Genetics and Neurobiology of Down Syndrome

By Bani Bandana Ganguly

Genetics and Neurobiology of Down Syndrome provides a thorough review of the genetic etiology and mechanisms of trisomy 21. The author discusses the history of the syndrome, along with the clinical features and health consequences, including physical features, cognitive, and neurologic symptoms. Genetic counseling on pros and cons of prenatal screening and testing and associated ethical issues are explored. This unique book also covers the societal and demographic aspects as well as the future direction of therapeutic development.

• Reviews genetic etiology and mechanisms of trisomy 21
• Discusses prenatal screening and genetic counseling, including ethical aspects
• Explores link between Down Syndrome and susceptibility to Alzheimer’s and early brain aging
• Covers cognitive and neurological symptoms and other health consequences
• Identifies future therapeutic developments

• Language: English
• Publisher: Academic Press
• Release date: Aug 21, 2022
• ISBN: 9780323904575

Bani Bandana Ganguly

The author is a Geneticist by education and profession, and has accumulated over 36 years of experience in research and diagnosis. Her main areas of research revolved around Human Genetics, including in vitro testing of industrial chemicals, hazard assessment of accidental and environmental exposures, radiation bio-dosimetry, genetic counseling and diagnosis of heritable and acquired genetic diseases. Her involvement in the screening of chromosomal alterations in methyl isocyanate gas (MIC) exposed population of Bhopal, India shortly after the disaster and 30 years later has earned wide recognition through publications, awards and felicitations. She has established India’s first CAP accredited Genetic Diagnostic Laboratory to cater the service across India and neighboring countries. The diagnostic service also included testing of Inteferon-a and Dasatinib trials on CML patients. Her research work has been reflected through her publications in peer-reviewed journals. She has been an assessor for accreditation of medical laboratories for ISO 17025 and ISO 15189 standards. Her current interest is to produce an atlas of chromosome aberrations causing birth defects, pubertal delay and reproductive failure, and another one on chromosomal rearrangements in hematologic malignancies. She has been actively involved in teaching and training to pass on the knowledge acquired in the field of Genetics. She is a proud mother of two children (one is Robotics Scientist, California; other is Assistant Professor of Dentistry, India) and lives with her husband Prodosh in CBD Belapur, Navi Mumbai, India.

Book preview

Preface

Down syndrome (DS) is the most common chromosomal disorder caused by trisomy 21 (HSA21) and is largely influenced by the maternal age (≥35years). The syndrome cannot be cured as of now but prevented through prenatal screening and testing. The search on the contribution of the triplet set of HSA21 genes on the clinical features of the syndrome, particularly cognitive skill and early onset of aging and Alzheimer disease (AD), has always been a primary concern for improving the life of individuals suffering from this syndrome. However, variable expression of the trisomic HSA21 on different individuals with the syndrome could not label the genes with the syndromic features. The therapeutic approach for improvement of the cognitive sense has limited success due to severe side effects, including seizures. Several transgenic and gene knockout mouse models, stem cell lines, and trisomic organoids were developed for precise recognition of genes contributing to specific phenotypes. Targeted chromosome therapy following heterochromatinization of the extra chromosome using noncoding RNA transcribed from the XIST gene was successful in trisomic induced pluripotent stem cells in vitro; however, application of this technique in medical practice is far away. Collectively, a clear understanding of the clinical impact of genetic-epigenetic-environmental interaction in the presence of the extra HSA21 has yet to be clearly reached.

More than 60years have passed since identification of trisomy 21 as the heart of this syndrome, and more than 160years have passed after clinical characterization of the syndrome. Screening and preventive practices have been established with extensive awareness and participation of the at-risk population. Yet, the epidemiological index of the syndrome is estimated at one in 600–700 live births, and ∼90% of pregnancies with this trisomy die in utero. Despite accelerated acceptance of these children, societal discrimination and stigmatization pose serious psychological impact on the children as well as their families. Nevertheless, an early initiation of supportive medical intervention, specialized education, and vocational training in special schools is enabling them to live a better life with an increased life-span and to walk alongside their peers with normal genetic makeup in various walks of life.

This book aims to discuss the history of the syndrome; phenotypic features and health consequences; genetic counseling, prenatal screening and testing and associated ethical issues, societal and demographic aspects; genetic etiology and underlying mechanism of nondisjunction, and de novo and hereditary factors on acquisition of the extra HSA21; HSA21-encoded genes and the impact of their overexpression; dosage-sensitive genes and genotype–phenotype association; mitochondrial dysfunction, oxidative stress and associated diseases of the syndrome; genetic consequences of neurogenesis and cognitive disability in Down syndrome; glutamatergic and GABAergic mechanisms and therapeutic targets; consequences of Alzheimer disease; microRNAs and epigenetic signatures; in vivo and in vitro models of DS research; and future directions of therapeutic developments. Such information is available in text books on medical genetics, research articles, and research magazines in fragmented sections; however, this book attempts to comprehensively present all major aspects of the syndrome in a holistic manner. The book will surely be attractive to the medical practitioners and professionals engaged in teaching and education, geneticists, to a wider circle of biologists, public health educators and regulators, and Parent-Patient Groups across the globe. In a nutshell, this book will occupy a coveted place in every book shelf of all those who participate in the health of each family and collective health of our society.

Diagnosis catered to thousands of children born with Down syndrome and thousands of prenatal diagnoses with full, partial, and translocated HSA21 in trisomy, and counseling offered to their parents has prompted me to learn more about the impact of the smallest human chromosome 21. This compiled knowledge has been reshaped into this book. Indeed, this book has gathered copious information on the gene–dosage imbalance and interaction of the trisomic and disomic genes at the backdrop of an individual's own genetic makeup, allelic variation, and genetic modifiers, along with the impact of noncoding RNAs, and epigenetic and environmental factors on the life of individuals afflicted with the syndrome. Besides the effect of the dosage imbalance of nuclear genome, the role of cytoplasmic mitochondrial DNA (mtDNA) on impaired energy metabolism contributing to syndromic heart and brain defects is significant. In total, motivation accrued from decades of diagnostic work has left enormous temptation for accumulating all aberrant chromosome configurations and linking them to the clinical histories of patients of different ages, which is under preparation. Many years ago, it was my father's wish for me to apply my knowledge for the benefit of the common people that prompted me for a transition from fundamental research in the field of radiation and chemical mutagenesis to diagnostic research of hereditary and acquired genetic diseases. Put together, I hope my contribution in diagnostic research, and the labor put into this book will make my parents happy in their heavenly abode.

I do express my sincere gratitude to the management of Mahatma Gandhi Mission Trust, Mr. Kamal kishor Kadam, Chairman and Prof. Dr. Sudhir Kadam, Director of MGM Hospitals, Navi Mumbai, India, in particular, for extending their all-round support for this book. Special thanks are due to Prof. Dr. Nitin N. Kadam, Medical Director of MGM New Bombay Hospital, Vashi, Navi Mumbai, and Pro-Vice Chancellor of the MGM Institute of Health Sciences, Navi Mumbai, India, for his continual impetus for writing a book on Down syndrome, and kindly extending the required financial and administrative supports. I would also like to acknowledge the support and encouragement extended by Prof. Dr. S. Dalvi, the Vice Chancellor of the MGM Institute of Health Sciences, Navi Mumbai, India. Contribution of Ms. Swati Bhilare is also acknowledged for her support in literature search on several aspects of Down syndrome. The members of the editorial team at Elsevier Inc., USA—Melina Tucker, Samantha Allard, Joslyn T. Chaiprasert-Paguio, Maria Bernad and others are specially remembered and thanked for their immense contribution to broadening the scope of this book, and their spirited support through its entire construction. Sincere acknowledgments are also due to my family—my sons Dr. Shameek Ganguly (Robotics Researcher, California) and Dr. Shouvik Mandal (Assistant Professor Conservative in Dentistry, India), and my daughters-in-law Debapriya Pal (Sr. Software Engineer, Microsoft, California) and Dr. Alivia Mandal (Sr. Clinical Researcher, India) for their continuous encouragement, guidance and valuable comments, in spite of their busy schedules. I cannot thank my husband Mr. Prodosh Ganguly (Consultant in Banking Regulations) enough who has been right by my side through this entire effort. Lastly, I express my sincere gratitude to all those patients who shared their stories with me during genetic counseling or otherwise—it is their stories and questions that have propelled me to learn incessantly about genetic disorders, and gain a deeper understanding that I can share with the society.

I dedicate this book to my beloved late parents Prahlad Chandra Ghosh and Satadal Basini Ghosh, who always wanted me to utilize my education and skill for the good of mankind, and also to my late brother Prof. Bijay Krishna Ghosh for his unwavering faith in me, continuous inspiration, and his deep interest in the compilation of this book.

Bani Bandana Ganguly, Ph.D., FICMCH

January 27, 2022

Chapter 1: Down syndrome

history and overview

Bani Bandana Ganguly, and Nitin N. Kadam

Abstract

John Haydon Langdon Down was the first to characterize Down syndrome (DS) with facial features reminiscent to Blumenbach's Mongolian race. Hence, the syndrome was known much as mongoloid or Down's syndrome. However, neither descrtibing the features of a genetic disorder based on some features of a race was justified nor the use of eponym such as Down's syndrome was approved. Down syndrome as the ideal name was demonstrated by the National Institute of Health, the United States. Males with DS are more affected than the females. The disease occurs in all populations at all geographical territories, though Hispanics are at a higher risk compared to other population. The syndrome is caused by trisomy 21 or presence of three copies of the chromosome 21, which is highly influenced by the maternal age and caused by nondisjunction or mis-segregation of chromosomes, most likely during meiosis or gametogenesis. As such, the risk of recurrence is negligible; however, if parental Robertsonian translocation or balanced translocation contributes to the trisomy 21, there would be a hereditary factor to increase the risk of recurrence. More so, if one of the parents carries a Robertsonian translocation involving both 21s, their 100% pregnancies will have trisomy 21 or DS. Therefore, genetic characterization or karyotyping of the affected child and both parents is essential before planning of future pregnancy.

Keywords

History of Down syndrome; Incidence of down syndrome; Racial or ethnic variations; Risk of recurrence

1. History

English physician John Haydon Langdon Down first characterized Down syndrome (DS) in 1862 on a small group of children who had common physical features and were different from normal children with a distinct form of mental disability. The description was widely published in a report in 1866 (Down, 1866). Due to shared physical and facial similarities (epicanthic folds) of DS with those of Blumenbach's Mongolian race, JHL Down used the term mongoloid, which was derived from the prevailing ethnic theory (Conor, 1999). Some of the prominent characteristics in infants with DS includes decreased muscle tone, flat face, upslanting eyes, irregular-shaped ears, ability to extend joints beyond the usual, large space between the big toe and its neighboring toe, large tongue relative to the mouth, intellectual disability, etc (Fig. 1.1).

Because of Dr. J. L. Down's contribution to research on DS more than 150 years ago, the syndrome is much known today, which was named after him. However, there was a controversy that the first description of DS was made in 1838 by Jean Etienne Dominique Esquirol (1772–840), a founder of modern alienism, followed by another clinical description made by Édouard Séguin (1812–80) in 1844 (Who named it: http://www.whonamedit.com/synd.cfm/322.html). Even several years before, psychiatrist Andrew Levitas and geneticist Cheryl Reid identified a 16th-century Flemish Nativity painting in which one angelic figure appears distinctly different from other individuals in the painting with an appearance of DS (Fig. 1.1).

Historically, most individuals with DS were killed, abandoned, or ostracized from the society. In the 20th century, it was common for individuals with DS to be institutionalized and was denied appropriate treatment for the associated medical complications such as heart disorders, vision defects, intestinal problems, and so on. Many children with the syndrome, therefore, used to die during infancy or early adulthood. By the 20th century, DS had become the most recognizable form of mental retardation. With the rise of the eugenics movement, the forced sterilization of individuals with DS and comparable degree of disability was introduced to 33 of the then 48 US states and several other countries. The ultimate expression of this type of public policy was Action T-4 in Nazi Germany, a program of systematic murder. The sterilization program killed large proportions of people with DS until court challenges, scientific advances, and protests came from the general public, which led to its discontinuation or repeal of such sterilization program during the decades after World War II. Although at that point in history (middle of 20th century), the cause of DS was not understood and the syndrome was noticed in all races with rarity of recurrence. It was presumed that combination of several heritable genetic factors, older maternal age, birth injuries, and injury during pregnancy cause DS and illness with other physical and mental disabilities (Warkany, 1971).

Figure 1.1  The most known personalities: (A) Down syndrome diagnosis at the Adoration of the Christ Child. Available in Public domain: http://www.downsyndromeprenataltesting.com/down-syndrome-diagnosis-at-the-adoration-of-the-christ-child/. 16th-century Flemish Nativity painting of Down syndrome by unknown Flemish painter (1515) showing typical characteristics of Down syndrome in the angel next to Mary and also in one of the shepherds (Metropolitan Museum of Art, New York). (B) Dr. Down; (C) Kay McGee (Founder of National Association for Down Syndrome, USA) and his wife; and (D) their daughter Tricia with Down syndrome (from left). Reproduced from: (A) Levitas and Reid (2003). (B–D): National Association of Down Syndrome. https://www.nads.org/about-us/history-of-nads/. Accessed June 25, 2021.

With the discovery of karyotyping techniques in the 1950s, it became possible to identify abnormalities of the chromosomal number or shape. In 1959, Jérôme Lejeune discovered that DS results from genetic consequences with an extra chromosome (Lejeune et al., 1959) (Table 1.1). The extra chromosome was subsequently labeled as the 21 and the genetic condition of DS was known as trisomy 21. However, Lejuene's discovery was disputed when the Scientific Council of the French Federation of Human Genetics awarded Marthe Gautier with the Grand Prize for this discovery in 2014.

As time went by, many other people contributed to the study of DS as well. In 1930, Brewster and Cannon were the first to report an association between DS and acute leukemia, and later Schunk and Lehman were the first to report an association between Down's descriptions of the syndrome and transient leukemia in 1954. In 1959, Lejeune was the first to associate DS features with trisomy 21 genetics. So, it all developed into a chain of research, but it was John Langdon Down who established the first solid base for the study of the disorder. DS patients are also affected with other conditions, including congenital heart disease, Alzheimer disease, and early