Down syndrome : one smart cookie [First edition.] 9781944749613, 1944749616

Table of contents :
Cover
Down Syndrome: One Smart Cookie
Contents
Acknowledgments
Introduction
CHAPTER 1: Symptoms and Diagnosis
CHAPTER 2: Causes and Contributing Factors
CHAPTER 3: Treatment and Therapy
CHAPTER 4: Future Prospects
Conclusion
Glossary
Bibliography
Index
Ad Page
Back Cover

Citation preview

Down Syndrome One Smart Cookie

ECKDAHL

EBOOKS FOR THE HEALTH LIBRARY

Todd T. Eckdahl

HUMAN DISEASES AND CONDITIONS COLLECTION A. Malcolm Campbell, Collection Editor

This book presents Down syndrome, which is the most common

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chromosomal disorder in humans, occurring at a rate of about 1 in

THE CONTENT

be diagnosed prenatally or at birth, and the cause of Down syn-

• Nutrition and Dietetics Practice • Psychology • Health, Wellness, and Exercise Science • Health Education

drome as extra copies of the approximately 250 genes on chromo-

THE TERMS

Dr. Todd T. Eckdahl earned a BS in chemistry from the University of

700 births. It describes the characteristic physical features caused by Down syndrome and the myriad of symptoms and health complications it brings, including heart defects, congenital vision and hearing loss, abnormalities of the musculoskeletal system, digestive problems, epilepsy, leukemia, an increased risk of infectious disease, dementia, and intellectual disability.

Down Syndrome

Readers will learn about methods by which Down syndrome can

syndrome, and approaches to the education of children with it. Future prospects for the diagnosis and treatment of Down syndrome are presented, including experimental drugs, stem cell therapies, a process by which embryos produced in a clinical laboratory can be screened for Down syndrome before being used to establish a pregnancy, and several Down syndrome gene therapy strategies.

Minnesota, Duluth, and a PhD in molecular genetics from Purdue

DOWN SYNDROME

• Perpetual access for a one time fee • No subscriptions or access fees • Unlimited concurrent usage • Downloadable PDFs • Free MARC records

some 21. The book describes treatments and therapies for Down

One Smart Cookie

University. He is a professor of biology at Missouri Western State University, where he teaches genetics and conducts research in collaboration with undergraduate students that is supported by the National Science Foundation. Dr. Eckdahl has published over 40  articles in professional journals that contribute to molecular genetics and synthetic biology research and to undergraduate science education. He is a member of the Missouri Academy of Science, the Genome Consortium for Active Teaching, and the Genomics Education Partnership. Dr. Eckdahl has been recog-

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nized for his teaching and research with the Missouri Governor’s Award for Excellence in Teaching, the Missouri Western Board of Governors Distinguished Professor Award, the James V. Mehl Outstanding Faculty Scholarship Award, the Missouri Western Alumni Association Distinguished Faculty Award, and the Jesse Lee Meyers Excellence in Teaching Award.

Todd T. Eckdahl

Down Syndrome

Down Syndrome One Smart Cookie Todd T. Eckdahl

Down Syndrome: One Smart Cookie Copyright © Momentum Press®, LLC, 2018. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means— electronic, mechanical, photocopy, recording, or any other—except for brief quotations, not to exceed 250 words, without the prior permission of the publisher. First published in 2018 by Momentum Press®, LLC 222 East 46th Street, New York, NY 10017 www.momentumpress.net ISBN-13: 978-1-94474-961-3 (paperback) ISBN-13: 978-1-94474-962-0 (e-book) Momentum Press Human Diseases and Conditions Collection DOI: 10.5643/9781944749620 Cover and interior design by S4Carlisle Publishing Services Private Ltd., Chennai, India First edition: 2018 10 9 8 7 6 5 4 3 2 1 Printed in the United States of America

Abstract This book presents Down syndrome, which is the most common ­chromosomal disorder in humans, occurring at a rate of about 1 in 700 births. The book describes the characteristic physical features caused by Down syndrome and the myriad of symptoms and health ­complications it brings, including heart defects, congenital vision and hearing loss, ­abnormalities of the musculoskeletal system, digestive problems, ­epilepsy, leukemia, an increased risk of infectious disease, intellectual d ­ isability, and dementia from Alzheimer’s disease. Readers will learn about methods by which Down syndrome can be diagnosed prenatally or at birth. Causes of Down syndrome include errors in the distribution of ­chromosomes ­during reproduction, and the effects of extra copies of the a­ pproximately 250 genes on chromosome 21. The book describes a ­positive ­correlation between maternal age and the risk of Down ­syndrome. It covers ­treatments for Down syndrome congenital defects and health ­complications; ­approaches to the education of children with Down ­syndrome; and ­physical, speech, occupational, and behavioral therapies that benefit c­ hildren and adults with Down syndrome. Future prospects for the diagnosis and treatment of Down syndrome are presented, including experimental drugs, stem cell therapies, a process by which embryos produced in a clinical ­laboratory can be screened for Down syndrome before being used to establish a pregnancy, and several Down syndrome gene therapy strategies.

Keywords aneuploidy, chromosomal disease, Down syndrome, genetic disease, heart defects, intellectual disability, mosaic Down syndrome, translocation Down syndrome, trisomy 21

Contents Acknowledgments....................................................................................ix Introduction...........................................................................................xi Chapter 1 Chapter 2 Chapter 3 Chapter 4

Symptoms and Diagnosis...................................................1 Causes and Contributing Factors.....................................17 Treatment and Therapy....................................................35 Future Prospects...............................................................45

Conclusion............................................................................................53 Glossary................................................................................................55 Bibliography..........................................................................................63 Index....................................................................................................69

Acknowledgments I am grateful to my friend Malcolm Campbell for encouraging me to take a leap of faith on this project, and on several others that have shaped my career as a science educator. I value Malcolm as a teaching and research collaborator, and I am proud of the positive impact that we have made together on science education and the improvement of science literacy. I am also grateful for the cheerful and professional support I received from the publishing team at Momentum Press. This book would not have been possible without the support of my wife, Patty Eckdahl. She understands my passion for science and s­ cience education and helps me to channel it in ways that benefit students and others around me. I also appreciate the support and encouragement that my parents, Tom and Bonnie Eckdahl, gave me in the pursuit of an ­education that would give me the privilege of sharing my love of DNA and genetics with undergraduate students and everyone else I meet. I am grateful to my undergraduate genetics professor at the University of Minnesota, Duluth, Stephen Hedman, for helping me to understand that I could pursue my love of genetics in graduate school. Thanks to John Anderson at Purdue University, who taught me to conduct m ­ olecular ­genetics research and to value undergraduate education. I appreciate the environment that Missouri Western State University provided me for ­following a path to becoming a science educator. I am grateful to my mentors in the Missouri Western Biology Department, Rich Crumley, Bill Andresen, John Rushin, and Dave Ashley, who helped me to learn how to engage students in the classroom and the research lab. I a­ ppreciate the many students that I have worked with in class and collaborated with on research projects outside of class. I take pride in the contributions that my former students have already made and will continue to make to society.

Introduction Collette Divitto was born in 1990 with Down syndrome. She grew up in Ridgefield, Connecticut, where she developed a passion for baking after taking classes in high school. After testing out several cookie recipes, she came up with an original cinnamon chocolate chip cookie that people really enjoyed. Because all of her friends and family raved, “This cookie is amazing,” Collette decided to call her recipe “The Amazing Cookie.” After high school, Collette attended Clemson University, and finished a 3-year LIFE program in just 2 years. With characteristic sass and a strong drive to work hard and succeed, she moved to Boston, where she was sure she would find a paying job. Although she went on many job interviews that seemed to go very well, she always got an email saying something like, “it was great to meet you, Collette, but at this time we feel you are not a good fit for our company.” Because she was determined not to let rejection stop her from earning a living and doing meaningful work, Collette decided to turn her passion for baking into a business and founded Collettey’s Cookies. She started by approaching a local grocery store, asking if they would sell “The Amazing Cookie.” The store became her first of many clients. Knowing firsthand the struggles that people with Down syndrome endure while looking for employment, Collette decided that her company would be not just a means of earning a living, but it would have a greater mission—to create jobs for other people with disabilities. In late 2016, the Boston CBS TV affiliate featured Collette and her company on their nightly news program. Soon, she was flooded with orders. The national news picked up her story, and Collettey’s Cookies went viral. She has been featured on CNN, Good Morning America, MSNBC, Inside Edition, BBC, and many other print and television media outlets around the world. She has sold over 180,000 cookies to date, and Collettey’s Cookies now employs 13 people, several with disabilities. Collette travels around the country to share her inspiring story, and constantly encourages people to focus on their abilities rather than what they can’t do. Her ultimate goal is to work with lawmakers in Washington, D.C. to

xii INTRODUCTION

create policies that would increase employment opportunities for people with disabilities. Collette is one smart cookie. The namesake of Down syndrome is John Langdon Down, a British physician who published a research paper in 1866 that drew correlations between the physical features of people with different ethnic backgrounds and the severity of their inherited intellectual disabilities. Down described people with Down syndrome as “Mongolian idiots.” For the next c­ entury, the pejorative terminology persisted as mongolism or Mongolian i­diocy, and people who had it were referred to as Mongols, ­Mongoloids, or ­Mongolian idiots. In 1959, French physicians Marthe Gautier and Jerome Lejeune reported their discovery that people with Down s­yndrome had 47 chromosomes instead of the normal c­ omplement of 46. They ­discovered that the increase in chromosome number was due to the presence of three copies of chromosome 21 instead of two, which is called a trisomy. The discovery led people in the early 1960s to refer to Down’s namesake condition as trisomy 21 Down syndrome, which is still in widespread use today. In 1965, the country of Mongolia sent a request to the World Health Organization (WHO) to stop referring to trisomy 21 as ­mongolism, and to people who have it as Mongoloids. The WHO responded to the request by adopting the name Down syndrome. In 2007, the WHO followed the French Association for Research on Trisomy 21 and established March 21 (3-21) as World Down Syndrome Day. The United Nations invited all of its member states to observe World Down Syndrome Day in 2012, when Secretary-General Ban ­Ki-moon said: On this day, let us reaffirm that persons with Down syndrome are entitled to the full and effective enjoyment of all human rights and fundamental freedoms. Let us each do our part to enable ­children and persons with Down syndrome to participate fully in the development and life of their societies on an equal basis with others. Let us build an inclusive society for all. The statement captured worldwide progress on the perception and treatment of people with Down syndrome, and called for equal o­ pportunities for them to become contributing members of societies. World Down Syndrome Day promotes awareness, advocates for equal o­ pportunity and

INTRODUCTION xiii

rights, and raises funds to support people with Down syndrome. Down Syndrome International maintains a website dedicated to World Down Syndrome Day to coordinate local and worldwide events, and provides a forum for people to participate and share their experiences (see URL in Bibliography). Many people stand to benefit from societal improvements p ­ romoted by World Down Syndrome Day. Worldwide, there are between 6 and 9 million children and adults living with Down syndrome. The worldwide occurrence of Down syndrome is about 1 in 700 births, which is about 130,000 babies per year. Most babies born with Down syndrome have three copies of chromosome 21 instead of two, but 1 in 25 of them has a chromosomal rearrangement in which part or all of chromosome 21 is attached to another chromosome. In both cases, the extra genetic ­material causes alterations in the embryological program of development that result in the symptoms and health complications of Down ­syndrome. Symptoms vary among people but can include congenital heart defects, gastrointestinal problems, obesity, epilepsy, leukemia, dementia, Alzheimer’s disease, and an increased risk of certain infectious diseases. The lower life ­expectancy for people with Down syndrome occurs primarily because of congenital heart defects, which occur in about half of babies born with Down syndrome. However, improved treatment in developed countries has increased the life expectancy for people with Down syndrome from less than 10 years a century ago, to 25 years in the 1970s, to over 60 years today. The rise in life expectancy of people with Down syndrome and the growing appreciation of their abilities to be educated and to pursue work mean they are increasingly likely to make important contributions to societies throughout the world. This book presents Down syndrome as a genetic condition caused by extra copies of most or all of the genes found on chromosome 21. Chapter 1 describes characteristic physical features caused by Down syndrome and the myriad of symptoms and health complications it brings, including heart defects, congenital vision and ­hearing loss, abnormalities of the musculoskeletal system, digestive p ­ roblems, epilepsy, leukemia, an increased risk of infectious disease, intellectual ­disability, and dementia from Alzheimer’s disease. It also presents m ­ ethods by which Down syndrome can be diagnosed prenatally, or after birth. The underlying causes

xiv INTRODUCTION

of Down syndrome are detailed in Chapter 2 as errors in the process by which chromosomes are distributed during the production of sex cells for reproduction, and as effects of extra copies of the approximately 250 genes found on chromosome 21. Chapter 3 describes treatments for Down syndrome congenital defects and health complications, approaches to the education of children with Down ­syndrome, and ­physical, speech, occupational, and behavioral therapies that b­ enefit c­hildren and adults with Down syndrome. Future prospects for the diagnosis and treatment of Down syndrome are presented in Chapter 4, including experimental drugs, stem cell therapies, a process by which embryos produced in a clinical laboratory can be screened for Down syndrome before being used to establish a pregnancy, and several Down syndrome gene therapy strategies.

CHAPTER 1

Symptoms and Diagnosis Down syndrome is called a syndrome because it affects a wide variety of organ systems. This chapter describes the effects of Down syndrome on physical appearance; catalogs its symptoms, including heart defects, congenital conditions affecting the musculoskeletal, digestive, and immune systems, intellectual disability, and dementia from Alzheimer’s disease; and describes additional health complications caused by Down syndrome. The ­chapter also explains methods by which Down syndrome can be diagnosed ­prenatally or after birth.

Down Syndrome Results in Characteristic Physical Features All of us have physical features that are strongly influenced by our DNA. We have tendencies to resemble our siblings and parents, and members of our extended families. The influence of family background on the ­appearance of people with Down syndrome is overshadowed by the o­ ccurrence of characteristic physical features (see Table 1.1), and the effect is strong enough that people with Down syndrome often appear to be more closely related to each other than to their families. The illusion of a close relationship among people with Down syndrome comes from distinctive facial features, ­including a more rounded face, upwardly slanted eyes that have pronounced ­epicanthal folds, a flattened nasal bridge, a small nose, a small mouth with a large tongue that tends to stick out more often, and crooked teeth that are irregularly shaped. The eyes often have lightly or darkly colored spots on the iris, which are called Brushfield spots. People with Down syndrome tend to have small ears that are set lower on the head. The back of the head is often flattened, and the neck is shorter and wider. Characteristic body shape features caused by Down syndrome include short stature, short and

2

DOWN SYNDROME

Table 1.1  Common Down syndrome physical features Body part

Description

Skull

Small, shortened skull that is flattened on the back, sloping forehead, missing or underdeveloped sinuses

Eyes

Upward slanted and wide-set eyes, epicanthal folds, Brushfield spots

Ears

Smaller ears with extra folds, ears set lower on the head

Nose

Smaller nose, flattened nasal bridge

Mouth

Smaller mouth, large tongue that tends to stick out more often, undersized teeth, crooked teeth, irregularly shaped teeth

Hands

Broad hands, only one crease across the palm, short fingers, curved fifth finger

Feet

Larger gap between the first and the second toe

Limbs

Short and stocky arms and legs with hyperflexible joints

Body

Short stature, shorter and wider neck, protruding stomach

stocky arms and legs with hyperflexible joints, and a stomach that sticks out from poor abdominal muscle tone. The hands tend to be broad with short fingers, and only one crease across the palm. The feet often have a larger gap between the first and the second toe.

Congenital Heart Defects from Down Syndrome Down syndrome affects the process by which the fetal heart is formed during pregnancy. All early embryos are divided into three primary germ layers that establish the overall spatial organization of the body and ­contain the progenitor cells for all tissues and organs. The heart forms ­during the third week after fertilization from mesoderm, the middle of the three primary germ layers that also gives rise to skeletal muscle, smooth muscle, bone, cartilage, and blood. Mesoderm cells grow, divide, migrate, and communicate with other cells to form a primitive heart that pumps blood throughout the fetal circulatory system to provide nutrients and oxygen to the developing embryo, and remove carbon dioxide and other wastes. The straight tube of cells that forms the primitive heart bends into an “S” shape during the fourth week of development, after which septa develop to separate the heart into four chambers. By week nine post-conception, four valves take shape that control blood flow ­between the heart c­ hambers, between the heart and the lungs, and b­ etween the



Symptoms and Diagnosis

3

heart and the rest of the developing embryo. The fully formed heart pumps blood through the c­irculatory system, which includes arteries to deliver oxygen and ­nutrients to cells and tissues, and veins to return blood carrying carbon dioxide and waste back to the heart for removal by other organs. The ­circulatory system has a second circulatory circuit that delivers blood from the heart to the lungs for the exchange of oxygen and carbon dioxide and returns blood to the heart for delivery to the rest of the body. About 50 percent of all infants born with Down syndrome have some type of heart defect. A common heart defect among Down ­syndrome infants is atrioventricular septal defect (AVSD), which occurs when the septa that normally separate the chambers of the heart, or the valves that control blood flow between the chambers, fail to develop properly. A ­complete AVSD incudes a hole in the septum between the two atria, a hole in the septum between the two ventricles, and abnormal valves between the atrial and ventricular chambers. An incomplete AVSD occurs when there is a hole in the atrial septum and one abnormal valve. AVSD reduces the ability of the heart to properly circulate oxygenated blood to the body, and deoxygenated blood to the lungs, which places an extra demand on the heart. The left ventricle normally generates high blood pressure to circulate blood to the whole body, but the hole in the septum between the two ventricles causes an abnormal increase in the pressure of blood in the pulmonary artery that leads to the lungs. The ­resulting pulmonary hypertension causes the lungs to fill with blood and ­results in breathing difficulty, increased heart rate, swelling of extremities, and cyanosis, which is a bluish skin color around the mouth, fingers, and toes. The combined effects of AVSD on the heart and lungs often ­result in ­congestive heart failure, during which infants develop symptoms such as faster and heavier breathing, sweating, and tiredness that ­gradually worsen over a period of one or two months. Some infants with a c­ omplete AVSD do not develop congestive heart failure because the lungs are protected from increased blood pressure by constricted blood vessels. Constricted blood vessels lead to pulmonary ­vascular disease because of the reduced capacity to deliver oxygen to ­tissue throughout the body. Some infants born with Down s­yndrome have a ventricular septal defect (VSD) or an atrial septal defect (ASD), the severity of

4

DOWN SYNDROME

which depends on the size and location of the hole in the septum. A small hole may produce no symptoms, whereas larger holes cause breathlessness and poor weight gain. Infants with Down s­ yndrome are ­sometimes born with patent ­ductus arteriosus (PDA), which is caused by the ­abnormal persistence of a fetal channel that connects the pulmonary artery and the aorta prior to birth. The ductus arteriosus directs blood away from the ­nonfun­ctioning fetal lungs that do not have access to air yet. At birth, when the lungs fill with air and begin to f­unction, the ­ductus arteriosus normally closes within one or two days. PDA occurs when the ductus ­arteriosus remains open, and the consequence is p ­ ulmonary hypertension, with symptoms that i­nclude breathing difficulty, tiredness, and i­ncreased heart rate. Some Down syndrome infants are born with t­ etralogy of ­Fallot (TOF), which includes the four congenital heart abnormalities of VSD, narrowing of the passageway to the pulmonary artery, enlargement of the right v­ entricle, and an enlargement of the valve leading to the aorta. These heart defects cause reduced blood flow to the lungs, which results in rapid breathing and cyanosis.

What Other Congenital Conditions Result from Down Syndrome? Down syndrome results in congenital conditions that affect a variety of body systems (Table 1.2). More than 60 percent of Down syndrome ­infants are born with vision problems, such as congenital cataracts that cause the lens of the eye to become opaque and result in ­sensitivity to bright light, poor night vision, and double vision. The severity of ­congenital cataracts varies from mild cases of dulled vision to severe cases of complete ­blindness. Cataracts can also develop during childhood or adulthood. Down syndrome infants are often born with amblyopia, which is commonly called “lazy eye” because one eye does not move ­normally and makes a much smaller contribution to vision than the other eye. Amblyopia occurs when the brain receives better visual input from one eye than the other eye due to nearsightedness, cataracts, or permanently crossed eyes. The symptoms of amblyopia include blurred vision, double vision, and poor depth perception. Amblyopia often causes the eyes to move independently of one another, instead of coordinately, which



Symptoms and Diagnosis

5

Table 1.2  Common Down syndrome congenital conditions Body system

Congenital conditions

Heart

Septal defects (ASD, VSD, AVSD), PDA, TOF

Vision

Refractive errors, cataracts, amblyopia, blepharitis, glaucoma

Hearing

Hearing loss (conductive and sensorineural), glue ear, otitis media

Musculoskeletal

Hypotonia, ligamentous laxity, atlantoaxial instability, hip abnormalities, kneecap instability, flat feet

Digestive

Hirschsprung disease, tracheoesophageal fistula, esophageal atresia, duodenal atresia, imperforate anus, GERD

Immune

Hypothyroidism, celiac disease, respiratory infections

compromises depth perception. Down syndrome also produces a higher incidence of refractive errors that are present at birth or develop during childhood, including farsightedness, nearsightedness, and astigmatism. Children and adults with Down syndrome are more likely to need corrective lenses. Down syndrome infants are often born with abnormal tear ducts that easily become clogged, which causes excessive watering of the eyes, or with blepharitis, which is recurrent inflammation of the eyelids. Down syndrome also increases the prevalence of glaucoma, during which abnormal drainage of the fluid inside the eye places pressure on the optic nerve, producing the symptoms of moderate to severe eye pain, eye redness, cloudy vision, and tunnel vision. Glaucoma can lead to permanently blurred vision and eventual blindness. Over 70 percent of Down syndrome infants are born with hearing problems. Hearing problems are categorized as conductive hearing loss when sound waves are not conducted properly from the outer ear to the eardrum and the bones of the middle ear. Sensorineural hearing loss results from dysfunction of the inner ear or its connection to the ­nervous system. Most cases of hearing loss in Down syndrome infants are ­conductive hearing loss, which is often caused by an abnormal buildup of wax in the ear canal that prevents the conduction of sound. Down syndrome can cause the development of a smaller ear canal that is more susceptible to wax blockage. Conductive hearing loss in Down syndrome infants can be also caused by glue ear, an abnormal accumulation of fluid in the middle ear, or by otitis media, infection of the middle ear. Glue ear and otitis media prevent the conduction of sound by the tiny bones of the

6

DOWN SYNDROME

middle ear. Both causes of conductive hearing loss occur because Down syndrome causes abnormal development of the Eustachian tube that normally drains mucus from the middle ear. The cause of sen­sorineural hearing loss is unknown for most people. The severity of sensorineural hearing loss ranges from mild to profound, and it can cause hearing loss of all sound frequencies, or it can selectively reduce hearing in the high, medium, or low frequency ranges. Sometimes sensorineural hearing loss develops later during childhood. It is important to distinguish between prelingual hearing loss that occurs before a child learns to speak and postlingual hearing loss because they present very different challenges to language acquisition. Another congenital problem that many Down syndrome infants have is hypotonia, which is the occurrence of weak muscles throughout the body. Infants with hypotonia seem “floppy” because of their weaker ­muscles, and are often delayed in meeting developmental milestones such as r­ olling over, sitting up, crawling, and walking. ­Hypotonia in the mouth and throat makes it difficult for Down syndrome infants to take in and swallow breast milk or formula, and weak muscles throughout the ­digestive tract impair digestion and can lead to constipation and poor weight gain. I­ nfants with Down syndrome are often born with ­ligamentous ­laxity due to loose ligaments in joints throughout the body. Ligamentous laxity impairs the s­tability of joints, making them more s­usceptible to ­hyperextension. Loose joints contribute to an increased incidence of hip dislocations among ­children and adolescents with Down syndrome. ­Another musculoskeletal condition caused by Down syndrome is ­atlantoaxial instability, in which a loose connection between neck vertebrae results in symptoms such as neck pain, limited neck mobility, clumsiness, and walking difficulties. C ­ hildren with Down syndrome also have an increased risk of hip abnormalities, kneecap dislocations, and flat feet. Down syndrome infants have a higher than normal incidence of birth defects affecting the digestive system. About 10 percent of infants born with Down syndrome have Hirschsprung disease, which is caused by missing nerve cell connections to the colon. Hirschsprung ­disease ­prevents normal colon function and causes intestinal blockage that can lead to a­ bdominal swelling, vomiting, and severe constipation. About 5 ­percent of infants born with Down syndrome have a c­ ongenital defect



Symptoms and Diagnosis

7

that prevents the normal function of the gastrointestinal tract. The most common ­examples are tracheoesophageal fistula, which is an ­abnormal connection between the trachea and the esophagus, ­esophageal ­atresia, which means that the esophagus does not properly connect to the ­stomach, and duodenal atresia, which is an improper connection from the stomach to the small intestine. The symptoms of these three c­ onditions ­include frothing at the mouth, coughing, ­choking, ­abdominal swelling, and vomiting. Down syndrome can also cause i­mperforate anus, which means that the opening from the anus to the rectum is blocked or m ­ issing, ­resulting in a swollen abdomen and the failure to pass a stool. The condition of g­astroesophageal reflux ­disorder (GERD) is characterized by the abnormal reflux of acidic stomach contents. About 5 ­percent of infants, children, and adults with Down syndrome have GERD, which causes mild to severe heartburn and intolerance of certain foods. About 10 percent of people with Down syndrome have h ­ ypothyroidism, which means the thyroid produces lower levels of the hormones that control ­metabolism throughout the body. The primary symptoms of hypothyroidism are fatigue, constipation, and abnormal weight gain. About 5 percent of children with Down syndrome have ­celiac disease, which is associated with an immune reaction to gluten, and causes bloating, severe gas, diarrhea, and anemia.

Down Syndrome Causes Delayed Development On average, children with Down syndrome achieve physical, emotional, and cognitive developmental milestones later than typically developing children. Motor skills such as holding up the head, pushing up, rolling over, sitting, standing, crawling, taking first steps, and walking, come later to children with Down syndrome. They reach developmental milestones that establish their independence later too, including feeding themselves with their hands, drinking from a cup, using eating utensils, becoming toilet trained, and dressing themselves. Children with Down syndrome are slower than most children to achieve emotional developmental ­milestones such as responding to smiles, expressing pleasure ­during play with ­others, discerning the emotions of others, and developing relationships. The process of learning how to think, known as cognitive learning, is also delayed

8

DOWN SYNDROME

by Down syndrome. The limited ability of children with Down syndrome to handle objects with fine motor skills, move about by crawling and walking, and explore their environments means that they take in less ­information during a critical period of cognitive development. Language plays an important role in cognition, and development of the ability to think is delayed in children with Down syndrome because of their delay in language acquisition. Delayed language acquisition is caused by slower development of coordinated muscle control in the mouth and throat. Children with Down syndrome make a slower transition from babbling to effective spoken communication. They usually say their first word at a time expected for most children, but thereafter, their vocabulary builds more slowly, and they are slower to learn how to form sentences. Once they begin speaking, they are harder to understand, a problem that is often worsened by hearing difficulties, but enunciation usually ­improves with age. The inability to pronounce words and organize them into meaningful sentences usually is not a­ ccompanied by a delay in language comprehension. Despite problems with expressing themselves orally, children with Down syndrome develop spoken language comprehension at a rate similar to typically developing children. U ­ nderstanding spoken ­language but not being able to speak can lead to feelings of f­ rustration for children with Down syndrome. The d ­ evelopment of s­ hort-term memory is also delayed in children with Down syndrome, and once it develops, it is usually not as extensive as it is in most children. C ­ hildren with Down syndrome usually have better short-term recall of visual i­nformation than of verbal information. Learning how to read is easier for children with Down syndrome than acquiring basic math skills. Down syndrome also affects the development and maturation of the reproductive system in both males and females. Girls with Down syndrome begin menstruating between the ages of 10 and 14, just as ­typically developing girls do, and they usually have regular cycles, unless they have hypothyroidism. Most sexually mature Down syndrome women are fertile, but fertility can be lower due to a smaller number of egg-producing follicles in the ovaries. Although men with Down syndrome are usually infertile, there have been rare cases in which men with Down syndrome have fathered children with the normal complement of 46 chromosomes.



Symptoms and Diagnosis

9

Cognitive Effects of Down Syndrome Intellectual disability occurs when a child fails to fully develop the ­intellectual capacity to think, reason, learn, and understand. Children with an intellectual disability also have trouble learning adaptive beh­avior, which encompasses the social and practical skills needed for everyday ­living. The most common known cause of intellectual disability is Down syndrome, and it accounts for at least 15 percent of cases ­worldwide. The impairment of intellectual capacity varies among individuals with Down syndrome. It ranges from severe intellectual impairment that makes ­ ­people fully ­dependent on caregivers, to mild effects that enable people to think and learn at levels that enable them to pursue higher ­education, retain a job, and live independently. The most common measure of intellectual capacity is the intelligence quotient (IQ), which expresses the results of standardized intelligence tests as a ratio of mental age to chronological age. The median IQ is 100, and 96 percent of all IQ scores fall in the range of 70–130. About 2 percent of people have an IQ below 70, and are considered to have an intellectual disability. Most people with Down syndrome are in this category. Those with an IQ of less than 50 are considered to have moderate intellectual disability, whereas those with an IQ of less than 30 have severe intellectual disability. People with Down syndrome do not struggle as much with adaptive behavior and the development of social skills as other people with intellectual disability. The intellectual developmental effects of Down syndrome lead to a ­variety of mental health problems that arise in childhood, a­ dolescence, and adulthood. Children with Down syndrome are ­susceptible to a­ nxiety, obsessive–compulsive disorder, hyperactivity, and autism s­pectrum ­ ­disorder. They are also more likely to be i­nattentive, ­self-absorbed, ­inflexible, and to display disruptive behaviors. ­Although children with Down syndrome often have a cheerful demeanor, a­dolescents and adults with Down syndrome can experience depression, extreme mood swings, or anxiety. They often develop chronic sleep problems, and have a four-fold increased risk of epileptic seizures. By the age of 40, about 30 percent of people with Down syndrome develop ­dementia from ­Alzheimer’s ­disease. Initial symptoms include inatte­ntion, aggres­s­ion, irritability, lack of interest, excitability, and anxiety. Later symptoms

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DOWN SYNDROME

include memory loss, seizures, sleeplessness, and movement disorders. The onset of dementia leads to a decline in the ability to think, reason, and understand.

How Is Down Syndrome Diagnosed? Prenatal tests for Down syndrome fall into the two categories of p ­ renatal screening, which provides information about the increased risk that a ­pregnancy will result in the birth of a child with Down syndrome, and ­prenatal diagnostic testing, which diagnoses Down syndrome with ­certainty. ­Parents seek information from Down syndrome prenatal scree­ ning and diagnostic tests for several reasons. One reason is to have time to prepare for the birth of a child with Down syndrome by informing family members, learning about Down syndrome, and joining a support group such as one of the 375 local affiliates of the National Down Syndrome ­Society (see URL in Bibliography). Medical professionals can also p ­ repare for the o­ ccurrence of congenital problems that accompany Down syndrome, and which might require medical or surgical intervention at the time of birth. P ­ renatal d ­ iagnosis of Down syndrome can also be used to make the ­decision to t­erminate a pregnancy, or to offer a child with Down ­syndrome for ­adoption. Parents who already have a child with Down synd­ rome might choose to seek a prenatal diagnosis of Down s­ yndrome ­because the risk of Down syndrome increases from 1 in 700 for the first child to 1 in 100 for the second child. The American ­Congress of ­Obstetricians and ­Gynecologists recommends that all pregnant women be o­ ffered a Down syndrome screening test for the potential value of knowing the proba­bility of delivering a child with Down syndrome. One example of prenatal screening is a blood test conducted at 11 to 14 weeks of pregnancy that has a Down syndrome detection rate of about 85 percent, and a false positive rate of 5 percent. The combined test measures the levels of pregnancy-associated plasma protein A (PAPP-A), an enzyme that controls the levels of growth hormones, and human chorionic growth hormone (HCG), which plays important roles in maintaining a pregnancy. Abnormal serum levels of these two ­proteins are ­correlated with Down syndrome, and also with Edwards s­yndrome, which is caused by an extra copy of chromosome 18. The quad screen



Symptoms and Diagnosis

11

blood test can be performed between 15 and 22 weeks of pregnancy, and it detects about 80 percent of Down syndrome cases, with a false ­positive rate of 5 percent. The test measures four blood constituents: HCG; pregnancy hormones estriol and inhibin A; and serum transport p ­ rotein ­alpha-fetoprotein (AFP). The results of a quad screen provide infor­ mation about the risk of Down syndrome, Edwards syndrome, ­neural tube ­defects, and spina bifida. Prenatal screening for Down syndrome can also be performed with ultrasound at 11 to 14 weeks of pregnancy. ­Diagnostic ultrasound indic­ators of Down syndrome are extra thickness of the ­nuchal fold in the neck of the developing fetus, and the absence of the nasal bone. When ultrasound observations are combined with the ­results of quad screen and PAPP-A blood tests, a Down syndrome ­detection rate of 95 percent can be achieved, with a false positive rate of 5 percent. Maternal blood ­screening is based on the observation that some fetal cells cross the p ­ lacenta and can be detected in the maternal bloodstream. Sensitive ­genetic tests can be used to detect fetal cells from among maternal cells, and measure fetal chromosomes and genes associated with Down syndrome or other genetic conditions. Maternal blood screening is noninvasive to the fetus because it only involves drawing a blood sample from the pregnant woman, and it can be performed as early as 7 weeks of pregnancy. The detection rate of maternal blood screening for Down syndrome is above 95 percent, with a false positive rate of 0.3 percent. However, the probability that a fetus has Down syndrome given positive test results is still surprising low, as calculated using Bayes’ theorem (see URL in Bibliography). Therefore, a positive test result should prompt the use of karyotyping as described in the next paragraph. Due to an increase in the frequency of errors in the distribution of chromosome 21 during the production of egg cells, the occurrence of Down syndrome increases with maternal age. Maternal age is used in combination with the results of prenatal screening for Down syndrome to justify prenatal diagnostic genetic testing, which can be used to d ­ etermine the occurrence of Down syndrome with a very high degree of certainty. Prenatal testing for Down syndrome involves collecting fetal cells by ­amniocentesis or chorionic villus sampling (CVS) that are subjected to genetic testing. Amniocentesis and CVS are w ­ ell-established methods for obtaining fetal cells, but they carry a small risk to the fetus. The risk

12

DOWN SYNDROME

of pregnancy complications from amniocentesis is about 0.5 p ­ ercent, and the risk of miscarriage caused by CVS is between 0.5 and 1 percent. ­Amniocentesis is conducted between weeks 14 and 22 of ­pregnancy. A needle is inserted through the abdominal wall and into the amniotic sac that surrounds the fetus. Amniotic fluid containing fetal cells is withdrawn. CVS is conducted between weeks 9 and 14 of the pregnancy. It i­nvolves the extraction through the cervix or the a­ bdominal wall of chorion cells from the fetal portion of the placenta. For Down syndrome diagnosis, fetal cells collected by amniocentesis or CVS are s­ ubjected to karyotype analysis, during which a microscopic image of the chromosomes from a single cell is produced. The normal ­complement of human chromosomes is 46. There are 24 different chromosomes and 2 of them, the X and the Y chromosomes, are referred to as the sex ­chromosomes ­because they determine sex. The other chromosomes are called a­ utosomes, and are numbered 1 through 22 in approximate order of size (Figure 1.1). A typical karyotype reveals 22 autosomes and a pair of sex chromosomes, which are X and Y for males, and 2 X chromosomes for females. The occurrence of an extra copy of chromosome 21 is diagnostic of trisomy 21 Down syndrome, which accounts for 95 percent of Down syndrome cases. Translocation Down syndrome is diagnosed by detecting one copy of chromosome 14 that is abnormally longer because of the addition of an extra copy of most or all of chromosome 21. Infrequently, chromosome 3, 15, or 22 can carry the extra DNA. Translocation Down syndrome occurs in about 4 percent of Down syndrome cases. Karyotype analysis can also detect mosaic Down syndrome, during which some cells in the body have an extra copy of chromosome 21, whereas other cells have the normal complement of only two copies of chromosome 21. Due to the inherent risks associated with amniocentesis and CVS, many expectant parents choose to forgo prenatal diagnostic testing for Down syndrome, even if prenatal screening warrants more definitive ­testing. Consequently, most cases of Down syndrome are diagnosed at the time of birth. The characteristic Down syndrome physical traits ­involving the shape of the skull, facial features, the structure of the hands and feet, and hypotonia provide clear indications that a newborn has Down ­syndrome. However, because not all infants with Down syndrome display the most distinguishing traits, and because these same traits can be found

17

16

2

18

10

3

19

11

4

20

12

13

21

5

22

14

6

XY

15

7

Mosaic Down syndrome • Extra copy of chromosome 21 in some cells but not others • 1–2 percent of cases

• 4 percent of cases

Translocation Down syndrome • Long arm of chromosome 21 attached to another chromosome

21

+

14

21

21

Figure 1.1  Human karyotype with chromosome pairs identified and information about the three types of Down syndrome

9

8

1

• 95 percent of cases

Trisomy 21 Down syndrome • Extra copy of chromosome 21 in all cells

Symptoms and Diagnosis 13

14

DOWN SYNDROME

among infants who do not have Down syndrome, karyotype analysis is needed to confirm a diagnosis of Down syndrome.

Health Complications of Down Syndrome Down syndrome produces serious health complications in children and adults. For example, an increased risk of infections occurs because Down syndrome compromises the immune system and causes c­ ongenital abnormalities that provide opportunities for pathogens to flourish. ­ Upper respiratory infections such as sinusitis and tonsillitis, and lower respiratory infections such as pneumonia and bronchiolitis, occur ­ more often in children and adults with Down syndrome because their ­airways tend to be smaller and their poor muscle tone makes coughing less ­effective. The most common microbes in respiratory infections are the bacterial pathogens Streptococcus pneumoniae and Haemophilus ­influenzae, and the viral pathogen respiratory syncytial virus (RSV). Respiratory ­infection symptoms of coughing, wheezing, fever, chills, and breathing difficulty are usually more severe for people with Down syndrome, and it takes longer for their infections to be cleared by their compromised ­immune systems. Children and adults with Down syndrome are more likely to get other types of infections, too. The risk of middle ear infections (otitis media) is increased by abnormalities in the bones and muscles of the skull that prevent proper drainage of the fluid from the middle ear, and by chronic upper respiratory infections. The symptoms of otitis media ­include ear pain, headache, fever, external drainage of fluid from the ear, loss of ­balance, and hearing loss. Infants and young children with middle ear i­nfections can display signs such as irritability, sleeplessness, loss of ­appetite, and ear tugging. Children and adults with Down syndrome also have an increased risk of urinary tract infections, which is correlated with a higher prevalence of congenital abnormalities in the kidneys, the bladder, the duct that carries urine from the kidneys to the bladder, and the duct that empties the bladder. Urinary tract infections often cause an increased frequency of urination, and produce symptoms such as pain in the pelvis or lower back, nausea, fever, and vomiting. Bacterial skin infections are more common among people with Down syndrome. They



Symptoms and Diagnosis

15

sometimes develop folliculitis, which is an infection of hair follicles by bacteria or fungi, or scabies, which is an infection by microscopic mites that burrow under the skin. Down syndrome also increases the risk of blood disorders such as ­anemia, in which low blood iron content causes symptoms such as ­dizziness, breathlessness, fatigue, and increased heart rate; ­polycythemia, in which an abnormally high red blood cell count causes headaches, dizziness, fatigue, bruising, excessive sweating, and blurred vision; ­thrombocytopenia, which is an abnormally low platelet count that can lead to uncontrolled bleeding; and transient myeloproliferative ­disorder (TMD), which is caused by an production of abnormally large white blood cells and results in fever, sweating, bruising, fatigue, h ­ eadache, and weight loss. Infants who are diagnosed with TMD should be m ­ onitored closely because the disorder can lead to leukemia, a type of cancer in which ­excess immature white blood cells suppress the ­formation of n ­ ormal white blood cells. Children with Down syndrome are about 15 times more likely to develop leukemia. The occurrence of solid tumor c­ ancers, such as carcinoma and neuroblastoma, is lower among people with Down syndrome. Investigations of the molecular genetic ­mechanisms by which trisomy 21 affords protection against some cancers might yield promising new approaches to cancer treatment. Another health complication of Down syndrome is obstructive sleep apnea, a sleep disorder caused by soft tissue at the back of the throat blocking the airway, which repeatedly interrupts breathing while ­sleeping and limits the flow of oxygen to the brain and the rest of the body. The risk factors for obstructive sleep apnea include large neck size, a large tongue, large tonsils, large adenoids, and sinus problems, all of which are a­ssociated with Down syndrome. During sleep, the s­ymptoms of ­obstructive sleep apnea include cessation of breathing, sweating, ­snoring, and ­sudden g­ asping or choking. Sleep apnea also causes ­daytime s­ leepiness, headaches, high blood pressure, and mood changes. The disruption of breathing ­during sleep can also have long-term effects on ­cognition and behavior. Infants and children with Down syndrome have a four-fold increase in the risk of epilepsy, which results in recurrent seizures that involve loss of consciousness and convulsions. In infants, seizures can produce m ­ uscles

16

DOWN SYNDROME

spasms that are manifested as unusual body movements, or lapses of ­consciousness that affect facial expressions. Seizures in children and adults with Down syndrome are sometimes triggered by sudden sensory inputs involving sound, touch, or taste. Severe seizures bring a risk of physical injury, including head trauma, and can cause incontinence, ­prolonged ­unconsciousness, fatigue, and headaches. Down syndrome is also associated with a higher risk of obesity, defined as having a body mass index (BMI) greater than the 95th ­percentile, adjusted for age and sex. As a consequence of hypothyroidism, d ­ uring which the hormonally controlled bodily metabolic rate is abnormally slowed, or because of abnormalities in the balance of energy m ­ etabolism, children with Down syndrome are twice as likely to develop obesity. ­Obesity is also caused by behavioral tendencies that children with Down syndrome have, such as inattention, disobedience, and impulsiveness, which affect their diet and level of physical activity. Childhood obesity leads to health complications such as type 2 diabetes, hypertension, liver disease, respiratory problems, and sleep apnea. Obesity in adults with Down syndrome puts them at a greater risk for osteoarthritis, heart disease, and stroke.

CHAPTER 2

Causes and Contributing Factors The underlying cause of Down syndrome is the inheritance of one extra copy of most or all of the 250 genes found on chromosome 21. Our ­understanding of how the myriad of Down syndrome symptoms arises from extra copies of these genes is incomplete, but it is rooted in 150 years of genetics research. The concept of a gene as a heritable unit of ­information was published by Gregor Mendel in 1866. By studying ­garden peas, Mendel learned that genes can exist in different forms called ­alleles, and that an allele can be dominant over a recessive allele when both are present in the same individual. He established that genotypes, which are inherited alleles, affect phenotypes, which are observable traits. Mendel developed a model of inheritance that applies equally well to ­humans and all other sexually reproducing organisms. For a trait that is deter­ mined by a single gene, each parent contributes one allele to the offspring and the dominance relationship of the two alleles determines phenotype. ­Offspring who inherit two copies of a recessive allele have the phenotype associated with it, and are referred to as having a homozygous recessive genotype. Those who receive two dominant alleles display the dominant phenotype, and are homozygous dominant. Offspring that inherit one dominant allele and one recessive allele have a ­heterozygous genotype and also display the dominant phenotype. M ­ endel’s abstract ­concept of a gene as a heritable unit took physical form when chromosomes were discov­ered to carry genes that engage in carefully choreographed move­ ments during both cellular and sexual reproduction. Chromosomes are found in all eukaryotes, which are organisms whose cells contain nuclei, including animals, plants, fungi, and protists. The number of

18

DOWN SYNDROME

c­ hromosomes a species carries varies widely, from 46 in humans, to 308 in black mulberry, 120 in paddlefish, 78 in dogs, 14 in garden peas, 8 in fruit flies, and 4 in the Penicillium mold. The number of chromosomes does not correlate with phenotypic complexity, nor does the number of genes found in eukaryotic genomes. Humans have about 22,000 genes, whereas fruit flies have about 17,000 genes, black mulberry plants have about 29,000 genes, and Penicillium mold has about 12,000 genes. Phe­ notypic complexity is determined by how and when genes are expressed during development, not the number of genes. During reproduction, off­ spring receive one copy of each type of chromosome from each parent. Sex cells have a haploid chromosome number, which means that they carry one copy of each chromosome, and during fertilization, sex cells unite to form a cell that has a diploid chromosome number. In humans, a typical sperm carries 23 chromosomes, one of which is either the X or the Y chromosome. A sperm fertilizes an egg cell that also typically carries 23 chromosomes to produce a diploid cell with 46 chromosomes that will develop into a male only if the sperm carries a Y chromosome. The pro­ cess by which sex cells, or gametes, are produced is called meiosis. Meio­ sis is the basis for sexual reproduction, and its two overall functions are to halve the number of chromosomes and to introduce genetic variation into gametes. Meiosis occurs in two phases, called meiosis I and meiosis II. As shown in Figure 2.1, the copies of one pair of chromosomes move about and are partitioned into four haploid gametes, but the same process ­occurs simultaneously for all the chromosome pairs. Before meiosis, each chromosome, and all of the genes it carries, is replicated, which is why the chromosomes at the top of Figure 2.1 are drawn to have two parts conne­ cted to each other. In the beginning of meiosis I, the four copies of each chromosome associate with each other, and line up in the middle of the cell. A physical exchange of alleles occurs among the chromosome c­ opies, resulting in genetic recombination and the introduction of genetic varia­ tion. Genetic variation also occurs because the 23 chromosome pairs line up independently of each other in the middle of the cell. This means that later in meiosis I, when one member of each chromosome pair goes to each of the two daughter cells, genetic variation derives from the many possible combinations of chromosomes and the alleles they carry. During meiosis II, the two connected copies of each chromosome separate, and

Fertilized egg cell

Gamete types

Normal Meiosis

Euploidy

Monosomy

Meiotic Nondisjunction I

Trisomy

Meiotic Nondisjunction II

Figure 2.1  Meiosis produces gametes with one copy of each chromosome, whereas meiotic nondisjunction type I and type II produce gametes with missing or extra chromosomes

B.

Gametes

Meiosis II

Meiosis I

A.

Causes and Contributing Factors 19

20

DOWN SYNDROME

are partitioned into two daughter cells. In men, all four of the haploid cells resulting from meiosis develop into haploid sperm cells, and this process occurs continuously after the onset of puberty to produce many sperm. Puberty in females brings about the monthly menstrual cycle, ­during which one diploid cell undergoes meiosis, after which only one of the haploid daughter cells develops into a mature egg. When two haploid gametes carrying 23 chromosomes join during fertilization, the resulting fertilized egg cell has the diploid chromosome number of 46. Division of the fertilized egg cell into two embryonic cells is accompanied by mitosis, by which one copy of each of the 46 chromosomes is partitioned to the two cells. Because mitosis does not introduce genetic variation, aside from the rare occurrence of mutations, mitosis is a process of cellular cloning. Mitotic cellular divisions are responsible for exponential growth in the number of cells during embryonic and fetal development, as well as the production and replacement of all of the human cells except gametes, which are produced by meiotic cellular divisions.

Trisomy 21 Causes Down Syndrome Trisomy 21 is the most common cause of Down syndrome, and it occurs when meiosis incorrectly partitions copies of chromosome 21 during gamete formation. There are two ways that meiosis can fail to distribute exactly one copy of chromosome 21, or of any of the other chromosomes, into sperm or egg cells. One way is called meiotic nondisjunction I, which is when the two members of a chromosome pair fail to disjoin during meiosis I. As shown in Figure 2.1, after meiotic nondisjunction I, the completion of meiosis II results in gametes that are either missing a chromosome and or have an extra one. These two types of abnormal gametes can also be produced by meiotic nondisjunction II, during which the error in chromosome separation occurs during meiosis II. When a gamete carrying an abnormal number of chromosomes partici­ pates in fertilization, the result is a fertilized egg that also has an a­ bnormal ­chromosome count, and this is called aneuploidy, in contrast to euploidy, which refers to a normal number of chromosomes. Figure 2.1 illustrates three examples of an abnormal egg cell fertilized by a normal sperm cell, but the reciprocal process of fertilization by an abnormal sperm cell of



Causes and Contributing Factors

21

a normal egg cell also occurs. An aneuploidy caused by a missing chro­ mosome is a monosomy. A fertilized egg that has a monosomy for any of the autosomes cannot survive early embryonic development and is spontaneously aborted, resulting in a miscarriage. In contrast, an embryo that has inherited a monosomy for the X chromosome is viable, and will develop into a person with Turner syndrome, with symptoms includ­ ing extra skin on the neck, short and stocky body, and swollen hands and feet, and health complications such as heart defects, diabetes, and thyroid ­problems. An aneuploidy that occurs because of an extra chro­ mosome is called a trisomy, and its viability depends on which chromo­ some is involved. Trisomy of the X chromosome (XXX) results in a female with triple X syndrome, with symptoms that include tall stature, poor muscle tone, and minor intellectual disability. Males with an extra copy of the X chromosome (XXY) have Klinefelter syndrome, with symp­ toms such as tall stature, weak muscles, hypogonadism, male sterility, and minor cognitive disability. A variety of other sex chromosome aneuploi­ dies, including XYY, XXYY, XXXY, and XYYY, produce various symp­ toms such as ­physical abnormalities, cognitive disabilities, and infer­tility. Aneuploidies with extra copies of a sex chromosome are less detri­mental than those involving extra autosomes, presumably because all but one of the X chromosome copies is inactivated during early development, and because there are comparatively few genes on the Y chromosome. Unlike the sex chromosomes, trisomies of most autosomes are not viable, and account for about 25 percent of spontaneous abortions. The only autosomal trisomies that can survive to term are trisomies of chro­ mosomes 8, 9, 13, 18, 21, and 22. A fetus that has inherited t­risomy 8, 9, or 22 rarely survives to term unless there is a mixture in the body of ­aneuploid and euploid cells, which is called mosaicism. Trisomy 13 causes Patau syndrome, which causes a myriad of developmental ­abnormalities including heart defects, neurological problems, and skeletal defor­mities. About 1 in 16,000 infants is born with Patau syndrome, and only 20 ­percent of them survive more than one year. Edwards ­syndrome is caused by trisomy 18, and it results in heart defects, breathing problems, nervous system abnormalities, a deformed digestive tract, and physical malfor­ mations. The occurrence of Edwards syndrome is about 1 in 5,000 births, and only about 10 percent of infants with Edwards syndrome survive past

22

DOWN SYNDROME

one year. The most common chromosomal aneuploidy that survives to term is trisomy 21, which occurs at a rate of 1 in 700 births, and causes Down syndrome. Whereas meiotic nondisjunction is responsible for the production of aneuploid gametes in people with the euploid number of 46 chromosomes, nondisjunction is not required to produce aneuploid gametes in people with trisomy 21 Down syndrome. On average, half of the children born to women with Trisomy 21 inherit an extra chromosome 21 and have Down syndrome, and the other half are born with two copies of chromosome 21. Although men with Down syndrome are usually infertile, a few men with trisomy 21 have fathered children with two copies of chromosome 21.

A Chromosomal Rearrangement Can Cause Down Syndrome About 4 percent of people with Down syndrome have translocation Down syndrome. Although they have the normal number of 46 chromosomes, these people have inherited an extra copy of most or all of chromosome 21 that is attached to itself or to a different chromosome. Translocation is an errant process by which genetic material is transferred from one chromosome number to another, instead of the normal process of equal exchange of genetic material between chromosomes of the same number during meiosis I. A specialized form of karyotyping called fluorescence in situ hybridization (FISH) uses fluorescently tagged DNA probes to detect chromosomal rearrangements that have occurred as a result of translocation. Translocations can occur during meiosis, with the conse­ quence that one or more abnormal chromosomes end up in gametes and can therefore be inherited. Alternatively, translocations can occur during mitosis, ­affecting only a particular type of cells in the body. ­Translocations involving bodily cells are one cause of acquired cancers, including t­ hyroid cancer, lymphoma, and several types of leukemia. If the exchange of chromosomal material is equal, it is called a reciprocal ­translocation. Although reciprocal translocations do not usually cause phenotypic ­ ­effects, about 6 percent of children with reciprocal translocations have some form of intellectual disability. People with a reciprocal transloca­ tion often have reproductive problems such as infertility and ­frequent



Causes and Contributing Factors

23

miscarriages. N ­ onreciprocal translocation is an unequal exchange of genetic material from one chromosome to another. The most common nonreciprocal translocation fuses genetic material from chromosomes 13 and 14, and it occurs at a rate of about 1 in 700 births. People with this translocation usually do not experience abnormal phenotypes, although they might ­experience reproductive problems. The most common cause of translocation Down syndrome is a nonreciprocal translocation called a Robertsonian translocation. First ­discovered in grasshoppers, Robertsonian translocations involve the ­fusion of two chromosomes that have broken into two parts. The breakpoint is the centromere, a chromosomal structure that connects two c­opies of each replicated chromosome that are normally distributed into two daughter cells during mitosis (see Figure 1.1). After two chromosomes break at their centromeres, the four parts fuse to form two new chromo­ somes. ­Robertsonian translocation in humans occurs in 1 in 700 births. Chromosomes 13, 14, 15, 21, and 22 undergo Robertsonian transloca­ tion much more frequently than the other chromosomes, perhaps because their centromeres are not positioned in the middle, causing one chromo­ some arm to be much longer than the other. Robertsonian translocations involving two of these chromosomes result in one abnormally longer chromosome that carries most of the genes from each original chromo­ some, and a second abnormally shorter chromosome that carries fewer genes. Because no genes are lost from a cell during translocation, the result is termed a balanced translocation, and it does not usually cause any phenotypic effect. Often the shorter chromosome is lost, reducing the chromosome number to 45, but phenotypic effects still do not usually occur because the longer chromosome carries a copy of most of the genes from the translocated chromosome. One way that a child can be born with translocation Down ­syndrome is that a Robertsonian translocation occurs during the formation of ­gametes in the father or mother. Usually, the long arm of chromosome 21 fuses to the long arm of chromosome 14 (see Figure 1.1), but the broken chromosome piece can also become connected to the long arm of ­chromosome 13, 15, or 22. Rarely, the long arm of chromosome 21 can fuse to itself, forming a linear isochromosome, or a circular ring ­chromosome. ­Translocation Down syndrome occurs when a gamete with

24

DOWN SYNDROME

one of these abnormal chromosomes engages in ­fertilization with a gamete ­carrying only normal chromosomes. The abnormal ­chromosome becomes part of the complement of chromosomes in the ­fertilized egg cell that is copied by mitosis and distributed to all the cells of the body. Another way that translocation Down syndrome occurs is by ­inheritance of an abnormal chromosome from a parent who has a ­balanced ­Robertsonian translo­cation. A parent with two copies of most of chromosome 21, with one copy attached to a different chromosome, and one retained on a nor­ mal chromosome 21, is said to be a balanced translocation carrier. Even though they carry a chromosome that can cause translocation Down syn­ drome, they do not have Down syndrome themselves, but they often have fertility problems and a higher rate of miscarriage. Half of the ­gametes produced by a balanced translocation carrier contain the abnormal chromosome, and if one of these engages in fertilization with a normal gamete, the resulting cell has an extra copy of most of chromosome 21, resulting in translocation Down syndrome. Inheritance of translocation Down syndrome from a balanced translocation carrier occurs at the same rate for male and female carriers, and the rate does not increase with the age of the mother. Translocation Down syndrome is also called familial Down syndrome because the risk that a balanced translocation carrier will have a child with Down syndrome applies to each conception. The occurrence of a balanced translocation in one family member increases the likelihood that others in the family also have a balanced translocation.

Mosaic Down Syndrome Approximately 1 to 2 percent of people with Down syndrome are said to have mosaic Down syndrome because they have a mixture of euploid cells that contain the typical complement of 46 chromosomes and ­aneuploid cells that have either trisomy 21, or a chromosomal translocation i­ nvol­ving chromosome 21. Karyotyping is used to determine the ratio of a­ neuploid to euploid cells, which varies among people with mosaic Down syndrome. The more aneuploid cells a person has, the more severe their Down syn­ drome symptoms are. For an individual with mosaic Down syndrome, the ratio of aneuploid cells in various tissues and organs also varies. The most commonly used source of cells for karyotype analysis is white blood



Causes and Contributing Factors

25

cells, but the fraction of aneuploid cells in other tissues might be ­different. Karyotyping of skin cells is common, and because skin and brain cells are derived from the same embryonic cell type, mosaicism in skin cells is often used as an indirect measure of mosaicism of brain cells. ­Aneuploid mosa­ icism of brain cells might be common in all people. A karyotype analysis of people without Down syndrome found that between 1.5 and 2.2 percent of functional brain neurons carry an extra copy of chromosome 21. It is not known whether trisomy 21 brain ­neurons c­ ontribute to the normal function of the brain, impair its function in ­subtle ways, or have no impact on its function at all. Karyotype analyses revealed that almost all cancers are associated with aneuploid mosaicism, and e­ vidence supports a causal relationship between aneuploidy and cancer. The cause of mosaic Down syndrome is an error in the process by which cells divide. All the cells in the body except gametes are called ­somatic cells, which are produced by the cellular division process of ­mitosis. Just as ­nondisjunction in meiosis results in gametes that carry an extra copy of chro­ mosome 21, mitotic nondisjunction can ­produce trisomy 21 of s­omatic cells. The mechanism leading to mitotic n ­ ondisjunction is s­ imilar to the way that meiotic nondisjunction occurs. Normally, two copies of chromosome 21 are distributed to each of two daughter cells during ­mitosis, but mitotic ­nondisjunction causes more than two copies to ­migrate to one side of the dividing nucleus, ­resulting in a cell with trisomy 21 and an inviable cell that has only 45 chromosomes. The key d ­ eterminants of the overall f­raction of cells that have trisomy 21 and which tissues have it are how early mitotic disjunction occurs during pregnancy, and where in the embryo it occurs. If mitotic nondisjunction occurs during the first division of a fertilized egg cell, ­mosaicism will not occur ­because the cell with 45 chromosomes will not survive. The embryonic cell with trisomy 21 will be the progenitor of all the cells in the body, and the result is complete trisomy 21. If mitotic nondisjunction ­occurs during the second embryonic cell division, mosaic Down ­syndrome ­results, because two of the four cells are euploid, one has trisomy 21, and one is inviable with 45 chromosomes and will not ­survive. The level of mosaicism is predicted to be 33 percent, because one of the three ­surviving cells has trisomy 21. Mitotic nondisjunction at each ­subsequent embryonic cell division results in a lower level of ­mosaicism. A less com­ mon cause of mosaic Down syndrome is a mitotic n ­ ondisjunction event that

26

DOWN SYNDROME

converts trisomy 21 to euploidy in a subset of the cells of an embryo that inherited trisomy 21 at conception. In people with mosaic Down syndrome, the specific types of cells, tissues, and organs in the body that have trisomy 21 is determined by which particular embryonic cell undergoes mitotic nondisjunction. As embryonic cells are produced by mitotic cell division, they organize themselves into tissues according to a carefully orchestrated series of movements as they gradually differentiate to gain specialized functions. All of the cells of the adult body can be traced back to progenitor stem cells in the embryo. Consequently, the place in the embryo where mitotic nondisjunction ­occurs determines which cells will have trisomy 21. For example, if mitotic nondisjunction occurs in the embryonic cells that give rise to skin, bone, and brain cells, then trisomy 21 cells will be found in those tissues, but not others. In this case, Down syndrome symptoms associated with learning and memory occur. In the case where mitotic nondisjunction occurs in the embryonic cells that give rise to muscles, symptoms such as hypotonia and heart defects are produced. If mitotic nondisjunction occurs in the embryonic cells that give rise to repro­ ductive organs, then adults with mosaic Down syndrome can pass on trisomy 21 to their offspring. Assistive reproductive technology has been used to separate euploid from aneuploid sperm cells, enabling a man with mosaic Down syndrome to have a child without Down syndrome.

How Do Extra Genes Cause Down Syndrome? Genes carry information in the form of sequences of four bases, c­ ommonly referred to as G, C, A, and T, and bases on one strand of the DNA double helix pair with bases on the other strand in a process called base pairing (G to C and A to T). There are about 22,000 protein-encoding genes in the human genome and the median size of a human gene is about 24,000 base pairs. About 98 percent of human genes are split into exons, which are the parts of genes that are expressed into the amino acids of proteins, and intervening sequences called introns. The average number of exons in human genes is about 10 and their average size is 288 base pairs. In order for the ­information in a gene to be used to make a protein, the DNA base sequences of exons and introns alike are used to encode a sequence of



Causes and Contributing Factors

27

RNA bases during a ­process called transcription. RNA produced by transc­ ription undergoes RNA splicing that removes all of the introns and splices together exons to make a contiguous protein-encoding messenger RNA (mRNA). The mRNA is transported from the nucleus, where transcription and RNA processing occur, to the part of the cell outside the nucleus called the ­cytoplasm, where translation occurs. Translation is the process by which the base sequence of mRNA is used to direct the synthesis of proteins. There are 20 primary amino acids, and their sequence in a protein determines its structure and function, or dysfunction. The bases of an mRNA are read in groups of three, called codons. Because there are four possible bases in each of the three positions of a codon, there are 4 × 4 × 4, or 64, different codons possible. Genetics, biochemistry, and molecular biology experiments in the 1960s revealed which amino acid is encoded by each of the 64 codons. This information is referred to as the genetic code. One of the codons is a start codon for the initiation of translation, and three are stop codons that signal the end of translation. The phenotypic consequences of an extra copy of chromosome 21 can be considered in terms of the probability that it contains one or more genes for which an additional copy has severe or lethal effects. ­Chromosomes that have a large number of genes are more likely to ­contain genes for which an additional copy is so detrimental that either the embryo fails to develop or the newborn child dies very soon. The average number of genes on human chromosomes is about 850, and embryos with tri­ somies involving chromosomes that have more than 850 genes do not survive to term. Although the X chromosome contains about 840 genes, it is a special case because extra copies of the X chromosome are inacti­ vated, including the extra copy typically found in females. The correlation ­between a decrease in chromosomal gene number and a decrease in the severity of phenotypic effects allows us to understand the observation that the only autosomal trisomies that can survive to term are trisomies 8, 9, 13, 18, 21, and 22. Each of these chromosomes contains fewer than the average number of genes. Trisomies of chromosomes 13, 18, and 21 have better survivability that any other autosomal trisomy, presumably because they contain only about 330, 270, and 490 genes, respectively. In general, having three copies of a gene has detrimental effects on human health, but whether the effects are mild, severe, lethal, or

28

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­ onexistent depends on the function of the gene. Information about the n ­dosage sensitivity of the approximately 250 genes on human chromo­ some 21 has been gained from several lines of research. A mouse model of trisomy 21 has been developed in which mice are genetically engineered to carry three copies of most of the genes on human chromosome 21. The mice display many Down syndrome symptoms, including learning and memory impairment, cardiac defects, low fertility, and abnormalities of the face and skull. The dosage sensitivity of genes can also be assessed by studying the phenotypic effects on people of partial trisomies of chromo­ some 21 in which only a subset of the genes on chromosome 21 have an extra copy. Studies of cells cultured in the lab reveal details about how gene dosage affects the regulation of gene expression and protein function. Table 2.1 lists examples of chromosome 21 genes that have been shown to be dosage sensitive, and which are therefore likely to major ­contributors to the symptoms and health complications of Down syndrome. Table 2.1  Examples of dosage-sensitive human chromosome 21 genes and their functions Gene

Protein

Protein function

APP

Amyloid beta precursor protein

Supports development, growth, and function of brain and spinal cord neurons

DYRK1A

Dual specificity tyrosinephosphorylation-regulated kinase 1A

Controls the balance between excitatory and inhibitory signals received by brain and spinal cord neurons

SIM2

Single-minded homolog 2

Controls the expression of genes during early brain development

DSCAM

Down syndrome cell adhesion molecule

Coordinates interactions among cells during early development and maintenance of the nervous system

COL6A1

Alpha-1 chain of collagen type VI

Provides structural support for tissues, including heart valves

ITSN1

Intersectin-1

Regulates transport across cell membranes

ADAMTS1

A disintegrin and metallopeptidase with thrombospondin type 1 motifs

Controls growth and maintenance of organs, and inflammatory response of the immune system

ETS2

C-ets-2

Controls the transcription of genes during embryonic development



Causes and Contributing Factors

29

One example of a dosage-sensitive gene is APP, which encodes amyloid beta precursor protein, an important contributor to the ­ ­development and maintenance of neurons in the brain and spinal cord during pregnancy and in children and adults. One of the breakdown products of amyloid-beta precursor protein is amyloid-beta, the primary component of amyloid plaques that accumulate in the brains of people with ­Alzheimer’s disease. More than 50 different mutations of the APP gene cause e­ arly-onset Alzheimer’s disease, and this provides insight into how an extra copy of APP contributes to the neurological symptoms and ­complications of Down syndrome. Another dosage-sensitive gene, DYRK1A, regulates the growth and development of central nervous system neurons. The product of DYRK1A is an enzyme called dual specificity ­tyrosine-phosphorylation-regulated kinase 1A, and it controls the balance between excitatory and inhibitory signals received by neurons. Mice that have an extra copy of DYRK1A, or mice that have been ­engineered to produce more DYRK1A protein, have severe impairment of both ­learning and memory. The role of DYRK1A in the acquisition of higher thinking skills in people is underscored by the observation that mutant DYRK1A alleles can result in intellectual disability. Excess DYRK1A protein is likely to contribute to the learning difficulties ­associated with Down syndrome. Another gene that displays dosage ­sensitivity is SIM2, which controls the transcription of other genes during early development of the brain. The product of SIM2 is single-minded homolog 2, a protein that is named for the mutant phenotype it causes in fruit flies. Mice that produce excess SIM2 protein have learning and memory impairment, suggesting that SIM2 is an ­important dosage-­sensitive gene that contributes to Down syndrome phenotypes associated with brain f­unction. Evidence suggests that the DSCAM gene is also dosage sensitive. The Down syndrome adhesion molecule (DSCAM) is a protein encoded by the DSCAM gene that coordinates interactions among cells that are important for the early development and maintenance of the nervous system. DSCAM is produced in over 38,000 possible forms by alternative splicing of its 24 exons. The RNA initially produced by transcription of DSCAM contains multiple copies of several of the exons, and RNA splicing removes all but one copy of each exon before translation produces one of the protein variants. The variability in DSCAM proteins enables subtle differences

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between the many cell-to-cell connections that establish and maintain the brain and the spinal cord. Overproduction of DSCAM inhibits the branching of nerve cells, and impairs learning and memory. An extra copy of DSCAM correlates with congenital heart defects in both mice and humans. Another dosage-sensitive gene is COL6A1, which encodes the alpha-1 chain of collagen type VI, an extracellular protein that forms lattices of structural support that function as scaffolds for the formation and maintenance of connective tissue layers throughout the body. The protein contributes to the function of the atrioventricular heart valve, and mutations in COL6A1 increase the risk of heart defects. O ­ verexpression of COL6A1 protein is likely to contribute to the increased risk of heart defects in infants born with Down syndrome. The dosage-sensitive ITSN1 gene encodes the intersectin-1 protein, which controls the trans­ port of materials across the outer membrane of cells, including the reup­ take of neurotransmitters that neurons secrete to communicate with their target cells. Overproduction of ITSN1 protein in experimental animals impairs the recycling of neurotransmitters from the junctions between neurons and muscle cells, and results in locomotor defects. This suggests that an extra copy of ITSN1 in people with Down syndrome might explain their symptoms of low muscle tone and strength. The protein product of the dosage-sensitive ADAMTS1 gene has a complex name that reflects its multiple functional and structural domains. It encodes a disintegrin and metallopeptidase with thrombospondin type 1 motifs protein (ADAMTS1), which is an enzyme that plays important roles in the growth and maintenance of organs, and contributes to the inflam­ matory response of the immune system. O ­ verproduction of ADAMTS1 in mice correlates with a reduction in tumor angiogenesis, the process by which a solid tumor attracts blood vessels. Increased gene dosage of ADAMTS1 might protect people with Down syndrome from cancers such as breast, bone, and colon cancer that are associated with solid tumors. The dosage-sensitive gene ETS2 encodes C-ets-2, which is a transcription factor that binds to regulatory regions of DNA near other genes and contributes to the process by which they are transcribed into mRNA that can be translated to make proteins. An extra copy of the ETS2 gene is protective against colorectal cancer in mice, suggesting that its protein product might f­unction as a tumor suppressor and benefit people with



Causes and Contributing Factors

31

Down syndrome. Mice with overexpressed ETS2 protein also have skel­ etal abnormalities of the face and skull that resemble those of people with Down syndrome.

Contributing Factors for Down Syndrome Although the overall occurrence of trisomy 21 Down syndrome is 1 in 700 births, its occurrence increases with maternal age, from 1 in 2,000 for women who are 20 years old, to 1 in 900 for those who are 30 years old, to 1 in 100 for those who are 40 years old, and to 1 in 10 for those who are 50 years old. The correlation between maternal age and trisomy 21 can be explained by a closer look at how meiosis produces egg cells. At birth, a human ovary contains many cells that have already undergone the first part of meiosis, and are arrested at the stage of meiosis I where four copies of chromosome 21 are closely associated with each other in a structure called a tetrad. Each egg progenitor cell must maintain this arrested state for years or decades, until it is chosen during the monthly menstrual cycle to proceed through the rest of meiosis for the production of a mature egg cell. If the delicate tetrad has been compromised, meiotic nondisjunction might occur, and this becomes increasingly likelier with age. In accord with this explanation is the observation that meiotic nondisjunction I is more common in older women than meiotic n ­ ondisjunction II. Meiotic nondisjunction is less common in males than in females because once a sperm precursor diploid cell enters meiosis, it completes the process of sperm cell production with no arrested stage. The age of the father has no known effect on the types or severity of Down syndrome symptoms. The primary cause of Down syndrome is an extra copy of most or all of the approximately 250 genes found on chromosome 21. However, genes found on other chromosomes contribute to the types and ­severity of Down syndrome symptoms. More than 4,000 genetic diseases are commonly described as monogenic, which means that they are caused by mutations in a single gene. However, much of the heritable variation in the age of onset, progression, and symptom severity among patients with a given monogenic disease cannot be explained by their genotypes for a single disease-causing gene. A significant fraction of the variation ­correlates with genotypes that patients carry for other genes. Genes that

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do not cause a disease but which affect its symptoms are called gene modifiers. The genotype for gene modifiers varies in people without a genetic disease in ways that have no observable phenotypic consequences, but in people with the genetic disease, the variation affects the course and ­severity of their disease. One way to discover gene modifiers is a genome-wide association study (GWAS). A GWAS relies on the avail­ ability of the reference DNA sequence of the human genome, a map of human genetic variation, and methods to analyze the genomes of many study participants. Researchers isolate DNA from thousands of partici­ pants and look for variations in their genomes. People in general share about 99.7 percent of the 3.2 billion DNA bases in the haploid human genome, which means that there are nearly 20 million places where the DNA base present in one person will be different in another person. These places are called single nucleotide polymorphisms, or SNPs (pro­ nounced “snips”). The term polymorphism means many shapes, although in this context there can only be four shapes because there are only four DNA bases. For ­example, C might be present at a particular position on chromosome 5 in the reference human genome, but some people might have a G in that position. To qualify as a SNP, the alternative base must be found in at least one percent of the population. Down syndrome is not a monogenic disorder. However, just as gene modifiers contribute to the severity of symptoms of m ­ onogenic ­diseases, complex syndromes such as Down syndrome are also likely to be i­nfluenced by gene modifiers. A GWAS study could look for a pattern of Down syndrome symptoms that correlates not only with an increase in copy number from two to three of the most or all of the approximately 250 genes on chromosome 21, but also allelic ­variations for gene modifiers. For example, A GWAS study might detect ­variation in the occurrence of an AVSD heart defect among infants born with Down s­yndrome and allelic variation of modifier genes either on c­ hromosome 21 or elsewhere in the genome. Although the risk of occurrence of AVSD among infants with Down syndrome is 2,000 times greater than the risk for infants born with a normal complement of chromosomes, only 1 in 5 Down syndrome infants are born with AVSD. The hypothesis that this variation might be due to modifier genes was supported by experiments using a mouse model of



Causes and Contributing Factors

33

Down syndrome which showed that mutations in two different gene modifiers increased the risk of AVSD in mice with a trisomy analogous to human trisomy 21, compared to mice with a ­normal chromosome number. Further testing of the hypothesis was pursued with a GWAS of 452 human infants born with Down syndrome, 210 of whom had AVSD and 242 of whom did not. After examination of more than 600,000 SNPs, the study did not find a strong correlation between genotype variation in the gene modifiers identified by the mouse ­ experiments and the occurrence of AVSD, and it did not discover new human gene modifiers that are major contributors to the risk of AVSD. However, the GWAS did identify genes on chromosomes 1, 5, 8, and 17 that might make small but additive contributions to the risk of AVSD. One of the genes is NPHP4, which encodes nephrocystin ­protein, and which plays a role in the development and function of the heart, ­kidney, liver, and skeletal muscle. Mutations in NPHP4 d ­ isrupt the formation of cilia, which are hair-like projections on the surfaces of cells that enable them to move or to sense their environments. Mutant cilia are known to produce kidney disorders, male infertility, and heart defects. Another gene found to make small additive contri­ butions to the occurrence of AVSD in infants with Down syndrome is FLJ33360, which is expressed in heart cells to produce an RNA that regulates the transcription of other genes. ­Disruption of FLJ33360 has been linked to cancer and ­neurodegeneration. The FZD6 gene was also ­correlated with AVSD, and its protein influences how embryonic heart cells receive signals from their s­ urroundings during early development. Future GWAS research is likely to clarify the role of gene modifiers in the occurrence of Down syndrome AVSD and in the types, progres­ sion, and severity of other Down syndrome symptoms.

CHAPTER 3

Treatment and Therapy There is considerable variation in the occurrence and severity of ­symptoms and health complications among people with Down syndrome. As a ­result, treatment for Down syndrome varies from person to person, and healthcare providers work closely with families to choose appropriate surgical, medical, and therapeutic interventions. This chapter presents treatments for Down syndrome congenital defects and health complications, approaches to the education of children with Down syndrome, and physical, speech, occupational, and behavioral therapies that benefit children and adults with Down syndrome. It describes ways that people with Down syndrome can be supported to live and work independently, and presents opportunities for them to connect to others through support groups.

How Are Down Syndrome Congenital Defects Treated? About 50 percent of infants born with Down syndrome have a congenital heart defect. Consequently, it is common practice to screen all Down syndrome infants for heart defects with an electrocardiogram, which measures the electrical activity of the heart, and an echocardiogram, which uses ultrasound to check for abnormalities in heart structure. The tests reveal the type and severity of a heart defect, and whether it can be managed with medical treatment or must be repaired surgically. The most common heart defect among Down syndrome infants is atrioventricular septal defect (AVSD), which is malformation of the septum that separates the heart into chambers, or of the valves that control blood flow between them. A complete AVSD generates abnormal blood flow and is caused

36

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by a large hole in the septum, and only one valve connecting the upper and lower chambers instead of the normal two valves between them. A partial AVSD is a smaller hole in the septum and malformation of one of the two valves. Both types of AVSD lead to ­pulmonary hypertension and congestive heart failure. The usual treatment for AVSD is surgery to patch the hole in the septum, and repair or replace the dysfunctional heart valves. AVSD surgery is performed as early as possible within the first half year of life to avoid permanent damage to the lungs caused by untreated AVSD. The most common complication of AVSD heart surgery is leakiness of one of the heart valves, which forces the heart to pump harder to deliver oxygen to tissues throughout the body. Heart surgery is also used to treat other heart defects that occur in Down syndrome infants, such as ventricular septal defect (VSD), atrial septal defect (ASD), patent ductus arteriosus (PDA), and tetralogy of Fallot (TOF). The success rate of infant heart surgeries is rising. In the United States, more than five out of six infants who undergo surgery for critical congenital heart defects survive past one year. Congenital defects of the gastrointestinal tract caused by Down ­syndrome can often be corrected with surgery. About 10 percent of infants born with Down syndrome are born with Hirschsprung disease, during which intestinal blockage occurs because of missing nerve c­ onnections to the colon. After diagnosis with a colon biopsy, Hirschsprung ­disease can be effectively treated by surgical removal of the dysfunctional portion of the colon. Surgery is also effective in treating congenital defects in the ­structure of the gastrointestinal tract that occur in about 5 p ­ ercent of Down syndrome infants. Corrective surgeries are used to repair an a­bnormal connection between the trachea and the esophagus ­(tracheoesophageal fistula), an improper connection between the esophagus and the stomach (esophageal atresia), an abnormal connection from the stomach to the small intestine (duodenal atresia), or a blockage of the opening from the anus to the rectum (imperforate anus). More than 60 percent of Down syndrome babies are born with vision problems. Down syndrome babies often have congenital cataracts, which cause the lens of the eye to become opaque, and can lead to impaired ­vision and blindness. Impaired vision from a cataract can be improved with the use of corrective lenses, sunglasses, or a magnifying glass. A lens



Treatment and Therapy

37

with a severe cataract can be surgically replaced with an artificial lens. ­Amblyopia is also a common occurrence among Down syndrome ­infants. There are two primary goals in the treatment of early childhood a­ mblyopia. One is to address the cause of poor vision in the weaker eye, and the other is to encourage the brain to rethink the way it processes visual signals it receives so that it does not ignore signals from the weaker eye. Children can be fitted with a patch that covers the stronger eye, or with glasses or eye drops that blur its vision, forcing their brains to pay ­attention to the signals from the weaker eye. Down syndrome babies also commonly have blepharitis, a recurrent inflammation of the eyelids that can be treated with antibiotics and anti-inflammatory drugs. Down s­ yndrome increases the risk of glaucoma, which is the accumulation of excess fluid inside the eye that reduces optic nerve communication to the brain. Glaucoma can be treated with eye drops, medications, or eye surgery. Congenital hearing loss caused by Down syndrome can take the form of conductive hearing loss, which occurs when sound waves are not t­ransmitted properly from the outer ear to the eardrum and the bones of the middle ear, or sensorineural hearing loss, which results from ­dysfunction of the inner ear or its connection to the nervous system. One course of treatment is surgery, and it is more effective in treating conductive hearing loss than sensorineural hearing loss. M ­ alformation of the outer or middle ear can be corrected by surgical procedures that clear the pathway for sound to travel, or restore the integrity of the eardrum. Surgery can also correct problems with the structure and function of the bones of the middle ear. Treatment of conductive hearing loss sometimes involves addressing a blockage of sound waves in the ear canal. Glue ear is an accumulation of fluid in the middle ear, and it is often treated with a drainage tube inserted into the ear. Infection of the middle ear (otitis media) is treated with antibiotics or anti-inflammatory drugs. The most common way to treat hearing loss is to fit the patient with a hearing aid. Hearing aids amplify sounds that enter the ear canal and arrive at the ­eardrum, so it can transmit stronger vibrations to the middle ear. A ­hearing aid receives sound with a microphone, converts it into a digital signal, amplifies and adjusts the signal, and transmits sound to the ear with tiny speakers. There is a wide range in the cost, effectiveness, and appearance of hearing aids. People with moderate to severe hearing loss

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who do not benefit very much or at all from a hearing aid are often treated with a cochlear implant that is surgically positioned in the inner ear, so that it can electrically stimulate the nerve that receives electrical signals from the cochlea and transmits this information to the brain. Sounds that people hear with cochlear implants are different than the sounds heard by people with normal hearing. Children or adults who receive a cochlear implant to treat hearing loss after they have learned to speak can be given therapy to adjust to the new sounds they are hearing.

Treatment of Down Syndrome Health Complications About 5 percent of people with Down syndrome have ­gastroesophageal reflux disorder (GERD), an abnormal movement of acidic ­ ­ stomach ­contents up the throat that causes mild to severe heartburn and ­intolerance of certain foods. GERD can be treated with medications such as aluminum hydroxide to counteract excess stomach acid, drugs such as ­pantoprazole that decrease stomach acid production, or b­ ismuth s­ubsalicylate, which reduces the fluid content of the stomach and has anti-inflammatory ­effects. About 5 percent of children with Down s­yndrome have celiac ­disease, an immune reaction to dietary gluten p ­ rotein that causes bloating, ­severe gas, diarrhea, and anemia. The ­primary treatment for celiac disease is an adjusted diet that avoids foods that contain gluten, such as wheat, barley, rye, and malt. Celiac disease can be treated with dietary mineral supplements such as iron and calcium, and vitamins such as folic acid and vitamin D. About 10 percent of people with Down s­ yndrome have hypothyroidism, during which the thyroid produces lower than ­normal levels of hormones that control metabolism throu­ghout the body, resulting in fatigue, constipation, and abnormal weight gain. ­Hypothyroidism can be treated with levothyroxine, a synthetic ­thyroid hormone that is on the list of essential medicines maintained by the World Health Organization. The dosage of levothyroxine must be c­ arefully determined, because mild overdosing can cause nausea, heart palpitations, anxiety, and insomnia, and extreme overdosing can lead to heart failure or coma. Infants, children, and adults with Down syndrome have an increased risk of pathogenic infections because of their compromised immune



Treatment and Therapy

39

s­ystems. Upper respiratory infections such as sinusitis and tonsillitis, and lower respiratory infections such as pneumonia and bronchiolitis, can lead to coughing, wheezing, fever, chills, and breathing difficulty. The most common causes of respiratory infections are the bacterial ­pathogens ­Streptococcus pneumoniae and Haemophilus influenzae, and the viral pathogen, RSV. Protection against S. pneumoniae is provided by the pneumococcal vaccine, and the Hib vaccine protects against ­infection by the most common type of H. influenzae bacteria. No RSV vaccine is c­ urrently available. Infections of the middle ear (otitis media) cause ear pain, headache, fever, and hearing loss, and are treated with pain r­elievers such as acetaminophen, nonsteroidal anti-inflammatory drugs such as ibuprofen, and antibiotics. Urinary tract infections cause an increased frequency of urination, and produce symptoms that include pain in the pelvis or lower back, nausea, fever, and vomiting. The treatment for ­urinary tract infections is pain medications and antibiotics. Folliculitis is an infection by bacteria or fungi of hair follicles, and scabies is an infection by microscopic mites that burrow under the skin. Both skin conditions can be treated with frequent cleansing of the skin, topical antiseptics, and antibiotics. Down syndrome also causes a higher risk of specific blood d ­ isorders. One example is anemia, which is low iron in the blood that can lead to dizziness, shortness of breath, fatigue, and increased heart rate. A ­ nemia can occur in infants, children, or adults with Down syndrome, and it is treated with iron supplements and changes in diet. Polycythemia, which is abnormally high red blood cell count, is common in babies with Down s­yndrome, and it can cause headaches, dizziness, fatigue, ­bruising, ­excessive sweating, and blurred vision. The primary treatment for ­polycythemia is p ­ hlebotomy, or bloodletting, to lower the number of ­circulating red blood cells. Medications such as hydroxyurea and aspirin are also ­effective in the treatment of polycythemia. Down syndrome babies also have a higher incidence of thrombocytopenia, an abnormally low platelet count that can lead to prolonged bleeding. Thrombocytopenia can be treated with platelet transfusions. Infants with Down syndrome are also at higher risk for transient myeloproliferative disorder (TMD), an overproduction of abnormally large white blood cells that results in fever, sweating, brui­sing, fatigue, headache, and weight loss. About 15

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DOWN SYNDROME

percent of infants born with Down syndrome are diagnosed with TMD. TMD is treated with leukapheresis, a procedure that physically filters out the larger white blood cells, or with chemotherapy medications such as cytarabine, a drug that is on the WHO list of essential medications for its effectiveness against cancers. Infants with TMD are monitored closely because TMD can lead to leukemia, a cancer of the white blood cells. About half of people with Down syndrome experience the health complication of obstructive sleep apnea. Disordered breathing during sleep can have negative effects on the cognitive development and growth rate of children, and can lead to heart and lung problems in children and adults. One mode of treatment is to surgically remove enlarged tonsils or adenoids that could obstruct the airway. If sleep apnea persists, a more ­aggressive surgical intervention can be used to alter the shape and size of the tongue, the oral cavity, or the jaw. Another mode of treatment for sleep apnea is the use of supplemental oxygen during sleep. Down syndrome increases the risk of obesity, which leads to health complications including hypertension, heart disease, stroke, respiratory problems, liver disease, type 2 diabetes, and osteoarthritis. The high blood pressure of hypertension is treated with a diet that is high in grains, fruits, and vegetables, and low in saturated fat and sodium, and with the administration of medications such as angiotensin-converting ­enzyme (ACE) inhibitors, beta-blockers, and diuretics. Increased ­physical a­ ctivity and regular exercise also lower blood pressure. Heart disease can lead to ­arrhythmia, which can treated with calcium channel blockers, beta ­blockers, or a pacemaker. Coronary artery disease is treated with statins, blood thinners, angioplasty, or bypass surgery. Congestive heart failure is usually treated with diuretics, ACE inhibitors, or bypass surgery. Therapy for stroke involves administration of blood thinners, ­antihypertensive drugs, ACE inhibitors, speech therapy, and physical therapy. R ­ espiratory problems caused by obesity include asthma and a progressive o­ bstruction of airflow that mimics chronic obstructive pulmonary disease (COPD), both of which can be treated with bronchodilators, steroids, and ­oxygen therapy. Liver disease caused by obesity often takes the form of ­nonalcoholic fatty liver disease (NAFLD), during which the abnormal ­accumulation of fat in the liver progressively impairs its function. NAFLD is treated with restriction of dietary fats and carbohydrates, and increased



Treatment and Therapy

41

exercise. Type 2 diabetes is treated with insulin therapy, blood thinners, changes in diet, and exercise. Treatments for osteoarthritis ­include ­regular exercise, nonsteroidal anti-inflammatory drugs, pain relievers, arthroscopy, and joint replacement.

Education for Children with Down Syndrome Until recently, the prevailing societal view about children with Down syndrome was that they were incapable of learning in an inclusive ­environment with other children. Ignorance of the learning potential of children with Down syndrome led to the misconception that they would not benefit from being in a classroom with other children, and that they would disrupt the learning environment. As a result, most c­hildren with Down syndrome were placed in institutions, shuttered away from ­society and not given access to appropriate education. As recently as 1970, only 20 percent of U.S. children with Down syndrome attended ­public schools. Gradually, attitudes shifted in the United States, and people began to accept that children with Down syndrome can learn in a typical public school environment that includes typically developing ­children, and that they have a right to do so. The United States Education for All H ­ andicapped Children Act of 1975, renamed the Individuals with ­Disabilities ­Education Act (IDEA), requires the availability of free and appropriate public e­ducation through high school for all children ­beginning at the age of 3 years in an environment that is as inclusive of all children as is practical. There are provisions in IDEA that ensure that a child with Down syndrome is not to be separated into a special education class, or forced to enroll in a separate school, unless the parents and teachers of the child agree that it is appropriate. IDEA stipulates that children with disabilities, including those with Down syndrome, should be p ­ rovided services such as transportation, nursing, c­ ounseling, and any other support they need to access free and inclusive public ­education. Because there is considerable variation in the extent to which Down ­syndrome causes developmental delays and cognitive disability, it is appropriate for parents and teachers to set individualized educational goals for each child, and to readjust the goals over time. IDEA mandates the formation of a team composed of parents or other caregivers, t­ eachers,

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DOWN SYNDROME

and child development specialists whose responsibility is to develop an individualized education program (IEP) tailored to the educational needs of a given child. Although IDEA requires the team to consider placing the child in the least restrictive environment possible, which is an inclusive classroom with typically abled children, it also allows for the consideration of special needs programs or schools. Efforts to improve the educational opportunities of children with Down syndrome throughout the world are underway, and are supported by organizations such as the National Down Syndrome Society, Down Syndrome International, and Down Syndrome Education International (see URLs in Bibliography), which provide information about current research, and access to educational resources and services.

Therapies for Down Syndrome At all stages of life, physical therapy can help individuals with Down syndrome manage the challenges brought about by their condition. ­ Infants with Down syndrome can benefit from physical therapy to help them develop the motor skills needed for achieving physical develop­ mental milestones such as sitting upright, crawling, and walking. Physical limitations caused by hypotonia, ligamentous laxity, atlantoaxial instability, hip abnormalities, kneecap instability, flat feet, broad hands with short fingers, heart defects, and respiratory problems are considered in the preparation and implementation of an appropriate physical therapy plan. The primary objective of early physical therapy is not to accelerate the rate at which infants learn motor skills, but to minimize the develo­ pment of detrimental compensatory movement patterns that can prevent them from developing good habits of movement. Early physical therapy also enables parents and caregivers to gain insights about personality charac­teristics that impact the ability of a given child to learn, such as the level of curiosity, the ability to accept challenges, and the tendency toward perseverance. Physical therapy also addresses common feeding problems among infants and young children with Down syndrome, such as ­difficulty nursing or sucking from a bottle, inability to properly bite, chew, and swallow solid food, and delays in learning how to handle food and utensils.



Treatment and Therapy

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The acquisition of language involves learning receptive language, which is the ability to receive and understand written and spoken communication, and expressive language, which is the ability to use vocabulary and grammar to put thoughts into written and spoken words and sentences. Although children with Down syndrome usually acquire language at a later age than is typical, they have more trouble with expressive language than with receptive language. The gap between the language they understand and what they can express can be narrowed with speech therapy. Speech therapy can overcome problems with intelligibility that occur because of respiratory difficulties, or poor tone of the muscles used for talking, by helping children with the mechanical process of speaking. Children can learn how to effectively communicate in various settings, such as home or at school, and with various people, including other children, family members, and teachers. Speech therapy also helps children with visual impairment or hearing loss that limit the acquisition of receptive and expressive language. Occupational therapy can help children develop the skills they need to become as independent as possible. An occupational therapist helps young children learn personal care skills, such as feeding, dressing, and grooming themselves. School age children learn skills such as printing, handwriting, and keyboarding. Adults learn skills required for independent living, recreation, and pursuing and maintaining a job. Occupational therapists can provide access to assistive devices such as specialized writing desks, pencils that are easier to grip, and targeted educational software. Children with Down syndrome sometimes need emotional and behavioral therapy to address harmful or disruptive behaviors that r­ esult from medical conditions such as sensory deficits, hypothyroidism, or sleep apnea, or as manifestations of depression, anxiety, or frustration over their communication challenges. Behaviors of concern include ­stubbornness, inattention, impulsivity, and obsessive–compulsive behavior. Emotional and behavioral therapists work with parents and caregivers to develop interventions that lessen or correct these behaviors.

CHAPTER 4

Future Prospects Publicly and privately funded research is ongoing in clinics, hospitals, universities, medical institutes, and government laboratories throughout the world to better understand how extra copies of approximately 250 protein-encoding genes on chromosome 21 lead to Down syndrome. An important outcome of this research would be the discovery of new pharmaceutical treatments for Down syndrome, examples of which are described in this chapter. The chapter also presents research that might lead to stem cell treatments for Down syndrome, describes a process by which embryos produced in the clinical laboratory can be screened for aneuploidy before being used to establish a pregnancy, and explains gene therapy strategies that might be used to cure Down syndrome.

Experimental Drugs for Down Syndrome The discovery of new drugs to treat Down syndrome depends on basic research of its underlying molecular, cellular, and physiological causes. ­Scientists employ methods from disciplines such as biochemistry, cell biology, developmental biology, physiology, and genetics to develop ­ ­experimental models of Down syndrome, and use them to invent or ­discover promising drug candidates that can enter clinical trials to test their ­efficacies. For e­ xample, researchers found that an e­ xperimental drug ­improved ­learning and memory in a mouse model of Down s­yndrome. The mice were ­genetically engineered to carry a third copy of about half of the approximately 250 genes found on human c­hromosome 21, and they ­displayed the human Down syndrome characteristics of r­educed ­cerebellum size and difficulties with learning and memory. The ­cerebellum is the part of the brain that coordinates voluntary muscle movements and is responsible for fine motor control. Researchers wanted to counteract the

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e­ ffect of the extra genes on the development of the cerebellum by ­injecting a drug called Sonic hedgehog agonist 1.1 (SAG 1.1) into Down syndrome mice at birth. SAG 1.1 stimulates an important ­biochemical ­signaling ­cascade that originally was named the Sonic hedgehog pathway because its disruption causes fruit flies to ­develop into prickly, rounded shapes similar to the video game character, Sonic the hedgehog. They hoped that injected SAG 1.1 would permit the ­development of a ­normally sized ­cerebellum. The cerebellum grew to ­normal size in the mice but unexpectedly, the mice also exhibited improved learning and memory, as measured by performance in a water maze test. Improvements in learning and memory were surpr­ ising because they are attributed to the hippocampus, not the cerebellum. Possible explanations include previously unknown effects of the cerebe­ llum on learning and memory, and cerebellar influences on the growth and development of the hippocampus. Translation of the experimental drug treatment for use in humans will depend on the discovery of ways to target the positive effects of SAG 1.1 on brain development without undesirable off-target effects elsewhere in the body. Another promising Down syndrome experimental drug is scyllo-inositol, also known as ELND005, which is being evaluated for its ability to ward off Alzheimer’s disease in people with Down syndrome. ­Scyllo-inositol is a naturally occurring sugar alcohol from coconut palms that has been shown to reduce the production of amyloid-beta that ­accumulates in amyloid plaques in the brains of people with A ­ lzheimer’s ­disease, and to decrease the production in the brains of children and adults with Down syndrome of a signaling molecule called myo-inositol that has been correlated with cognitive disability. A four-week clinical trial of scyllo-inositol administered to 23 adults with Down syndrome demonstrated its safety, but more studies are needed to determine its ­effectiveness in improving cognition. A fundamental aspect of Down syndrome pathology is alteration of the pattern of transcription of the genes carried by chromosome 21. Drugs that affect transcription by modifying proteins bound to the DNA of chromosomes might improve the symptoms and health complications of people with Down syndrome. The emerging field of epigenetics studies the complex transcriptional effects produced by chemical modifications of histone proteins that interact with chromosomal DNA. Epigenetic



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histone modifications happen naturally in response to environmental ­factors, and these modifications are passed from parents to their children. One category of experimental Down syndrome drugs affects an enzyme called histone deacetylase (HDAC) that reverses histone acetylation, a form of epigenetic modification. The drugs are called HDAC inhibitors, and some of them might be effective in the treatment of Down syndrome. HDAC inhibitors under investigation include vorinostat and r­ omidepsin, which have been shown to be effective in the treatment of a specific type of leukemia associated with Down syndrome.

Stem Cell Therapy for Down Syndrome During early development, successive mitotic cell divisions of a fertilized egg produce embryonic stem (ES) cells, from which all the cells types of the body are derived. Because ES cells are capable of becoming any cell type in the human body, they are referred to as totipotent. In the fully formed human body, adult stem cells located in tissues ­throughout the body are used for repair and replacement. Adult stem cells are called ­pluripotent because the range of cell types they can become is limited to the types of cells found in the tissues in which they are located. The field of regenerative medicine harnesses the power of stem cells to d ­ ifferentiate into specialized cells for the treatment of a variety of diseases, including Parkinson’s disease, diabetes, heart disease, and stroke. Whether or not an effective regenerative medicine strategy can be developed for Down ­syndrome is unknown. There are hundreds of clinics throughout the world that offer stem cell therapies which have not been validated for their safety and efficacy, and which have not been subjected to any regulatory control. Many of these clinics claim to have effective stem cell therapies for the improvement of Down syndrome, but scientific evidence suppor­ting their claims is lacking. For example, a clinic in India reported that an infant with Down syndrome who received injections of ES cells into his blood, back muscles, and under his skin showed improved muscle tone, better understanding, and ability to recognize relatives after a three-year period. Critics of the study offered the alternative conclusion that improvements seen in the infant occurred as a consequence of ­normal growth and development. The study lacked a comparison to Down syndrome infants who

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did not receive the treatment. Skeptics doubted that the injected ES cells would survive the expected immune response, and that the ES cells would be capable of homing to the brain to improve cognition. Further research is needed before ES cell therapy for Down syndrome can be c­ onsidered safe and effective. One way that ES cell therapy might work is to use ES cells that are not rejected by the immune system. ES cells that are harvested from embryos are called allogeneic because they carry a different genotype than the patient to whom they are administered, as was the case with the Indian ES cell treatment described above. A viable alternative is to produce ES cells that are autologous, which means that they are derived from cells taken from the patient undergoing the stem cell treatment, and therefore have the same genotype as the patient. The technology for generating autologous ES cells is called somatic cell nuclear transfer (SCNT), and it is based on the process by which the first cloned mammal was produced from an adult cell. In 1996, scientists at the Roslin Institute in Scotland announced that they had cloned Dolly the sheep by removing the nucleus from an egg cell and replacing it with a nucleus from an adult mammary gland cell. The use of SCNT to clone humans is fraught with ethical and legal challenges, and has not been tried by any reputable labs. The use of SCNT to produce cells similar to ES cells that could be used to treat diseases has gained some acceptance among researchers, caregivers, patients, and policy makers. These laboratory-produced ES cells would be autologous, and therefore unlikely to be destroyed by the immune system after injection into a patient. Many moral and legal concerns surround the use of ES cells for the treatment of Down syndrome or any genetic condition. The source of ES cells is human embryos, which many people believe have the s­tatus of ­personhood, and therefore should not be destroyed. The debate over whether or not embryos should be considered the moral equivalent of a human being cannot be settled by science. However, science might ­enable us to avoid the debate altogether. Scientists have developed a process for the production of adult stem cells that avoids the moral and ethical c­ oncerns that arise from the use of ES cells. The process involves ­harvesting adult cells from a patient, and reprogramming them in the lab to revert to a pluripotent genetic state. These induced pluripotent stem



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cells (iPS) are then given a combination of proteins that force them to become specific cells that can be used for drug screening, for tissue repair, or for non-ES cell therapy to treat disease. Researchers at the University of California, Davis, learned how to induce skin cells taken from a Down syndrome patient to develop into iPS cells. The cells were then coaxed to differentiate into nerve cells and another type of cell that supports nerve cell function. This line of research, and others, supports the view that it might be possible to treat Down syndrome with non-ES cell therapy.

Preimplantation Genetic Diagnosis of Down Syndrome Some prospective parents who have an increased risk of conceiving a child with Down syndrome because of maternal age, or because they already had a child with Down syndrome, seek an alternative to ­prenatal ­diagnosis of Down syndrome and termination of the pregnancy. An a­ lternative for these parents is preimplantation genetic diagnosis (PGD). PGD is ­carried out in the same manner as genetic testing of adults, children, or fetuses, except that it is conducted on cellular samples taken from p ­ reimplantation embryos that are produced by in vitro fertilization (IVF). For IVF, the woman receives a hormonal injection to stimulate egg maturation, and ultrasound is used to locate and harvest mature egg follicles in her ovaries. Fertilization is achieved in a clinical laboratory by mixing the eggs with semen collected from the prospective father, and the resulting IVF embryos are either implanted to establish a pregnancy or frozen for later use. Over 5 million IVF babies have been born since the first one, Louise Brown, was born in 1978. There are two methods by which a s­ ample is extracted from IVF embryos for use in PGD. B ­ lastomere biopsy involves allowing the fertilized egg to divide three times over a three-day period into an embryo that contains eight cells called blastomeres. One of the eight blastomeres is carefully removed from the embryo and used for genetic testing. Because all eight of the blastomeres are totipotent ES cells, the loss of one blast­omere has no known effect on healthy development. However, blastomere biopsy has been shown to reduce the frequency at which IVF embryos s­ uccessfully implant into the uterus for pregnancy. Because of this problem, ­trophectoderm biopsy was developed, during which the embryo is allowed to develop until the fourth or fifth day after fertilization. At this point, the embryonic cells have ­specialized into an

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inner cell mass that will become the fetus and an outer cell layer called the trophectoderm that will interact with maternal cells to form the placenta. A trophectoderm biopsy involves removal of about 10 of the trophectoderm cells. This process results in a higher rate of successful embryo implantation and pregnancy. DNA ­isolated from embryonic cells can be tested to achieve a diagnosis of a genetic c­ ondition. For Down s­yndrome testing, karyotype analysis is used to determine whether each embryo is euploid or aneuploid. ­Aneuploid embryos that would develop into children with Down syndrome are ­discarded, and one or more of the euploid embryos is chosen for implantation and the establishment of a pregnancy. Cryopreservation can be used to carefully freeze unused euploid embryos for the establishment of future pregnancies. Whether or not it is ethical to destroy viable human embryos to avoid Down syndrome is a an important question for families and an ongoing societal debate.

Gene Therapy for Down Syndrome Gene therapy is the process of introducing therapeutic DNA into human cells to treat or cure disease. The first gene therapy patient was a four-year-old girl named Ashanti DeSilva, who was born with a ­genetic immune system deficiency. Since her disease was caused by being ­homozygous recessive for a recessive disease-causing allele, ­researchers developed a gene ­therapy procedure that used a virus to deliver a normal dominant allele to her white blood cells. The hope was that the white blood cells would be able to contribute to the development of a normal immune system. Although this did happen, the effects were not ­long-lasting. ­Nonetheless, the procedure carried out in 1990 with Ashanti DeSilva is the first documented gene therapy trial. Although the 1990s saw a surge of gene therapy research and clinical trials, the field had a tragic setback in 1999 when Jesse Gelsinger died from an immune ­reaction to the virus that was used to deliver a therapeutic allele to treat his genetic disease. The tragedy caused the FDA to suspend several ­clinical trials so the safety of gene therapy could be carefully considered. Improvements have been made in the process by which beneficial DNA is delivered by viruses for gene therapy. The first completely successful gene therapy trial was reported in 2000, and involved the use of a retrovirus to deliver a gene



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51

for the treatment of a rare X-linked recessive immune deficiency disease. Over 2,400 gene therapy trials have been performed since, and ­successful examples include the treatment of hemophilia, adrenoleukodystrophy, chronic granulomatous disease, chronic lymphocytic leukemia, and a rare form of hereditary blindness. One approach to gene therapy for Down syndrome would be to deliver a gene to the extra copy of chromosome 21 that would ­inactivate it. The XIST gene is normally found on the X chromosome, and it ­functions to silence one of the two X chromosomes typically found in females. XIST encodes an RNA that is not translated into protein, but which covers one X chromosome and leads to tighter packaging of its genes. In a proof of concept study, XIST was shown to direct the ­inactivation of ­chromosome 21 in iPS cells from a Down syndrome patient. Another strategy for Down syndrome gene therapy would be to introduce a gene into the extra copy of chromosome 21 that causes it to be lost. The TKNEO gene was added to the long arm of the extra chromosome 21 in iPS cells from a Down syndrome patient. These cells were treated with a chemical that only becomes toxic after it is altered by an enzyme encoded by the TKNEO gene. Aneuploid cells that carry the extra chromosome 21 are selected against, whereas cells that have lost the extra chromosome are able to ­survive. A third approach to Down syndrome gene therapy would involve a gene called ZSCAN4 that is required to maintain a normal complement of chromosomes during early embryonic development. Introduction of ZSCAN4 to skin cells taken from trisomy 21 Down syndrome patients led to between 24 and 49 percent elimination of the aneuploid state.

Conclusion We have learned a lot about Down syndrome since John Langdon Down first described it over 150 years ago. We know that most cases are caused by trisomy 21, and that the remaining ones are due to an inherited ­translocation onto another chromosome of part or all of c­hromosome 21. We can use this information for prenatal diagnosis, which helps ­prospective parents prepare for the birth of a child with Down s­ yndrome, or to make the difficult decision to terminate a Down syndrome ­pregnancy. We have learned that Down syndrome causes a myriad of ­symptoms and health complications, including heart defects, c­ ongenital vision and hearing loss, abnormalities of the musculos­keletal system, intellectual disability, ­digestive problems, leukemia, an increased risk of infectious disease, ­epilepsy, and dementia from ­Alzheimer’s disease. We have come to understand that the underlying cause of Down syndrome is extra copies of the approximately 250 genes found on chromosome 21, and that this can result from errors in the production of sex cells, ­atypical reproduction of embryonic cells, or ­inheritance of abnormal chromosomes. In developed countries, we have made advances in the treatment of symptoms and health complications that have improved the life expectancy of people with Down syndrome from fewer than 10 years a century ago to more than 60 years today. We have discovered new pharmaceutical treatments for Down s­yndrome, and pursued research that might lead to stem cell treatments for it. We have developed preimplantation genetic diagnosis to screen IVF embryos for Down syndrome before they are used to establish a pregnancy, and are working toward the realization of gene therapy strategies that might lead to cures for Down syndrome. We have learned a lot about Down syndrome since John Langdon Down first described it, but perhaps the most important thing we have learned is how to treat people who have Down syndrome with the respect they deserve. Down syndrome causes intellectual and developmental disabi­lities that make it difficult for children to learn, and challenging for adults to be independent and have meaningful work lives. However, we have made progress in

54 CONCLUSION

the establishment of laws such as the Individuals with Disabilities Education Act and the Americans with Disabilities Act that ensure access to education and employment for people who have Down syndrome. On World Down Syndrome Day (3/21), we celebrate these advances while challenging ourselves to “do our part to enable children and persons with Down syndrome to participate fully in the d ­ evelopment and life of their societies on an equal basis with others.” We can all be inspired by Collette Divitto and “The Amazing Cookie” she bakes to build inclusive societies that provide equal opportunities for all people with Down syndrome.

Glossary adult stem cells. Pluripotent cells used for repair and replacement of tissues throughout the body. allele. One of several possible forms of a gene that differ in base sequence. alternative splicing. The inclusion of different combinations of exons during RNA splicing, resulting in the production of different proteins. Alzheimer’s disease. A chronic neurodegenerative disease that destroys memory and other cognitive functions. amblyopia. Commonly called “lazy eye,” because one eye makes a much smaller contribution to vision than the other eye. amniocentesis. A process by which fetal cells are extracted from amniotic fluid for genetic analysis. amyloid plaques. An accumulation of amyloid-beta that occurs in the course of Alzheimer’s disease that interferes with the normal function of brain nerve cells. anemia. A low blood iron level that causes dizziness, breathing difficulty, fatigue, and increased heart rate. aneuploidy. A cell with an abnormal chromosome count. aorta. A blood vessel that receives oxygenated blood from the left ventricle and delivers it to the arterial circulatory system. arteries. Blood vessels that deliver blood that is rich in oxygen and nutrients to the cells and tissues of the body. atlantoaxial instability. A condition in which a loose connection between neck vertebrae results in symptoms such as neck pain, limited neck mobility, ­clumsiness, and walking difficulties. atria. The right atrium is the chamber of the heart that receives deoxygenated blood from the body and delivers it to the right ventricle. The left atrium is the chamber of the heart that receives oxygenated blood from the lungs and delivers it to the left ventricle. atrioventricular septal defect (AVSD). A heart defect characterized by a hole in the septum that separates the chambers of the heart, and malformation of the valves that control blood flow between them. autosomes. All of the human chromosomes except the X and the Y. balanced translocation. Results from a transfer of part of one chromosome to another without an overall loss of genetic material. balanced translocation carrier. A person who has inherited a translocated ­chromosome that can cause Down syndrome, but who does not have Down ­syndrome themselves. blastomere biopsy. The removal of several blastomeres from an IVF embryo for preimplantation genetic diagnosis.

56 GLOSSARY

blepharitis. A recurrent inflammation of the eyelids. bronchiolitis. Inflammation and congestion of the airways caused by infection. Brushfield spots. Lightly or darkly colored spots on the iris of the eye. carcinoma. A cancer of the epithelial tissue of the skin or of the lining of the internal organs. cataracts. Clouding of the lens of the eye. celiac disease. An immune reaction to gluten, and causes bloating, severe gas, diarrhea, and anemia. centromere. A structure that connects the two copies of each chromosome that are distributed into two daughter cells during mitosis. cerebellum. A part of the brain that coordinates muscular activity. chorionic villus sampling (CVS). A process by which fetal cells are extracted from the chorion of the placenta for genetic analysis. chromosomes. Complexes of DNA and protein in the nucleus of cells that carry genetic information. cilia. Hair-like projections on the surfaces of cells that enable them to move or to sense their environments. cochlea. The part of the inner ear that transduces sound into nerve signals. combined test. A Down syndrome prenatal screening test that measures the ­levels of pregnancy-associated plasma protein A (PAPP-A) and human chorionic growth hormone (HCG). conductive hearing loss. Occurs when sound waves are not conducted properly from the outer ear to the eardrum and the bones of the middle ear. congenital. A trait, condition, or disease that is present at birth. congestive heart failure. A chronic condition during which the heart fails to circulate enough blood to supply tissues throughout the body with oxygen and nutrients and to remove waste from them. cyanosis. The development of a bluish skin color around the mouth, fingers, and toes. diploid. A cell that carries two copies of each type of chromosome. dominant. An allele that produces a phenotype when present with a recessive allele in a heterozygous individual. dosage sensitivity. The extent to which the phenotype produced by a gene ­depends on the number of copies of it. ductus arteriosus. A channel that connects the pulmonary artery and the aorta during fetal development. duodenal atresia. A birth defect caused by an improper connection from the stomach to the small intestine. echocardiogram. An ultrasound test that checks for abnormalities in the ­structure of the heart.

GLOSSARY 57

Edwards syndrome. An aneuploid condition caused by trisomy 18, and resulting in heart defects, breathing problems, nervous system abnormalities, a deformed digestive tract, and physical malformations. electrocardiogram. A test that measures the electrical activity of the heart. embryonic stem (ES) cells. Cells found in the embryo that are capable of ­becoming any cell type in the human body. epicanthal folds. Skin folds of the upper eyelid that cover the inside corner of the eye. epigenetics. The study of heritable effects of chemical modification of DNA ­histone proteins on gene expression. epilepsy. A neurological disorder that causes sudden recurrent seizures. esophageal atresia. A birth defect in which the esophagus does not properly connect to the stomach. eukaryotes. Organisms whose cells contain nuclei, including animals, plants, fungi, and protists. euploidy. A cell with a normal chromosome count. Eustachian tube. A tube that connects the upper part of the throat to the middle ear. exons. DNA information in genes interspersed with exons that codes for amino acids. familial Down syndrome. An alternative name for translocation Down syndrome. fluorescence in situ hybridization (FISH). A technique that uses fluorescently tagged DNA probes to determine the location of genes on chromosomes and to detect chromosomal rearrangements. folliculitis. An infection of hair follicles by bacteria or fungi. gametes. Sex cells (sperm and egg) that carry a haploid number of chromosomes. gastroesophageal reflux disorder (GERD). An abnormal reflux of acidic ­stomach contents. gene modifiers. Genes that have been found to be contributing factors for ­genetic disease. gene therapy. Introduction of DNA into human cells for the correction of ­genetic disease. genes. Units of heredity that carry the information needed to determine or ­contribute to a phenotype. genetic recombination. The introduction of genetic variation by exchange of genetic material between chromosomes. genome. The collection of DNA found in an organism. genome-wide association study (GWAS). A powerful research approach to the discovery of DNA variations that affect a disease or condition. genotype. The forms of genes that an individual carries.

58 GLOSSARY

glaucoma. An abnormal drainage of the fluid within the eye that places pressure on the optic nerve, producing the symptoms of moderate to severe eye pain, eye redness, cloudy vision, and tunnel vision. glue ear. An abnormal accumulation of fluid in the middle ear. haploid. A cell that carries one copy of each type of chromosome. heterozygous. A genotype that includes one dominant and one recessive allele. hippocampus. The part of the brain that controls emotion, memory, and the function of internal organs. Hirschsprung disease. A disease in which missing nerve cell connections to the colon prevent its normal function and cause intestinal blockage, resulting in the symptoms of abdomen swelling, vomiting, and severe constipation. histone. One of several basic proteins that interact with DNA to form chromosomes. homozygous dominant. A genotype composed of two dominant alleles. homozygous recessive. A genotype composed of two recessive alleles. human genome. The approximately 3.2 billion DNA bases found on all the nuclear chromosomes and in the mitochondria of a human being. hypothyroidism. A condition during which the thyroid produces lower than normal levels of hormones that control metabolism throughout the body. hypotonia. The occurrence of week muscles throughout the body. imperforate anus. A birth defect in which the opening from the anus to the rectum is blocked or missing. individualized education program (IEP). A document that details the plan for the public school education of a child with special needs. Individuals with Disabilities Education Act (IDEA). A U.S. law that requires the availability of free and appropriate public education through high school. isochromosome. Results from a rare translocation event that results in the ­attachment of most or all of a chromosome to itself. in vitro fertilization (IVF). The process by which sperm and egg cells are mixed outside of the body to produce embryos that are used to establish pregnancy. induced pluripotent stem (iPS) cells. Adult cells such as skin cells that have been reprogrammed to become stem cells. intelligence quotient (IQ) test. The most common measure of intellectual ­capacity, which expresses the results of standardized intelligence tests as a ratio of mental age to chronological age. introns. DNA information in genes interspersed with exons that does not code for amino acids. karyotype. A microscopic image of the chromosomes from a single cell. Klinefelter syndrome. Caused by an extra copy of the X chromosome in males, resulting in tall stature, weak muscles, hypogonadism, male sterility, and minor cognitive effects.

GLOSSARY 59

leukapheresis. A procedure that filters out atypically large white blood cells that occur during transient myeloproliferative disorder. leukemia. A type of cancer in which an excess of immature white blood cells ­suppress the formation of normal white blood cells. ligamentous laxity. A condition in which there are loose ligaments in joints throughout the body. maternal blood screening. Use of fetal blood cells isolated from maternal blood for genetic testing. meiosis. The sexual cellular division that produces gametes, accompanied by the introduction of genetic variation. mesoderm. The middle of the three primary germ layers that gives rise to heart, skeletal muscle, smooth muscle, bone, cartilage, and blood. messenger RNA (mRNA). RNA produced by transcription of DNA that carries information for the production of protein by translation. mitosis. The asexual cellular division process by which two genetically identical daughter cells are produced. monogenic. A disease or condition that is caused by mutation of a single gene. monosomy. An aneuploidy that occurs because of a missing chromosome. mosaic Down syndrome. A type of Down syndrome during which some cells in the body have an extra copy of chromosome 21 and other cells have the normal complement of two copies of chromosome 21. mosaicism. A mixture in the body of aneuploid and euploid cells. mutations. Changes in the DNA sequences that may might be deleterious, ­beneficial, or neutral. neuroblastoma. A rare cancer usually found in the adrenal gland. neurons. Cells in the nervous system that transmit information to other nerve cells, muscle cells, or gland cells. nonreciprocal translocation. An unequal exchange of genetic material from one chromosome to another. nuchal fold. An anatomical landmark that develops in the neck of a fetus. obstructive sleep apnea. A sleep disorder during which blockage of the airway by the soft tissue at the back of the throat repeatedly interrupts breathing and limits the flow of oxygen to the brain and the rest of the body. otitis media. An infection of the middle ear. Patau syndrome. An aneuploid condition caused by trisomy 13, and resulting in heart defects, neurological problems, and skeletal deformities. patent ductus arteriosus (PDA). The abnormal persistence of a channel that connects the pulmonary artery and the aorta during fetal development. phenotype. Traits that result from genotypes. phlebotomy. Removal of blood for the treatment of polycythemia and other conditions.

60 GLOSSARY

pluripotent. Refers to stem cells that can develop into any of several specialized types of cells. pneumonia. Infection of the air sacs of the lungs. polycythemia. An abnormally high red blood cell count that results in ­headaches, dizziness, fatigue, bruising, excessive sweating, and blurred vision. postlingual hearing loss. Hearing loss that occurs after a child learns to speak. preimplantation genetic diagnosis (PGD). Genetic testing of cellular samples taken from embryos that are produced by in vitro fertilization (IVF). prelingual hearing loss. Hearing loss that occurs before a child learns to speak. prenatal diagnostic testing. Genetics testing of fetal cells collected by ­amniocentesis or chorionic villus sampling. prenatal screening. Provides information about the increased risk that a ­pregnancy will result in the birth of a child with Down syndrome, or another genetic condition. primary germ layers. Embryonic tissue layers that establish the overall spatial organization of the body and contain the progenitor cells for all its tissues and organs. pulmonary hypertension. Causes the lungs to fill with blood and causes ­breathing difficulty, increased heart rate, swelling of extremities, and cyanosis. pulmonary vascular disease. Abnormal blood flow between the heart and the lungs. quad screen test. A Down syndrome prenatal screening test that measures HCG, estriol, inhibin A, and alpha-fetoprotein (AFP). recessive. An allele that does not produce a phenotype when present with a ­dominant allele in a heterozygous individual. reciprocal translocation. An equal exchange of genetic material between two chromosomes. refractive errors. Caused by changes in the shape of the eye, and resulting in blurred vision. regenerative medicine. A field of medicine that seeks to harness the power of stem cells differentiation for the treatment of a variety of diseases, including ­Parkinson’s disease, diabetes, heart disease, and Down syndrome. RNA splicing. Removal of introns and splicing together of successive exons to make an mRNA that contains a contiguous protein-encoding sequence. Robertsonian translocation. The fusion of two chromosomes that have broken into two parts. scabies. An infection by microscopic mites that burrow under the skin. scyllo-inositol. A naturally occurring sugar alcohol from coconut palms that has been shown to reduce the production of amyloid-beta that accumulates in amyloid plaques. sensorineural hearing loss. Hearing loss from dysfunction of the inner ear or its connection to the nervous system.

GLOSSARY 61

single nucleotide polymorphisms (SNPs). Approximately 10 million places in the human genome where the DNA base present in one person is different in another person. sinusitis. Inflammation of the nasal passages by infection. somatic cells. All the cells in the body except gametes. Sonic hedgehog agonist 1.1 (SAG 1.1). Stimulates an important biochemical signaling cascade called the Sonic hedgehog pathway. stem cells. Undifferentiated cells that can become specialized cell types ­throughout embryonic and fetal development and during the process of repair and ­replacement that occurs throughout the body. tetrad. The structure that occurs when two members of a chromosome pair, each with two copies, align during meiosis. tetralogy of Fallot (TOF). A heart defect that includes the four heart ­abnormalities of ventricular septal defect, narrowing of the passageway to the pulmonary artery, enlargement of the right ventricle, and an enlargement of the valve leading to the aorta. thrombocytopenia. An abnormally low platelet count that can lead to ­uncontrolled bleeding. tonsillitis. Inflammation of the tonsils caused by infection. totipotent. Refers to stem cells that can develop into any of several specialized types of cells. tracheoesophageal fistula. A birth defect in which there is an abnormal ­connection between the trachea and the esophagus. transcription. The process by which the information in the form of the ­nucleotide sequence of DNA is converted into the nucleotide sequence of RNA. transcription factor. A protein that controls the rate of transcription by binding to DNA. transient myeloproliferative disorder (TMD). An overproduction of ­abnormally large white blood cells that results in fever, sweating, bruising, fatigue, headache, and weight loss. translation. The process by which the nucleotide sequence of mRNA is used to direct the synthesis of proteins. translocation. An abnormal process by which genetic material is transferred from one chromosome type to another. translocation Down syndrome. Caused by an extra copy of most or all of ­chromosome 21 that is attached to itself or a different chromosome. triple X syndrome. Trisomy of the X chromosome (XXX) that causes tall stature, poor muscle tone, and minor intellectual disability. trisomy. The occurrence of three copies of a chromosome instead of two. trisomy 21 Down syndrome. Caused by the inheritance of three copies of ­chromosome 21 instead of two.

62 GLOSSARY

trophectoderm biopsy. Collection of cells from outer layer of an embryo for use in preimplantation genetic diagnosis. tumor angiogenesis. The process by which cancer cells from a solid tumor enter a blood vessel and are circulated to a site where they can establish a new tumor. tumor suppressor. A gene that protects a cell from becoming a cancer cell. Turner syndrome. A monosomy of the X chromosome that causes a webbed neck, short and stocky body, swollen hands and feet, and health complications such as heart defects, diabetes, and thyroid problems. veins. Blood vessels that take blood that is rich in carbon dioxide and waste away from the cells and tissues of the body. ventricles. The left ventricle is the chamber of the heart that receives oxygenated blood from the left atrium and delivers it to the body. The right ventricle is the chamber of the heart that pumps deoxygenated blood to the lungs. ventricular septal defect (VSD). A heart defect caused by an abnormal septum between the ventricles.

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Lana-Elola, E., S. Watson-Scales, A. Slender, D. Gibbins, A. Martineau, C. Douglas, T. Mohun, E.M.C. Fisher, and V.L.J. Tybulewicz. 2016. “Genetic Dissection of Down Syndrome-Associated Congenital Heart Defects Using a New Mouse Mapping Panel.” eLife 5, p. e11614. Lana-Elola, E., S.D. Watson-Scales, E.M.C. Fisher, and V.L.J. ­Tybulewicz. 2011. “Down Syndrome: Searching for the Genetic Culprits.” Disease Models and Mechanisms 4, no. 5, pp. 586–595. Lejeune, J., M. Gauthier, and R. Turpin. 1959. “Études des c­ hromosomes somatiques de neuf enfants mongoliens.” Comptes Rendus de l’Académie des Sciences 248, pp. 602–603. Li, H., S. Cherry, D. Klinedinst, V. DeLeon, J. Redig, B. Reshey, M.T. Chin, S.L. Sherman, C.L. Maslen, and R.H. Reeves. 2012. “Genetic ­Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down ­Syndrome Population.” Circulation Cardiovascular Genetics 5, no. 3, pp. 301–308. Li, L.B., K. Chang, P. Wang, R.K. Hirata, T. Papayannopoulou, and D.W. Russell. 2012. “Trisomy Correction in Down Syndrome ­Induced ­Pluripotent Stem Cells.” Cell Stem Cell 11, no. 5, p. 615. Malt, E.A., R.C. Dahl, T.M. Haugsand, I.H. Ulvestad, N.M. Emilsen, B. Hansen, Y.E. Cardenas, R.O. Skold, A.T. Thorsen, and E.M. ­Davidsen. 2013. “Health and Disease in Adults with Down S­ yndrome.” Tidsskrift for Den Norske Laegeforening 133, no. 3, p. 290–294. Mégarbané, A., A. Ravel, C. Mircher, F. Sturtz, Y. Grattau, M.O. ­Rethoré, J.M. Delabar, and W.C. Mobley. 2009. “The 50th Anniversary of the Discovery of Trisomy 21: The Past, Present, and Future of Research and Treatment of Down Syndrome.” Genetics in Medicine 11, no. 9, pp. 611–616. Mejía-Aranguré, J. Manuel, M.L. Pérez-Saldivar, J. ­ Flores-Lujano, C.B. Méndez, S.P. Cardoso, D.A. Duarte-Rodríguez, and A. Fajardo-Gutiérrez. 2011. “Infections and Acute Leukemia in ­Children with Down Syndrome.” “National Down Syndrome Congress,” National Down Syndrome ­Congress. http://www.ndsccenter.org/ (accessed March 20, 2017). “National Down Syndrome Society,” The Leading Human Rights ­Organization for All Individuals with Down Syndrome. 2017. http:// www.ndss.org/ (accessed March 20, 2017).

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Rafii, M.S., B.G. Skotko, M.E. McDonough, M. Pulsifer, C. Evans, E. Doran, G. Muranevici, P. Kesslak, S. Abushakra, and I.T. Lott. 2017. “A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (Scyllo-Inositol) in Young Adults with Down Syndrome without Dementia.” Journal of Alzheimer’s Disease 58, no. 2, pp. 401–411. Ram, G, and J. Chinen. 2011. “Infections and Immunodeficiency in Down Syndrome.” Clinical and Experimental Immunology 164, no. 1, pp. 9–16. Ramachandran, D., Z. Zeng, A. E. Locke, J.G. Mulle, L.J.H. Bean, T.C. Rosser, K.J. Dooley, C.L. Cua, G.T. Capone, R.H. Reeves, D.J. Cutler, E. Feingold, S.L. Sherman, and M.E. Zwick. 2015. “Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.” G3: Genes Genomes Genetics 5, no. 10, pp. 1961–1971. Ryoo, S.R., H.J. Cho, H.W. Lee, H.K. Jeong, C. Radnaabazar, Y.S. M.J. Kim, M.Y. Son, H. Seo, S.H. Chung, and W.H. Song. 2008. “Dual-Specificity Tyrosine(Y)-Phosphorylation R ­egulated Kinase 1A-Mediated Phosphorylation of Amyloid Precursor ­Protein: ­Evidence for a Functional Link between Down Syndrome and Alzheimer’s D ­ isease.” Journal of Neurochemistry 104, no. 5, pp. 1333–1344. Sacks, B., and A. Wood. 2003. “Hearing Disorders in Children with Down Syndrome.” Down Syndrome News and Update 3, no. 2, pp. 38–41. Sumarsono, S. H., T. J. Wilson, M. J. Tymms, D. J. Venter, C. M. C ­ orrick, R. Kola, M. H. Lahoud, T. S. Papas, A. Seth, and I. Kola. 1996. “Down’s Syndrome-like Skeletal Abnormalities in Ets2 ­Transgenic Mice.” Nature 379, no. 6565, pp. 534–537. Tepperberg, J., M. J. Pettenati, P. N. Rao, C. M. Lese, D. Rita, H. ­Wyandt, S. Gersen, B. White, and M. M. Schoonmaker. 2001. ­“Prenatal Diagnosis Using Interphase Fluorescence in Situ H ­ ­ ybridization (FISH): 2-Year Multi-Center Retrospective Study and Review of the Literature.” Prenatal Diagnosis 21, no. 4, pp. 293–301. Wapner, R.J., C.L. Martin, B. Levy, B.C. Ballif, C.M. Eng, J.M. Zachary, M. Savage, L.D. Platt, D. Saltzman, W.A. Grobman, S. Klugman,

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Index Acetaminophen, 39 ADAMTS1 gene, 30 Adult stem cells, 47 Alleles, 17 Allogeneic, 48 Alternative splicing, 29 Aluminium hydroxide, 38 Alzheimer’s disease, 9 Amblyopia, 4–5, 37 American Congress of Obstetricians and Gynecologists, 10 Amniocentesis, 11–12 Amyloid plaques, 29 Anemia, 15, 39 Aneuploidy, 20 Angiotensin-converting enzyme (ACE) inhibitors, 40 Antibiotics, 39 Aorta, 4 APP gene, 29 Arteries, 3 Aspirin, 39 Atlantoaxial instability, 6 Atria, 3 Atrial septal defect (ASD), 3, 36 Atrioventricular septal defect (AVSD), 3, 32–33, 35–36 Autologous, 48 Autosomes, 12 Balanced translocation, 23 carrier, 23 Beta-blockers, 40 Bismuth subsalicylate, 38 Blastomere biopsy, 49 Blepharitis, 5, 37 Body mass index (BMI), 16 Bronchiolitis, 14, 39 Brushfield spots, 1 Carcinoma, 15 Cataracts, 4, 36–37

Celiac disease, 7, 38 Centromere, 23 Cerebellum, 45–46 Chorionic villus sampling (CVS), 11–12 Chromosomal rearrangement, 22–24 Chronic obstructive pulmonary disease (COPD), 40 Cilia, 33 Cochlea, 38 Codons, 27 COL6A1 gene, 30 Combined test, 10 Conductive hearing loss, 5, 37 Congenital defects of gastrointestinal tract, 36 hearing loss, 37 of heart, 2–4, 35–36 Congestive heart failure, 3, 40 Coronary artery disease, 40 Cyanosis, 3 Cytarabine, 40 Delayed language acquisition, 8 Diabetes, 41 Diploid, 18 Diuretics, 40 Dosage sensitivity, 28 Down syndrome causes of, 17–20 chromosomal rearrangement, 22–24 extra genes, 26–31 mosaic Down syndrome, 24–26 trisomy 21, 20–22 in characteristic physical features, 1–2 cognitive effects of, 9–10 congenital heart defects from, 2–4 contributing factors for, 31–33 delayed development, 7–8 diagnosis of, 10–14

70 INDEX

Down syndrome (continued) education for children with, 41–42 experimental drugs for, 45–47 gene therapy for, 50–51 health complications of, 14–16 other congenital conditions result from, 4–7 preimplantation genetic diagnosis of, 49–50 stem cell therapy for, 47–49 therapies for, 42–43 treatment congenital defects, 35–38 health complications, 38–41 Down Syndrome Education International, 42 Down Syndrome International, 42 DSCAM gene, 29–30 Ductus arteriosus, 4 Duodenal atresia, 7, 36 DYRK1A gene, 29 Echocardiogram, 35 Edwards syndrome, 21–22 Electrocardiogram, 35 ELND005. See Scyllo-inositol Embryonic stem (ES) cells, 47 Epicanthal folds, 1 Epigenetics, 46 Epilepsy, 15–16 Esophageal atresia, 7, 36 ETS2 gene, 30–31 Euploidy, 20 Eustachian tube, 6 Exons, 26 Familial Down syndrome, 23 FLJ33360 gene, 33 Fluorescence in situ hybridization (FISH), 22 Folic acid, 38 Folliculitis, 15, 39 FZD6 gene, 33 Gametes, 18 Gastroesophageal reflux disorder (GERD), 7, 38 Genes, 11 modifiers, 32

therapy, 50–51 Genetic code, 27 Genetic recombination, 18 Genome-wide association study (GWAS), 32 Genomes, 18 Genotypes, 17 Glaucoma, 5, 37 Glue ear, 5–6, 37 Haemophilus influenzae, 14, 39 Haploid, 18 HDAC inhibitors, 47 Hearing aids, 37–38 Hearing loss. See specific hearing losses Heterozygous genotype, 17 Hib vaccine, 39 Hippocampus, 46 Hirschsprung disease, 6, 36 Histone, 46 Histone deacetylase (HDAC), 47 Homozygous dominant alleles, 17 Homozygous recessive genotype, 17 Human genome, 26 Hydroxyurea, 39 Hypertension, 40 Hypothyroidism, 7, 8, 38 Hypotonia, 6 Ibuprofen, 39 Imperforate anus, 7, 36 In vitro fertilization (IVF), 49 Individualized education program (IEP), 42 Individuals with Disabilities Education Act (IDEA), 41–42 Induced pluripotent stem cells (iPS), 48–49 Intellectual capacity, 9 Intellectual disability, 9 Intelligence quotient (IQ), 9 Introns, 26 Isochromosome, 23 ITSN1 gene, 30 Karyotyping, 12, 24–25 Klinefelter syndrome, 21

INDEX 71

Language acquisition, 43 delayed, 8 Lazy eye. See Amblyopia Leukapheresis, 39 Leukemia, 15 Levothyroxine, 38 Ligamentous laxity, 6 Liver disease, 40 Maternal blood screening, 11 Meiosis, 18, 19 Meiotic nondisjunction I, 20 Meiotic nondisjunction II, 20 Mesoderm, 2 Messenger RNA (mRNA), 27 Mitosis, 20 Mitotic nondisjunction, 25 Monogenic, 31 Monosomy, 21 Mosaic Down syndrome, 12, 13, 24–26 Mosaicism, 21 Mutations, 20 National Down Syndrome Society, 10, 42 Neuroblastoma, 15 Neurons, 25 Nonalcoholic fatty liver disease (NAFLD), 40–41 Nonreciprocal translocation, 23 NPHP4 gene, 33 Nuchal fold, 11 Obesity, 16, 40 Obstructive sleep apnea, 15, 40 Occupational therapy, 43 Otitis media, 6, 37, 39 Pantoprazole, 38 Patau syndrome, 21 Patent ductus arteriosus (PDA), 4, 36 Penicillium, 18 Phenotypes, 17 Phlebotomy, 39 Physical therapy, 42 Pluripotent, 47 Pneumococcal vaccine, 39

Pneumonia, 14, 39 Polycythemia, 15, 39 Postlingual hearing loss, 6 Preimplantation genetic diagnosis (PGD), 49–50 Prelingual hearing loss, 6 Prenatal diagnostic testing, 10 Prenatal screening, 10–11 Primary germ layers, 2 Pulmonary artery, 3 Pulmonary hypertension, 3 Pulmonary vascular disease, 3 Quad screen blood test, 10–11 Recessive allele, 17 Reciprocal translocation, 22–23 Refractive errors, 5 Regenerative medicine, 47 Reproductive system, 8 Ring chromosome, 23 RNA splicing, 27 Robertsonian translocation, 23 RSV vaccine, 39 Scabies, 15 Scyllo-inositol, 46 Seizures. See Epilepsy Sensorineural hearing loss, 5, 37 Septa, 2 Short-term memory, 8 SIM2 gene, 29 Single nucleotide polymorphisms, 32 Sinusitis, 14, 39 Sleep apnea, 15, 40 Somatic cell nuclear transfer (SCNT), 48 Somatic cells, 25 Sonic hedgehog agonist 1.1 (SAG 1.1), 46 Speech therapy, 43 Stem cells, 26 therapy, 47–49 Streptococcus pneumoniae, 14, 39 Tetrad, 31 Tetralogy of Fallot (TOF), 4, 36 Thrombocytopenia, 15, 39

72 INDEX

TKNEO gene, 51 Tonsillitis, 14, 39 Totipotent, 47 Tracheoesophageal fistula, 7, 36 Transcription factor, 27, 30 Transient myeloproliferative disorder (TMD), 15, 39–40 Translation, 27 Translocation Down syndrome, 12, 13, 23–24 Triple X syndrome, 21 Trisomy 21, 12, 13, 20–22 Trophectoderm biopsy, 49 Tumor angiogenesis, 30 Tumor suppressor, 30–31 Turner syndrome, 21

United States Education for All Handicapped Children Act of 1975, 41 Urinary tract infections, 39 Veins, 3 Ventricles, 3 Ventricular septal defect (VSD), 3, 36 Viral pathogen respiratory syncytial virus (RSV), 14, 39 Vitamin D, 38 XIST gene, 51 ZSCAN4 gene, 51

OTHER TITLES IN OUR HUMAN DISEASES AND CONDITIONS COLLECTION A. Malcolm Campbell, Editor • • • • • • • •

Hereditary Blindness and Deafness: The Race for Sight and Sound by Todd T. Eckdahl Genetic Diseases or Conditions: Cystic Fibrosis, The Salty Kiss by Todd T. Eckdahl Gradual Loss of Mental Capacity from Alzheimer’s by Mary E. Miller Hemophilia: The Royal Disease by Todd T. Eckdahl Sickle Cell Disease: The Evil Spirit of Misshapen Hemoglobin by Todd T. Eckdahl Auto-Immunity Attacks the Body by Mary E. Miller Huntington’s Disease: The Singer Must Dance by Todd T. Eckahl Nerve Disease ALS and Gradual Loss of Muscle Function: Amytrophic Lateral Sclerosis by Mary E. Miller • Infectious Human Diseases by Mary E. Miller • Breast Cancer: Medical Treatment, Side Effects, and Complementary Therapies by K.V. Ramani, Hemalatha Ramani, B.S. Ajaikumar, and Riri G. Trivedi • Acquired Immunodeficiency Syndrome (AIDS) Caused by HIV by Mary E. Miller Momentum Press offers over 30 collections including Aerospace, Biomedical, Civil, Environmental, Nanomaterials, Geotechnical, and many others. We are a leading book publisher in the field of engineering, mathematics, health, and applied sciences.

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Down Syndrome One Smart Cookie

ECKDAHL

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Todd T. Eckdahl

HUMAN DISEASES AND CONDITIONS COLLECTION A. Malcolm Campbell, Collection Editor

This book presents Down syndrome, which is the most common

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chromosomal disorder in humans, occurring at a rate of about 1 in

THE CONTENT

be diagnosed prenatally or at birth, and the cause of Down syn-

• Nutrition and Dietetics Practice • Psychology • Health, Wellness, and Exercise Science • Health Education

drome as extra copies of the approximately 250 genes on chromo-

THE TERMS

Dr. Todd T. Eckdahl earned a BS in chemistry from the University of

700 births. It describes the characteristic physical features caused by Down syndrome and the myriad of symptoms and health complications it brings, including heart defects, congenital vision and hearing loss, abnormalities of the musculoskeletal system, digestive problems, epilepsy, leukemia, an increased risk of infectious disease, dementia, and intellectual disability.

Down Syndrome

Readers will learn about methods by which Down syndrome can

syndrome, and approaches to the education of children with it. Future prospects for the diagnosis and treatment of Down syndrome are presented, including experimental drugs, stem cell therapies, a process by which embryos produced in a clinical laboratory can be screened for Down syndrome before being used to establish a pregnancy, and several Down syndrome gene therapy strategies.

Minnesota, Duluth, and a PhD in molecular genetics from Purdue

DOWN SYNDROME

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some 21. The book describes treatments and therapies for Down

One Smart Cookie

University. He is a professor of biology at Missouri Western State University, where he teaches genetics and conducts research in collaboration with undergraduate students that is supported by the National Science Foundation. Dr. Eckdahl has published over 40  articles in professional journals that contribute to molecular genetics and synthetic biology research and to undergraduate science education. He is a member of the Missouri Academy of Science, the Genome Consortium for Active Teaching, and the Genomics Education Partnership. Dr. Eckdahl has been recog-

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nized for his teaching and research with the Missouri Governor’s Award for Excellence in Teaching, the Missouri Western Board of Governors Distinguished Professor Award, the James V. Mehl Outstanding Faculty Scholarship Award, the Missouri Western Alumni Association Distinguished Faculty Award, and the Jesse Lee Meyers Excellence in Teaching Award.

Todd T. Eckdahl