than usual level of white blood cells. A typical immunological reaction, leukocytosis is not necessarily a reason for alarm. The majority of the time, this indicates your system is battling an illness or inflammation. A higher white blood cell count, though, may sometimes be a sign of something a little more dangerous, like leukemia (Giangrande, 2005).

Figure 8.3. Blood leukocytes with and without leukocytosis. Source: https://www.medindia.net/education/familymedicine/leukocytosis.htm

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8.3.1 Types of Leukocytosis Based on whatever kind of white blood cell (monocytes) is impacted, there are five different forms of leukocytosis (Böhm et al., 2006): Neutrophilia leukocytosis is brought on by an abundance of neutrophils (the maximum abundant kind of white blood cell, which supports the resolution of infections and reconciles injured tissues). Lymphocytosis refers to the existence of many lymphocytes (white blood cells that defend your lymphatic system). Monocytosis is brought about by an abundance of monocytes (white blood cells that improvement your resistant replies). Eosinophilia refers to the presence of many inflammatory cells (white blood cells that show a character in aggressive pollution and irritation). Eosinophilia is frequent and frequently associated with inflammatory disorders, parasite diseases, or allergens. Basophilia, the most uncommon kind of leukocytosis, is caused by a rise in basophils (white blood cells that perform a part in belligerent parasitic contagions, avoiding blood coagulation and replying to allergic responses) (Feldman et al., 2012).

8.4 POLYCYTHEMIA VERA Red blood cell production is excessive in people with polycythemia vera (PV), a blood condition. A surplus of red blood cells may thicken and slow down the circulation, which raises the risk of difficulties and other issues including heart attacks and stroke. Additionally, it may result in oblique but bothersome symptoms including itching, ringing in the ears, stomach ache, bloody noses, and confusion or dual vision (Liu et al., 2021). Medical treatment may help you overcome your signs as well as the danger of problems if you have polycythemia vera, a long-term disorder that has no known cure. Basic polycythemia, polycythemia rubra vera, erythema, and Osler-Vaquez disease are further synonyms for polycythemia vera (Ingram, 1976).

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Figure 8.4. Standard versus Polycythemia Vera. Source: https://patientpower.info/myeloproliferative-neoplasms/what-is-polycythemia-vera

8.4.1 Affects of Polycythemia Vera PV develops gradually, but excessive blood cell synthesis poses acute hazards including blood clots. Additional diseases may develop as a result of polycythemia vera throughout time. Occasionally it develops into a more dangerous form of cancer (Abramson & Melton, 2000)?

8.4.1.1 Blood clots The propensity for blood coagulation is indeed the polycythemia vera concern that requires immediate attention. A heart condition or stroke may be brought on by a thrombus that goes to the brain or heart. A blood clot, that becomes lodged in the lungs, may result in pulmonary arterial hypertension and heart failure. Tissue damage and deep venous thrombosis may result from a thrombus that plugs a vein (vascular thrombosis). Budd-Chiari syndrome, which results in hepatitis and liver problems, may be brought on by a thrombus that stops the primary blood artery from entering your liver (hepatic vein thrombus) (Coller, 2005).

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8.4.1.2 Secondary conditions Excessive quantities of uric acid are also produced by the high red blood cell cycle. This leads to several secondary illnesses, such as kidney stones (caused by an accumulation of uric acid in the kidneys) and the excruciating arthritic ailment rheumatism (when uric acid shapes up in your joints). Additional gastric acid is produced as a result of extra red blood cells, and this might result in a peptic ulcer. Your body’s natural immune system reacts to the excess red blood cells. Histamine is just a substance that is released by your system, but your gut reacts by producing more acid to ward against illness. Peptic ulcer disease was 4 times more prevalent in PV patients than in the general population (Riley & Rupert, 2015).

8.4.1.3 Leukemia progression A persistent bone marrow condition or malignancy called polycythemia vera typically poses little immediate danger. Neuropathy can be effectively treated for so many generations with consistent therapy. However, PV may sometimes proceed to other, more severe blood diseases, such as acute leukemia, which occurs seldom (McKee Jr, 1985).

8.4.1.4 Stages of polycythemia vera progression Early PV:  Signs at this period are often absent or minimal. Advancing PV:  You can start to experience increasingly bothersome signs when polycythemia vera worsens or the emergence of other illnesses. Spent phase:  Whenever the altered blood cells which produced the disorder have expanded out of the regulator at this point where they have completely controlled your bone tissue, PV enters its so-called “spent phase.” Mark tissue gradually substituted the altered cells when they reached the end of their life and disintegrated. Your bone material will stop producing healthy red blood cells once sufficient of that has been displaced by scar tissue. Paradoxically, a shortage of strong red blood cells results in anemia. Additionally, it raises your chances of bleeding-related bleeding (Yamada et al., 2020).

8.4.1.5 Post-polycythemia vera blood disorders Myelofibrosis:  Myelofibrosis and hemolytic anemia vera are two different types of blood cancers that have many similarities in their “spending phase”

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(MF). Some medical professionals don’t differentiate between the binary. Myelofibrosis develops whenever granulation tissue replaces your bone core as a result of altered cells. The abnormal lymphocytes may start to feast on your form’s various organs from your bone marrow. A different myelodysplastic syndrome disease is MF. Myelogenous leukemia may develop in around 10% of MF patients (Beckman et al., 2009). Myelodysplastic syndrome:  Occasionally, PV might evolve into a condition called myelodysplastic syndrome (MDS), wherein the blood cells are unable to properly grow. In contrast to MDS, which typically causes cells to grow incorrectly or poorly and eventually die, PV often generates a large number of red blood cells which develop appropriately. Different blood levels are decreased as a result of the failure to build healthy as well as matured cells (can be one kind of low totals or a grouping). Myelofibrosis and MDS may happen alone or together. This has a 30% probability of developing into myeloid leukemia and is more severe than PV or MF (AML) (YANKOWITZ & WEINER, 1996). Acute myeloid leukemia (AML):  Over around 10 years after diagnosis, about 3% of blood disorders vera patients may develop acute myeloid. AML is indeed a cancer of the blood that is invasive and starts in the bone marrow. It rapidly enters the circulation and can spread to certain other organ systems. AML does have a greater chance of survival than chronic leukemia but needs more prompt medical attention. Just under 2% of cancer-related fatalities are attributable to it (Dale et al., 1975).

8.5 SICKLE CELL DISEASE Your red blood cells are impacted by sickle cell anemia, a genetic condition that has a significant effect on health. Hemoglobin that has SCD is abnormal and also can readily flow across blood arteries. Your red blood cells contain a protein called hemoglobin. It is the component of the blood that transports oxygen (Lucroy & Madewell, 2001). Spherical normal red blood cells could transfer oxygen via the body’s tiny blood capillaries. Longer rods arise as a result of a chemical alteration in hemoglobin in SCD. These stiff rods transform the red blood cell into a sickle shape (which expressions like a curved one). Blood arteries cannot readily accommodate sickle-shaped cells. They may clog or disintegrate, which also shortens the lifespan of red blood cells. Normal red blood cells have a longer lifespan than sickle - cell disease. The hepatic and the heart will store more iron as just a result, which might harm these systems. The

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injury may lead to illnesses including liver problems, irregular heartbeats, cardiomyopathy, an increased risk of heart disease, and heart problems (Evans & Duane, 1949).

Figure 8.5. Sickle cell anemia. Source:https://www.mayoclinic.org/-/media/kcms/gbs/patient-consumer/images/2013/08/26/10/24/ds00324_im01729_r7_sicklecellsthu_jpg.jpg

SCD is caused by the sickle cell trait (SCT). People who have one human gene but one sickle-cell disease gene is said to have the sickle cell gene. When you just get the SCT, you often don’t even have any indications of SCD. You may, nonetheless, pass SCT on to your offspring. The likelihood that the kid will have some kind of sickle cell anemia may increase when both parents possess the mutation. Only approximately 100,000 Americans with SCD, compared to the expected 1 million to 3 million persons in the U.S. do have SCT (Passamonti et al., 2010).

8.5.1 Symptoms of Sickle Cell Disease (SCD) Whenever a kid is 4 to 5 months old, SCD clinical signs start to appear. Myoglobin prevents the red blood cells from changing their shape before just that (sickling). The sign and symptoms of SCD vary from individual to individual. While a few individuals have very moderate symptoms, others usually need hospitalization due to more severe problems (Milhorat et al., 1942).

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SCD indications and warning signs are including (Heukelbach et al., 2006): • • • • •

Pain. Fatigue and weakness may be signs of anemia. inflammation and swelling of the joints. blood clots in the liver or spleen. Yellow color to one’s skin (yellowing of skin and eyes).

8.6 THALASSEMIA Thalassemia is a hereditary blood condition (pronounced thal-uh-see-meuh). Your body’s capacity to make healthy hemoglobin is impacted. Red blood cells contain the protein hemoglobin. It makes it possible for your RBCs can carry oxygenated blood, replenishing all other cells (Ivanov et al., 1997).

Figure 8.6. Analyzing the differences between thalassemia and normal blood. Source: https://www.news-medical.net/health/Thalassemia-Genetic-Prevalence.aspx

Your system as well as bone tissue both create less normal hemoglobin proteins and functional red blood cells if you do have thalassemia. Anemia is the medical term for the absence of enough red blood cells. A lack of strong red blood cells may restrict your body’s cells of both the oxygen those who need to create energy and flourish because red blood cells play a crucial function in transporting oxygen to the body’s tissues (Landolfi et al., 2007).

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8.6.1 Affects of Thalassemia Thalassemia may produce moderate or severe anemia as well as other consequences throughout time (including such iron excess) (such as iron excess). Indications of anemia contain (Unda et al., 2021): • Feeling cold. • Fatigue. • Trouble breathing. • Pale skin. • Dizziness Humanity developed the mutated genes that produce thalassemia as just a partial defense against malaria. In light of this, thalassemia mostly affects individuals with ancestry in Africa, Southern Europe, and Western, Southern, and East Asia. Thalassemia is hereditary, which means the ailment is transferred from the biological parent onto their kid (Bashour et al., 2000).

8.6.2 Types of Thalassemia To indicate how serious the problem is, thalassemia is divided into four categories: trait, minor, intermedial, and major. These symbols depict a spectrum in which carrying a thalassemia trait indicates that you could have very little or no indications of anemia. You might not require therapy. The most severe kind, thalassemia severe, often needs ongoing therapy (Ware et al., 2017). There are two forms of thalassemia The flaws in such chains gave rise to the names alpha and beta-thalassemia.

Alpha thalassemia Making alpha-globin polypeptide chains includes 4 genes, two from every parent. You get alpha thalassemia whenever one or even more genes are damaged. Your likelihood of developing anemic symptoms, and their severity, will depend on how many faulty genes you inherited (Koshy et al., 1995). •

One defective or missing alpha gene translates to a lack of signs for you. Alpha thalassemia minimum is another term for this disease.

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•

•

•

Two defective or missing alpha genes translate to the likelihood that any signs you have will be minor. Alpha thalassemia minimal also goes by this name. Three defective or missing alpha genes translate to feelings that are mild to severe. Haemoglobin H syndrome is also another term for this illness. Four defective or missing alpha genes often end in death. If a baby does recover, it will probably require blood donations for the rest of their lives. Hydrops fetalis without Hemoglobin Barts is also another term for this syndrome.

Beta thalassemia Two beta-globin genes are turned down to you, each from every parent. The number of faulty genes and also the location of the deficiency within betaglobin polypeptide chains determine your anemia indicators and the severity of your illness (Pearson et al., 1969). •

•

One defective or missing beta gene indicates that you’ll just have minor symptoms. Beta thalassemia mild is also another term for this disorder. Two defective or missing beta genes translates to sensations that are mild to severe. Β - thalassemia intermedia seems to be the name for the mild form. Beta thalassemia specialty, also known as Cooley’s anemia, would be a more serious form of betathalassemia caused by the two genetic mutations.

8.6.3 Symptoms of Thalassemia The kind and severity of your thalassemia would determine how you react (Lervolino et al., 2011).

Asymptomatic (no symptoms) Whenever one alpha gene is absent, you most likely won’t experience any symptoms. You may not have any symptoms if you are lacking two alpha genes and one beta gene. You can also be experiencing moderate anemic signs like weariness.

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Mild to moderate symptoms Beta thalassemia type ii may result in minor anemic signs or the following signs of a more severe condition (Creary et al., 2007): • • • •

Growth issues. Postponed puberty. Anomalies of the bones, including osteoporosis. An expanded spleen is an organ within your belly involved in infection prevention. Surgery can ultimately be required to fix skeletal issues. If your spleen becomes too big, your doctor might need to extract it (SYDENSTRICKER, 1924).

Severe symptoms Three alpha genes are lacking in hemoglobin H disorder, which frequently results in serious chronic anemia and anemic signs from birth. By the age of two, significant anemia health problems caused by beta-thalassemia significant (Cooley’s anemia) are often present. The clinical signs of mild to severe illness might also occur in serious complications. Additional signs might be (Frenette & Atweh, 2007): • • • •

Sluggish appetite. Skin that is yellow or pale (jaundice). Dark-colored or tea-colored urine. Irregular facial body shape.

8.7 VON WILLEBRAND DISEASE Von Willebrand disease (VWD) would be a bleeding ailment wherein your blood has problems clotting. It is hereditary, which means that parents pass it on to their offspring (Brousseau et al., 2010). Occasionally greater loads of bleeding from wounds, surgeries, and, in women, menstruation, and delivery, affects people having von Willebrand syndrome. Anemia and discomfort are two conditions that might result from this hemorrhage (low number of red blood cells). The hemorrhage sometimes ends in death. Von Willebrand’s disease is brought on by issues with such a blood protein. Von Willebrand factor (VWF), a protein, aids in blood coagulation (Vichinsky et al., 1980).

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VWF blood levels may sometimes be too low. In the others, the protein does have a flaw. The blood’s capacity to clot appropriately is compromised in each of these cases. Several genetic mutations result in either decreased or poorly functioning VWF synthesis. Even though the source of these abnormalities is unclear, the defective gene is transmitted from one group to additional (Li et al., 2017).

Figure 8.7. Normal and von Willebrand Disease contrasted. Source: https://cancer.osu.edu/-/media/images/cancer/website/pages-andcarousels/for-patients-and-caregivers/learn-about-cancers-and-treatments/ cancers-conditions-and-treatments/benign-blood-diseases/von-willebrand-disease-illustration.jpg

8.7.1 Symptoms of von Willebrand Disease Several von Willebrand syndrome sufferers have moderate cases with no indications. More serious instances present with indications like (Okpala, 2004): • •

Prolonged stuffy noses; frequently excessive bleeding during surgery or trauma; easy bruises Women’s heavy periods of bleeding

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Prolonged gum hemorrhage during dental procedures Blood within pee or stools

8.8 EFFECTS OF BLOOD DISORDERS Mixing liquids and solids may be found in your blood. Water, proteins, and salts are found in the liquid portion (plasmic). A blood issue might arise when a component of your blood isn’t functioning properly. Blood diseases often include (Leikin et al., 1989): •

The platelet, WBCs, or rRBCs make up your blood’s solid constituent. • The blood proteins are involved in blood coagulation. Individuals having red blood cell abnormalities also consume sufficient strong red blood cells to transport oxygen for their tissues. They might feel chilly, fatigued, or feeble. White blood cell abnormalities may make a person feel sick and increase their risk of becoming infected. Bleeding and clotting issues may occur in people having platelet problems (Darghouth et al., 2011).

8.8.1 Types of Blood Disorders White blood cell diseases, red blood cell diseases including anemia, and hemorrhage (platelet) problems are all examples of benign blood conditions. Including sickle cell disease, leukemia, and lymphoma, various blood abnormalities may be fatal or lead to chronic sickness (Yusuf et al., 2011).

Bleeding (platelet) disorders Platelets assist to stop bleeding by forming clots. Disorders of bleeding (platelets) are rare. If you have a bleeding problem, you can bleed excessively after an accident or following surgery. Medical illnesses or drugs may contribute to polycythemia vera or they may be acquired. Some are genetically determined. Sometimes bleeding problems have no recognized etiology (Jenerette et al., 2005).

Red blood cell disorders Oxygen is carried by red blood cells all over the system. When one of these blood cells’ components is malfunctioning, you might have a red blood cell problem. Diseases of the red blood cell include (Pearson et al., 1985):

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• • • •

Anemia. Polycythemia vera. Sickle cell disease. Thalassemia.

White blood cell disorders The bone marrow is where WBCs are mostly produced. You create roughly 100 billion white blood cells daily, excluding infections or blood disorders. WBCs, come in five different varieties: neutrophils, lymphocytes, monocyte, eosinophils, and basophils. In human blood, each kind of white blood cell serves a distinct purpose (Damanhouri et al., 2015). Leukopenias were a blood condition characterized by unusually low numbers of white blood cells. You are more vulnerable to infections if you already have leukopenia. Leukocytosis is just a blood condition marked by excessively high amounts of WBCs (Tanabe et al., 2019).

8.8.2 Symptoms and causes of Blood Disorder Medical illnesses or drugs may contribute to bleeding complaints or they may be developed. Many are familial. Occasionally bleeding problems have no recognized etiology. White blood cell counts that are abnormally low (leukopenias) may be caused by (Sachdev et al., 2021): • Acute infections. • Fasting. • Excessive physical strain. • Corticosteroids. • Cancer treatments such as chemo and radiotherapy. • Malnourishment. White blood cell overproduction (leukocytosis) has a variety of causes, such as (Platt, 2008): • • •

Infection. Emotional or physical stress is too great. Burns.

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Diseases of the immune response, such as lupus and autoimmune diseases. Thyroid issues.

8.9 DIAGNOSIS AND TESTS Medical professionals with a specialty in blood disorders and health are known as hematologists. Individuals with blood problems are treated there (Vanderhave et al., 2018). To diagnose blood problems, your hematologist will require a medical, a physical exam, and request laboratory tests. Your doctor may request several blood tests, such as a complete blood count (CBC), to check your hemoglobin levels, red blood cell shape and size, and the variety of platelet and white blood cells in your blood. To screen for particular blood diseases such as von Willebrand disease as well as polycythemia vera, your doctor may prescribe additional, more focused tests. Your doctor could request bone marrow biopsies under unusual circumstances (Connes et al., 2011). It may occasionally be challenging to diagnose clotting issues. Even after rigorous testing, no problems were found despite the bleeding sensations you could be experiencing. This may cause you and your doctor frustration, particularly when determining whether or not it is acceptable to do the procedure. Despite these challenges, coagulation therapy is a highly researched field, and significant advancements have been achieved even in the previous 10 years (Lee et al., 2019).

8.9.1 Management And Treatment Treatment options exist for several blood diseases. Others could benefit from therapy even if the disease is not resolved since it may reduce stress and anxiety and avoid consequences. To discover further about your prognosis and the best course of therapy for you, speak to contact your medical physician. Based on the condition, treatments might range from simple monitoring to using corticosteroids and other immune-suppressing drugs, transfusion or clotting factors assistance, growth factor augmentation, chemotherapy, and bone marrow transplants. Just like with any prescription, it’s crucial to follow your doctor’s instructions about how often to just have blood tests or in what way to take your medicines (Treadwell et al., 2006).

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Anemia •

•

•

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Autoimmune hemolytic anemia:  A disorder known as autoimmunity hemolysis occurs when your body produces autoantibodies that attack your natural red blood cells. The immune response may be suppressed as well as red blood cell apoptosis can be stopped by steroids. However, using steroids over an extended period might have negative long-term repercussions including osteoporosis. Most patients react well to steroid therapy. Your doctor may try alternative medications, including intravenous immunoglobulin (IVIG), cyclophosphamide, or cyclosporine, when you recover. There may be a must to extract your spleen. Chronic anemia:  Treatments of the underlying pathology may result in improvements for persistent anemia (contamination, stiffness, heart, lung, or kidney disease). A red blood cell transplant can be required if it is not feasible and severe anemia is creating symptoms. Additionally, your doctor could advise a hormonal (recombinant human erythropoietin). In cases when there aren’t enough red blood cells inside the bone marrow, including in systemic therapy anemia, genetic defects, and severe anemia, erythropoietin also is helpful. They are especially helpful in treating anemia brought on by kidney illness, which is brought on by a lack of antidiuretic hormone synthesis in a few kidney cells with specific functions. Nutritional deficiency anemia:  Your doctor can advise oral iron pills, vitamin B12 injection, or oral folic acid for anemia brought on by dietary deficits. Sickle cell anemia:  It might be challenging to treat sickle cell disease. Rapid treatment may lessen the severity of a sickle-cell disease crisis and hasten your recovery if indeed the underlying issue, including an infection, could be found. Strong painrelieving narcotics drugs are necessary to manage an extreme pain episode. Additionally, if you do have serious symptoms that affect your ability to breathe and cardiac functioning or whether you›re undergoing surgery, your doctor could prescribe blood products. Patients with this condition who get regular transfusions or exchange transfusions may also avoid recurrent

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strokes. However, iron overload issues caused by continuous transfusion lead to excess iron deposits inside the liver, cardiac, as well as other organs. These organs may have issues as a result. To assist prevent these issues, your physician could administer preliminary treatment (Exjade®) or desferrioxamine. It’s been discovered that the medication hydroxyurea reduces both the frequency and intensity of sickle-cell disease crises.

Low platelet count (thrombocytopenia) With anemia, there is no medication known that consistently improves the hematocrit levels for disorders involving contains a definition of platelets inside the bone marrow. Nevertheless, even a somewhat low platelet count may not need to be treated when it does not result in fatal bleeding. Platelet transfusions are necessary to either lower the risk of bleeding or stop hemorrhage in patients with bone marrow disorders that cause very decreased platelet levels or in those who have serious thrombocytopenia with bleeding following chemotherapy. Platelet transfusions are only done shortly to get you through a time of maximum danger since transfused platelet circulation for approximately 3–4 days and since antiplatelet antibodies might develop following prolonged exposure to injected directly cells (Mulumba & Wilson, 2015).

Bleeding disorders You might not have a diagnosis for moderate hemophilia and the majority of cases of von Willebrand disease before maturity when you have invasive procedures and your pre-operative examination reveals irregular clotting times. When you can visit a hematologist, your operation can be postponed. Desmopressin, which raises levels of clotting factors (factors VIII or von Willebrand factor) when administered as a test dosage, may be administered if an underlying problem is discovered. This drug may assist hemostasis after a small surgical operation if a significant enough rise is seen. If not, or whether it was a serious procedure (such as a heart or brain operation), factor VIII or von Willebrand factor concentrations should be given just before the operating condition and kept up for a few days thereafter (Rosendaal et al., 1990).

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Clotting disorders Many blood clotting (coagulation) diseases are hereditary, but normally don’t reveal symptoms before later in life. Certain clots may form naturally or without clear reason. However, blood clots that occur following surgery or long periods without movement are more prevalent. Anti-coagulant treatment seems to be the recommended course of action in every situation. Your chance of forming a clot is higher after specific kinds of operations, including orthopedic surgeries just on lower limbs or spinal surgery. Clinical studies have established the effectiveness of administering blood thinners (heparin or warfarin) to patients who have these operations to lower the occurrence of clots (Ronner et al., 2020). Blood clots that have already formed may also be treated with blood thinners. Systemic heparin will be the first step of the treatment, then oral warfarin. You might be able to independently drugs at home if the thrombus is straightforward. The typical duration of anticoagulant medication is 3 to 6 months. Your medication may continue longer or be ongoing if you already have repeated thrombotic events, particularly pulmonary embolism, especially if you do have blood clotting disorder test indicators (Corwin & Krantz, 2000).

8.9.2 Prevention There are things you may do to lower your risk of consequences even if certain blood abnormalities cannot be avoided. Early diagnosis and treatment are crucial for this reason. Although blood diseases cannot be avoided, taking excellent care of yourself may lower your chance of consequences. This implies (Inokuchi et al., 2003): •

• • • • •

Consume foods high in iron such as egg, turkeys, ground beef, organ meats like kidney and liver, legume like black beans, green leafy vegetables, and brown rice as part of a balanced diet. Exercise often to stay active. Avoid being still for extended stages of time. Keep a healthy mass. Sip a lot of water. Visit your doctor for routine checkups, and make sure to comply with any orders for blood testing.

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Take precautions against infection. Always hands should be washed frequently. Discuss the seasonal flu vaccination with your doctor (vaccine).

8.9.3 Outlook / Prognosis You might have to get blood testing if your doctor suspects you could have a blood issue. You would need to take excellent care of yourself, which includes eating a planned, healthy diet that includes adequate exercise if indeed the blood tests reveal a blood problem. You could need medicine or other therapies, and a hematologist might be suggested. While certain blood diseases may be managed with medication, others might be lifelong. The great news would be that therapy often reduces discomfort and aids with complication management (Ye et al., 2009). •

•

•

•

Anemia:  Whenever your anemia is not addressed, it may result in heart failure, an oversized heart, or perhaps arrhythmias. Additionally, you have a higher chance of contracting illnesses and developing depression. Clotting disorders:  Thrombosis may form in both the arteries which take blood out of the heart and the veins that supply blood to the heart among individuals having clotting problems (veins). Your probability of cardiac arrest, strokes, acute leg pain, trouble moving, and even amputation is increased by thrombosis in the arteries. Thrombosis inside the veins may enter the circulation and move to the lungs or deep into the body, where it can fully or partly block veins (pulmonary embolism). Hemophilia:  Some hemophiliacs produce antibodies that are treatment-inhibiting inhibitors. This implies that the drug you use to halt bleeding may not be effective. To prevent harm, you must exercise caution. Joint degeneration and discomfort from arthritis may also result from hemophilia. Sickle cell anemia:  Sickle cell issues start early in childhood and persist all the way through. The damage to your lungs, neurological issues, visual loss, or acute or persistent discomfort are all possible. Additionally, you have a higher chance of getting thrombus in your lungs or deep venous thrombosis, which may fully or partly block veins throughout your body (pulmonary

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•

•

embolism). Sickle cell illness increases the risk of hypertension, blood clots, miscarriages, birth weight, and early delivery in pregnant women. A syndrome that occurs when malformed cells obstruct flow from the head of the penis might affect men having sickle cell anemia (priapism). A long-lasting erection of the penis may result in discomfort and even impotence. Thrombocytopenia:  Severe internally and externally loss of blood is a possibility for you (hemorrhage). Intracerebral hemorrhage, internal injuries to the brain or gastrointestinal system, may be fatal. You are often more susceptible to infections if you already have your spleen removed. Make careful to adhere to your doctor’s directions about the use of drugs and vaccinations. Von Willebrand disease:  Von Willebrand syndrome problems are more common in women than in males. In menstrual periods and then after delivery, excessive bleeding might be problematic. If you already have bleeding in your joints or soft tissues, it might hurt like hell. Internal bleeding may sometimes result in death if left untreated.

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REFERENCES 1.

Abramson, N., & Melton, B. (2000). Leukocytosis: basics of clinical assessment. American family physician, 62(9), 2053-2060. 2. Bashour, F. N., Teran, J. C., & Mullen, K. D. (2000). Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease. The American journal of gastroenterology, 95(10), 2936-2939. 3. Beckman, J. D., Belcher, J. D., Vineyard, J. V., Chen, C., Nguyen, J., Nwaneri, M. O., ... & Vercellotti, G. M. (2009). Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1243-H1253. 4. Bi, L., Lawler, A. M., Antonarakis, S. E., High, K. A., Gearhart, J. A., & Kazazian, H. H. (1995). Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nature genetics, 10(1), 119-121. 5. Böhm, M., Täschner, S., Kretzschmar, E., Gerlach, R., Favaloro, E. J., & Scharrer, I. (2006). Cold storage of citrated whole blood induces drastic time-dependent losses in factor VIII and von Willebrand factor: potential for misdiagnosis of haemophilia and von Willebrand disease. Blood coagulation & fibrinolysis, 17(1), 39-45. 6. Brousseau, D. C., Panepinto, J. A., Nimmer, M., & Hoffmann, R. G. (2010). The number of people with sickle-cell disease in the United States: national and state estimates. Am J Hematol, 85(1), 77-78. 7. Carmeliet, P. (2003). Blood vessels and nerves: common signals, pathways and diseases. Nature Reviews Genetics, 4(9), 710-720. 8. Chulilla, J. A. M., Colás, M. S. R., & Martín, M. G. (2009). Classification of anemia for gastroenterologists. World Journal of Gastroenterology: WJG, 15(37), 4627. 9. Coller, B. S. (2005). Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene?. Arteriosclerosis, thrombosis, and vascular biology, 25(4), 658-670. 10. Connes, P., Machado, R., Hue, O., & Reid, H. (2011). Exercise limitation, exercise testing and exercise recommendations in sickle cell anemia. Clinical hemorheology and microcirculation, 49(1-4), 151-163.

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RNA and Life Threatening Diseases

11. Corwin, H. L., & Krantz, S. B. (2000). Anemia of the critically ill:“Acute” anemia of chronic disease. Critical care medicine, 28(8), 3098-3099. 12. Creary, M., Williamson, D., & Kulkarni, R. (2007). Sickle cell disease: current activities, public health implications, and future directions. Journal of women’s health, 16(5), 575-582. 13. Dale, D. C., Fauci, A. S., & Wolff, S. M. (1975). Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone. The Journal of clinical investigation, 56(4), 808-813. 14. Damanhouri, G. A., Jarullah, J., Marouf, S., Hindawi, S. I., Mushtaq, G., & Kamal, M. A. (2015). Clinical biomarkers in sickle cell disease. Saudi journal of biological sciences, 22(1), 24-31. 15. Darghouth, D., Koehl, B., Madalinski, G., Heilier, J. F., Bovee, P., Xu, Y., ... & Roméo, P. H. (2011). Pathophysiology of sickle cell disease is mirrored by the red blood cell metabolome. Blood, The Journal of the American Society of Hematology, 117(6), e57-e66. 16. Dou, X., Poon, M. C., & Yang, R. (2020). Haemophilia care in China: achievements in the past decade. Haemophilia, 26(5), 759-767. 17. Elstrott, B., Khan, L., Olson, S., Raghunathan, V., DeLoughery, T., & Shatzel, J. J. (2020). The role of iron repletion in adult iron deficiency anemia and other diseases. European journal of haematology, 104(3), 153-161. 18. Evans, R. S., & Duane, R. T. (1949). Acquired hemolytic anemia: I. The relation of erythrocyte antibody production to activity of the disease. II. The significance of thrombocytopenia and leukopenia.  Blood,  4(11), 1196-1213. 19. Faux, N. G., Rembach, A., Wiley, J., Ellis, K. A., Ames, D., Fowler, C. J., ... & Bush, A. I. (2014). An anemia of Alzheimer’s disease. Molecular psychiatry, 19(11), 1227-1234. 20. Feldman, B. M., Berger, K., Bohn, R., Carcao, M., Fischer, K., Gringeri, A., ... & Schramm, W. (2012). Haemophilia prophylaxis: how can we justify the costs?. Haemophilia, 18(5), 680-684. 21. Ferguson, B. J., Skikne, B. S., Simpson, K. M., Baynes, R. D., & Cook, J. D. (1992). Serum transferrin receptor distinguishes the anemia of chronic disease from iron deficiency anemia. The Journal of laboratory and clinical medicine, 119(4), 385-390

Blood Diseases

223

22. Frenette, P. S., & Atweh, G. F. (2007). Sickle cell disease: old discoveries, new concepts, and future promise. The Journal of clinical investigation, 117(4), 850-858. 23. Gater, A., Thomson, T. A., & Strandberg-Larsen, M. (2011). Haemophilia B: impact on patients and economic burden of disease. Thrombosis and haemostasis, 106(09), 398-404. 24. Giangrande, P. (2005). Haemophilia B: christmas disease. Expert opinion on pharmacotherapy, 6(9), 1517-1524. 25. Gomollón, F., & Gisbert, J. P. (2013). Current management of iron deficiency anemia in inflammatory bowel diseases: a practical guide. Drugs, 73(16), 1761-1770. 26. Gonzalez-Casas, R., Jones, E. A., & Moreno-Otero, R. (2009). Spectrum of anemia associated with chronic liver disease. World journal of gastroenterology: WJG, 15(37), 4653. 27. Heukelbach, J., Poggensee, G., Winter, B., Wilcke, T., Kerr-Pontes, L. R. S., & Feldmeier, H. (2006). Leukocytosis and blood eosinophilia in a polyparasitised population in north-eastern Brazil. Transactions of the Royal Society of Tropical Medicine and Hygiene, 100(1), 32-40. 28. Hunter, N., Foster, J., Chong, A., McCutcheon, S., Parnham, D., Eaton, S., ... & Houston, F. (2002). Transmission of prion diseases by blood transfusion. Journal of General Virology, 83(11), 2897-2905. 29. Ingram, G. I. (1976). The history of haemophilia. Journal of clinical pathology, 29(6), 469. 30. Inokuchi, K., Dan, K., Takatori, M., Takahuji, H., Uchida, N., Inami, M., ... & Shimada, T. (2003). Myeloproliferative disease in transgenic mice expressing P230 Bcr/Abl: longer disease latency, thrombocytosis, and mild leukocytosis. Blood, 102(1), 320-323. 31. Ivanov, S. D., Korytova, L. I., Yamshanov, V. A., Ilyn, N. V., & Sibirtsev, V. S. (1997). Leukopenia prognosis by radiation therapy of patients with Hodgkin’s disease. Journal of Experimental & Clinical Cancer Research: CR, 16(2), 183-188. 32. Jenerette, C., Funk, M., & Murdaugh, C. (2005). Sickle cell disease: a stigmatizing condition that may lead to depression. Issues in Mental Health Nursing, 26(10), 1081-1101. 33. Knobe, K., & Berntorp, E. (2011). Haemophilia and joint disease: pathophysiology, evaluation, and management. Journal of Comorbidity, 1(1), 51-59.

224

RNA and Life Threatening Diseases

34. Koshy, M., Weiner, S. J., Miller, S. T., Sleeper, L. A., Vichinsky, E., Brown, A. K., ... & Kinney, T. R. (1995). Surgery and anesthesia in sickle cell disease. Cooperative Study of Sickle Cell Diseases, (Vol. 1, pp. 3-9). 35. Landolfi, R., Di Gennaro, L., Barbui, T., De Stefano, V., Finazzi, G., Marfisi, R., ... & European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP). (2007). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood, 109(6), 2446-2452. 36. Lee, L., Smith-Whitley, K., Banks, S., & Puckrein, G. (2019). Reducing health care disparities in sickle cell disease: a review. Public Health Reports, 134(6), 599-607. 37. Leikin, S. L., Gallagher, D., Kinney, T. R., Sloane, D., Klug, P., & Rida, W. (1989). Mortality in children and adolescents with sickle cell disease. Pediatrics, 84(3), 500-508. 38. Lervolino, L. G., Baldin, P. E. A., Picado, S. M., Calil, K. B., Viel, A. A., & Campos, L. A. F. (2011). Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Revista brasileira de hematologia e hemoterapia, 33, 49-54. 39. Li, X., Dao, M., Lykotrafitis, G., & Karniadakis, G. E. (2017). Biomechanics and biorheology of red blood cells in sickle cell anemia. Journal of biomechanics, 50, 34-41. 40. Liu, W., Xue, F., Poon, M. C., Chen, L., Jin, Z., Zhang, L., & Yang, R. (2021). Current status of haemophilia inhibitor management in mainland China: a haemophilia treatment centres survey on treatment preferences and real‐world clinical practices. British Journal of Haematology, 194(4), 750-758. 41. Lucroy, M. D., & Madewell, B. R. (2001). Clinical outcome and diseases associated with extreme neutrophilic leukocytosis in cats: 104 cases (1991–1999). Journal of the American Veterinary Medical Association, 218(5), 736-739. 42. Mazurier, C. (1992). von Willebrand disease masquerading as haemophilia A. Thrombosis and haemostasis, 67(04), 391-396. 43. McCullough, S. (2003). Immune-mediated hemolytic anemia: understanding the nemesis. Veterinary Clinics: Small Animal Practice, 33(6), 1295-1315.

Blood Diseases

225

44. McKee Jr, L. C. (1985). Excess leukocytosis (leukemoid reactions) associated with malignant diseases. Southern medical journal, 78(12), 1475-1482. 45. Milhorat, A. T., Small, S. M., & Diethelm, O. (1942). Leukocytosis during various emotional states. Archives of Neurology & Psychiatry, 47(5), 779-792. 46. Miller, J. L. (2013). Iron deficiency anemia: a common and curable disease. Cold Spring Harbor perspectives in medicine, 3(7), a011866. 47. Mulumba, L. L., & Wilson, L. (2015). Sickle cell disease among children in Africa: an integrative literature review and global recommendations. International Journal of Africa Nursing Sciences, 3, 56-64. 48. Okpala, I. (2004). The intriguing contribution of white blood cells to sickle cell disease–a red cell disorder. Blood reviews, 18(1), 65-73. 49. Passamonti, F., Rumi, E., Pietra, D., Elena, C., Boveri, E., Arcaini, L., ... & Cazzola, M. (2010). A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia, 24(9), 1574-1579. 50. Pearson, H. A., Gallagher, D., Chilcote, R., Sullivan, E., Wilimas, J., Espeland, M., ... & Cooperative Study of Sickle Cell Disease. (1985). Developmental pattern of splenic dysfunction in sickle cell disorders. Pediatrics, 76(3), 392-397. 51. Pearson, H. A., Spencer, R. P., & Cornelius, E. A. (1969). Functional asplenia in sickle-cell anemia. New England Journal of Medicine, 281(17), 923-926. 52. Platt, O. S. (2008). Hydroxyurea for the treatment of sickle cell anemia. New England Journal of Medicine, 358(13), 1362-1369. 53. Poggiali, E., De Amicis, M. M., & Motta, I. (2014). Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. European journal of internal medicine, 25(1), 12-17. 54. Prakash, D. (2012). Anemia in the ICU: anemia of chronic disease versus anemia of acute illness. Critical care clinics, 28(3), 333-343. 55. Riley, L. K., & Rupert, J. (2015). Evaluation of patients with leukocytosis. American family physician, 92(11), 1004-1011. 56. Ronner, L., Podoltsev, N., Gotlib, J., Heaney, M. L., Kuykendall, A. T., O’Connell, C., ... & Mascarenhas, J. (2020). Persistent leukocytosis

226

57.

58.

59.

60.

61.

62. 63.

64.

65.

66.

RNA and Life Threatening Diseases

in polycythemia vera is associated with disease evolution but not thrombosis. Blood, 135(19), 1696-1703. Rosendaal, F. R., Briet, E., Stibbe, J., Herpen, G. V., Leuven, J. G., Hofman, A., & Vandenbroucke, J. P. (1990). Haemophilia protects against ischaemic heart disease: a study of risk factors. British journal of haematology, 75(4), 525-530. Sachdev, V., Rosing, D. R., & Thein, S. L. (2021). Cardiovascular complications of sickle cell disease. Trends in Cardiovascular Medicine, 31(3), 187-193. Socié, G., Rosenfeld, S., Frickhofen, N., Gluckman, E., & Tichelli, A. (2000, January). Late clonal diseases of treated aplastic anemia. In Seminars in hematology (Vol. 37, No. 1, pp. 91-101). WB Saunders. Song, X., Liu, W., Xue, F., Zhong, J., Yang, Y., Liu, Y., ... & Yang, R. (2020). Real‐world analysis of haemophilia patients in China: a single centre’s experience. Haemophilia, 26(4), 584-590. Stevens, T., Rosenberg, R., Aird, W., Quertermous, T., Johnson, F. L., Garcia, J. G., ... & Garfinkel, S. (2001). NHLBI workshop report: endothelial cell phenotypes in heart, lung, and blood diseases. American Journal of Physiology-Cell Physiology, 281(5), C1422-C1433. SYDENSTRICKER, V. P. (1924). Further observations on sickle cell anemia. Journal of the American Medical Association, 83(1), 12-17. Tanabe, P., Spratling, R., Smith, D., Grissom, P., & Hulihan, M. (2019). Understanding the complications of sickle cell disease. The American journal of nursing, 119(6), 26. Treadwell, M. J., McClough, L., & Vichinsky, E. (2006). Using qualitative and quantitative strategies to evaluate knowledge and perceptions about sickle cell disease and sickle cell trait. Journal of the National Medical Association, 98(5), 704. Unda, S. R., Antoniazzi, A. M., Altschul, D. J., & Marongiu, R. (2021). Peripheral Leukocytosis Predicts Cognitive Decline but Not Behavioral Disturbances: A Nationwide Study of Alzheimer’s and Parkinson’s Disease Patients. Dementia and geriatric cognitive disorders, 50(2), 143-152. Van Vulpen, L. F. D., Holstein, K., & Martinoli, C. (2018). Joint disease in haemophilia: Pathophysiology, pain and imaging. Haemophilia, 24, 44-49.

Blood Diseases

227

67. Vanderhave, K. L., Perkins, C. A., Scannell, B., & Brighton, B. K. (2018). Orthopaedic manifestations of sickle cell disease. JAAOSJournal of the American Academy of Orthopaedic Surgeons, 26(3), 94-101. 68. Vichinsky, E. P., & Lubin, B. H. (1980). Sickle cell anemia and related hemoglobinopathies. Pediatric Clinics of North America, 27(2), 429447. 69. Ware, R. E., de Montalembert, M., Tshilolo, L., & Abboud, M. R. (2017). Sickle cell disease. The Lancet, 390(10091), 311-323. 70. Weiss, G., & Goodnough, L. T. (2005). Anemia of chronic disease. New England Journal of Medicine, 352(10), 1011-1023. 71. Yamada, T., Wakabayashi, M., Yamaji, T., Chopra, N., Mikami, T., Miyashita, H., & Miyashita, S. (2020). Value of leukocytosis and elevated C-reactive protein in predicting severe coronavirus 2019 (COVID-19): a systematic review and meta-analysis. Clinica chimica acta, 509, 235-243. 72. YANKOWITZ, J., & WEINER, C. P. (1996). Blood transfusion for haemolytic disease as a cause of leukocytosis in the fetus. Prenatal diagnosis, 16(8), 719-722. 73. Ye, L., Chang, J. C., Lin, C., Sun, X., Yu, J., & Kan, Y. W. (2009). Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases. Proceedings of the National Academy of Sciences, 106(24), 9826-9830. 74. Yusuf, H. R., Lloyd-Puryear, M. A., Grant, A. M., Parker, C. S., Creary, M. S., & Atrash, H. K. (2011). Sickle cell disease: the need for a public health agenda. American journal of preventive medicine, 41(6), S376-S383. 75. Zadrazil, J., & Horak, P. (2015). Pathophysiology of anemia in chronic kidney diseases: A review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 159(2), 197-202.

INDEX

A

C

Acetylcholinesterase 150, 154 Acute rheumatic fever 120 Allpahuayo virus (ALLV) 100 Alzheimer’s disease (AD) 15 Anemia 196, 197, 198, 199, 208, 211, 214, 216, 219, 222, 225, 227 angina 118, 119 aortic aneurysms 118 Arenavirions 96 Arenavirus 97, 99, 100, 101, 102, 105, 111, 114, 115 Artibeus jamaicensis trinitatis 98 ataxia 68, 69, 70, 71, 72, 73, 82, 83, 84, 85, 87, 88, 89, 90, 91, 92, 93 autism spectrum disease 68

Calomys callosus 98 Calomys musculinus 98 cardiac abnormalities 120, 133 cardiac systems 50 cardiovascular disease 118, 119, 121, 122, 123, 124, 128, 132, 136, 138, 139, 140, 141, 142, 143, 145 cell plasma membrane 98 Central nervous system 68 Chandipura virus 104 Chapare virus (CHPV) 100 chromosome 50, 51, 53, 57, 62, 65 chronic tiredness 71 circulatory system 118, 134 Collierville virus 103, 105, 107 colon 167, 171, 173, 175, 181 confidence interval (CI) 177 congenital heart defects 118 Coronary artery disease 118 cystic fibrosis transmembrane regulator (CFTR) 15

B Basophilia 203 Bear Canyon virus (BCNV) 100 bladder 167, 172 branch point sequence (BPS) 8 breast cancers 167

230

RNA and Life Threatening Diseases

D DALYs (disability-adjusted life years) 148 deep vein thrombosis (DVT) 121 Dementia 150 dementia care 152, 154 Diabetes mellitus (DM) 166 disease control 148 disease-free survival (DFS) 175 Dysautonomia 71 dystrophia myotonic protein kinase (DMPK) 52 dystrophin 6, 13, 36, 39

E echocardiogram 58 Electrocardiogram 58 electromyographic (EMG) 52 electromyography 51, 57 endometrial 167, 172, 175, 177, 188 endoplasmic reticulum (ER) 97 Eosinophilia 203 Exonic splicing enhancers (ESEs) 10 exonic splicing silencers (ESSs) 10

F Flexal virus (FLEV) 100 fragile Cross neuropsychiatric (FXAND) 69 fragile X-associated tremor/ataxia syndrome 68, 71, 87, 88, 89, 90, 91, 92, 93 fragile X-associated uncontrollable shaking syndrome (FXTAS) 69 Fragile X disorder 68 fragile X intellectual disabilities protein (FMRP) 69

G Gene mutation 6, 15 Genetic loci 6 glycoprotein precursor (GPC) 96 Guanarito virus (GTOV) 100

H hearing impairment 71 Heart disease 119 heart lining disorders 121 heart valve illnesses 121 Hemophilia 196, 201, 219 Hepatitis B and C virus (HBV and HCV) infections 169 hepatocellular carcinomas (HCC) 169 herbicides 72 host cell ribosomes 96 Human rights abuses 149 hyperthyroidism 58

I insecticides 70, 72 intergenic noncoding region (IGR) 96 internal hemorrhage 199 International Committee on Nomenclature of Viruses (ICNV) 99 intracellular nucleotide protein complex 54 intronic splicing enhancers (ISEs) 10

K kidney 167, 172, 176, 177, 189

L Lassa virus 99, 102, 113

Index

Leukocytosis 196, 203, 214, 221, 223, 224, 225, 226 liver 167, 168, 169, 171, 172, 174, 175, 176, 178, 179, 186, 190, 191, 192 Lujo virus (LUJV) 100 lymphocytic choriomeningitis virus 98 Lymphocytosis 203

M Machupo virus (MACV) 98 mammalian arenaviruses 96, 104, 108, 109, 110 mammals 96, 97, 103, 104 mental disorders 71 mental illnesses 148 mental stress 152 mixed dementia 150 Mobala virus (MOBV) 100 Monocytosis 203 Mopeia virus (MOPV) 100 muscle hypertrophy 57 mutation 9, 11, 13, 15, 16, 21, 22, 24, 27, 29, 31, 34, 39 myocarditis 118 Myotonia 51, 53, 57, 59 myotonic dystrophy 50, 52, 55, 58, 61, 63, 64, 65, 66 Myotonic dystrophy type 2 (DM2) 50

N neurological disorder 71 neurological disorders 148, 149 Neutrophilia leukocytosis 203 next-generation 102

231

nonalcoholic fatty liver disease (NAFLD) 169 non-lymphoma 167, 173 nucleoprotein (NP) 96

O open reading frames (ORF) 96 oral hypoglycemic agents (OHA) 177 ostracization 149 overall survival (OS) 175

P pancreatic 167, 168, 171, 172, 175, 177, 178, 179, 188, 189, 190, 191, 192, 194 pathophysiology 55, 56 peripheral artery disease 118 Pirital virus (PIRV) 100 polycythemia vera (PV) 203 polymerase chain reaction (PCR) 53 polypeptides 8, 19, 35 premature stop codon (PTC) 14 proximal myotonic myopathy 57, 64 psychiatric disorders 148 Pulmonary Embolism (PE) 121

R Red blood cell deficiency 196 Rheumatic fever 120 ribonucleoprotein 2 ribonucleoprotein (RNP) 97

S Sabia’ virus (SABV) 100 sensory deficit 71 sensory impairment 71

232

RNA and Life Threatening Diseases

Sickle cell disease 196, 214, 222, 223, 225, 227 skinny systems 54 Snipping procedure 13 Social segregation 152 spliceosome 4, 6, 9, 17 stable signal peptide (SSP) 97 strokes 118, 119, 122, 123, 127, 129 such atherosclerotic lesions 119 Symptomatic epilepsy 156

T Tacaribe virus (TCRV) 98 Tamiami viruses (TAMV) 98 Thalassemia 196, 208, 209, 210, 214 thromboembolism 118

Thyroid function testing 58 transcriptase 2 transformation 2, 8, 19, 23

U untranslated regions (UTRs) 4

V vascular dementia 150, 152 ventricular septal defect (VSD) 120 viral ecology 102 viral genomes 102 viral metagenomics 102, 103 virion envelope 98 Von Willebrand disease 196, 211, 220