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Muscular Dystrophy

Muscular Dystrophy

I’m Grateful I’ve Proved Them Wrong

Todd T. Eckdahl

Muscular Dystrophy I’m Grateful I’ve Proved Them Wrong Todd T. Eckdahl

Muscular Dystrophy: I’m Grateful I’ve Proved Them Wrong 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

ISBN-13: 978-1-94474-967-5 (paperback) ISBN-13: 978-1-94474-968-2 (e-book)

Momentum Press Human Diseases and Conditions Collection

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.


This book presents muscular dystrophy (MD) as a group of genetic diseases with a worldwide occurrence of about 1 in 3,500 births that causes muscle wasting and weakening. It describes Duchenne MD as the most common type of MD, almost exclusively affecting males at a rate of about 1 in 5,000 boys, and eight rarer types of MD that are categorized by age of onset, muscles affected, disease progression, severity of symptoms, and health complications. The book describes how MD is diagnosed by physical examination, muscle biopsy, medical imaging, and genetic testing. It explains the underlying causes of the various types of MD as mutations in genes that encode proteins needed for the development, function, maintenance, and replacement of muscle cells and illustrates patterns by which they are inherited. There is no treatment that can reverse the progressive deterioration of muscles caused by MD, but the book describes drug treatments and physical therapies that help maintain muscle strength and reduce health complications. The book concludes with explanations of promising new ways to treat or perhaps cure MD, including experimental drugs, stem cell therapy, and gene therapy.


autosomal dominant, autosomal recessive, Becker muscular dystrophy, congenital muscular dystrophy, distal myopathy, Duchenne muscular dystrophy, Emery–Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, muscular dystrophy, myopathy, myotonic dystrophy, oculopharyngeal muscular dystrophy, spinal muscular atrophy, X-linked recessive






Chapter 1

Symptoms and Diagnosis


Chapter 2

Causes and Contributing Factors


Chapter 3

Treatment and Therapy


Chapter 4

Future Prospects








About the Author





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 science 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 for genetics in graduate school. Thanks to

John Anderson at Purdue University, who taught me to conduct molecu- lar genetics research and to value undergraduate education. I appreciate the supportive environment that Missouri Western State University has provided me, and 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 appreciate the many students whom

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.

I would also like to thank Joe Akmakjian for permitting the use of his

quote, “I’m grateful I’ve proved them wrong,” on the cover of this book and allowing me to tell his life story in it. The strength that Joe and his family have shown in the face of the many challenges presented by his neuromuscu- lar disease is remarkable. I hope that readers will be as inspired by Joe as I am.


Joe Akmakjian was born in 1991 in Denver, Colorado. Joe developed emo- tionally and intellectually like most children as he learned to babble, react to the sound of his name, respond to touch, recognize faces, and return af- fection. However, Joe did not achieve physical developmental milestones such as crawling, standing, and walking on a typical timeline. When Joe was 15 months old, doctors concluded that many of his muscles were rap- idly weakening and wasting away and that he had a neuromuscular dis- ease called spinal muscular atrophy type 2 (SMA 2). SMA 2 is a genetic disease that causes progressive deterioration of muscles close to the center of the body. Children with SMA 2 cannot stand upright or walk and are confined to wheelchairs for the rest of their lives. They are at risk for serious health complications such as respiratory failure, respiratory infec- tions, heart problems, abnormal curvature of the spine, and eating prob- lems. Although his doctors told his parents that he would not live past the age of 12 and would not go to high school or college, Joe benefitted from important advances in the treatment of SMA 2 during his lifetime and was able to say, “I’m grateful I’ve proved them wrong,” after he graduated from high school and earned a bachelor’s degree in journalism and public relations from Colorado State University. The inspirational story of Joe Akmakjian caught the attention of the Muscular Dystrophy Association (MDA), which named him the 2007–2008 MDA State Ambassador for Colorado and the 2016–2017 MDA National Ambassador. Joe contin- ued the tradition established over 60 years earlier of ambassadors who gained widespread support from sponsors and the general public for the mission of MDA to provide care and support for people with muscular dystrophy (MD). The MDA supports MD patients and their families, as well as people with related neuromuscular diseases, and funds drug research and clinical trials for new treatments and cures. After 40 children ambassadors, Joe was the first adult National Ambassador for MDA, and he served as an effective champion for improved services that help children and teens with MD and other neuromuscular diseases transition



to adulthood, gain more independence, and fulfill their personal and pro- fessional aspirations. At the age of 24, when he had lived twice as long as expected, Joe celebrated by going skydiving, proclaiming “YOLO!” as he emerged from the airplane. The various types of MD fall into nine categories that are based on the age of onset, the muscles affected, symptom severities, and health complications. MD types are also distinguished by their underlying genetic causes, which determine the patterns by which they are inherited. All forms of MD have genetic causes and are characterized by a gradual loss of muscle strength and flexibility that occurs because of the absence or failure of physiological systems by which the body maintains and nourishes muscles. Failure to support muscles is captured by the term dystrophy, which means “bad feeding.” Dystrophy was originally used to describe conditions caused by malnutrition but has been general- ized to include any disorder in which an organ or tissue wastes away, including MD. The chapters that follow present MD as a group of genetic diseases with a worldwide occurrence of about 1 in 3,500 births that cause muscle wasting and weakening. Chapter 1 describes the nine types of MD that produce progressive deterioration of muscles and lead to a progression of symptoms, including loss of independent mobility and the ability to swallow, and health complications such as severe muscle spasms, heart problems, and respiratory disease. The chapter explains how a diagnosis of MD is made based on the age of onset combined with clinical tests. Chapter 2 describes the underlying genetic and cellular causes of the major types of MD and explains the patterns by which they are inherited. Chapter 3 presents available treatments for children and adults with MD, including hormone treatments for muscle strength, heart medications, braces and mobility aids, and breathing assistance. It presents MD physical therapy standards of care that can improve joint flexibility, range of motion, and muscle strength. Chapter 4 describes experimental drug research that might lead to better treatment of MD and evaluates prospects for curing MD by the correction of genetic defects or the delivery of therapeutic genes to patients.


Symptoms and Diagnosis

MD is a group of diseases characterized by progressive weakening and

wasting of muscles. Nine types of MD are commonly recognized that vary

in the age of onset, muscles affected, progression of myopathy, severities of symptoms, and health complications (Table 1.1). The age of onset of

MD types ranges widely. Some types of MD cause symptoms at birth,

whereas others cause symptoms in infancy, early childhood, adolescence, or adulthood. Some types affect muscles lying near the center of the body, whereas others affect muscles in the extremities. A subset of MD diseases causes deterioration of the larger muscles of the trunk and legs, but others

affect the smaller muscles of the face or throat. Life-threatening effects on

heart muscle are associated with some types of MD, but not others. The

symptoms and health complications caused by most types of MD lower life expectancy, but a few types do not.

Symptoms of Muscular Dystrophies

Duchenne muscular dystrophy (DMD) is the most common type of MD, and it affects males almost exclusively, at a rate of about 1 in

5,000 boys. The rate is expressed in Table 1.1 as 20 in 100,000 for easy comparison to other types of MD. The symptoms of DMD appear at the age of 2 to 5 years and result from effects on muscles in the hips, thighs, and calves. An early sign of DMD is pseudohypertrophy of the leg muscles, especially those in the calves, which means that they ap-

pear to have been enlarged by becoming stronger but are actually en-

larged by the abnormal accumulation of scar tissue within the muscles. Compared to typically developing children, toddlers with DMD have

more trouble getting up from the floor, and often grasp their legs to push



Table 1.1 The nine most common types of MD



Age of onset

Muscles affected

Duchenne MD



in 100,000

2–5 years

Hips, thighs, shoulders, calves, heart



Myotonic dystrophy



in 100,000

Infancy to

Face, neck, arms, hands, hips, calves, heart




Becker MD (BMD)


in 100,000

5–15 years

Hips, thighs, shoulders, calves, heart




in 100,000

Adolescence to

Face, shoulders, upper arms, hips, calves

al MD (FSHD)



Congenital MD


in 100,000

Birth or infancy

Neck, arms, trunk, legs



Limb-girdle MD


in 100,000

Childhood to

Shoulders, hips, heart




Emery–Dreifuss MD


in 100,000

5–15 years

Upper arms, calves, heart



Distal myopathy


in 100,000

Childhood to

Lower arms, hands, calves, feet





in 100,000

40 years or later

Eyelids, throat



themselves to an upright position, which is known as Gower’s sign. They also have difficultly learning to walk, and when they do, they develop an unusual gait, swaying from side to side, planting their feet unevenly, and keeping their balance by sticking their bellies out while pulling back their shoulders. Although they learn to use their legs to jump, climb stairs, and run, they display a lack of coordination when doing so. The progres- sive deterioration of leg muscles causes children with DMD to fall with increasing frequency and gradually eliminates their ability to walk, which is called ambulation. Most of these boys require the use of a wheelchair by the age of 7 to 12 years. As the effect of their disease spreads to shoulder muscles, children with DMD at first have trouble raising their arms above their heads, and in their teenage years, gradually lose arm strength and coordination. Children with DMD also develop muscle contractures, which are permanent shortenings of muscles that prevent their limbs from functioning. The life expectancy of people with DMD is reduced by health complications associated with the deterioration of heart muscle and muscles used for breathing. The average life expectancy of DMD



patients is currently 27 years, but good health care enables some to sur- vive 40 years or more. Other common health complications of DMD include intellectual disability, scoliosis, and eating problems. Becker muscular dystrophy (BMD) is closely related to DMD because it results in similar symptoms and has a similar underlying genetic cause. The distinction between the two diseases is in their severity, age of onset, and rate of progression of symptoms and health complica- tions. BMD is less common than DMD, with a rate of occurrence of about 1 in 25,000 boys. The first signs of BMD appear in late childhood or adolescence as weakness of muscles in the hips and thighs. As muscle weakness progresses and spreads to the calves, pseudohypertrophy often follows. The extent to which these children can run, climb stairs, walk, and stand upright varies widely. Some maintain most or all of their abil- ity to walk, whereas others require assistive devices, such as a wheelchair. Upper-body muscles are not as severely affected, but effects on shoulder muscles can limit arm strength and range of motion. The degree to which BMD leads to heart disease varies, and there is a positive correlation between early onset and the development of heart problems. Respiratory problems such as restricted breathing and recurrent lung infections some- times occur for patients with BMD due to weakening of muscles needed for breathing and coughing. Although the life expectancy for people with BMD correlates with their access to good health care, most survive to the age of 40 or 50 years. The second most common type of MD, occurring in about 1 in 9,000 people, is myotonic dystrophy (DM). The name of the disease comes from myotonia, which is the inability to relax voluntary muscles after they have been contracted. Myotonic dystrophy is often abbreviated as DM, for its Greek name, dystrophia myotonica. DM occurs as two types, referred to as DM1 and DM2, both characterized by progressive weak- ening and wasting of muscles in the hands, face, neck, arms, hips, and calves, and eventually of muscles needed for the function of the heart, lungs, and other organs. The symptoms of DM2 are not as severe as those of DM1, and DM2 is less common than DM1. The onset of symptoms for DM2 is always in adulthood, whereas DM1 symptoms can appear at any age from infancy to adulthood. The first muscles to be affected by DM2 are hip muscles, and progressive weakening of them can cause



ambulation problems. Later, weakness spreads to the muscles of the face and the extremities. For DM1, there is a positive correlation between the age of onset and the severity of symptoms. The earlier the onset, the more severe the symptoms become. Congenital DM1 (symptoms appearing at birth) is the most severe form and is associated with life-threatening symp- toms caused by heart and respiratory problems. Infants with DM1 usually have physical and cognitive developmental delays. When DM1 appears in a child or an adolescent, cognitive and behavioral effects are more preva- lent than physical ones. Muscles of the hand are most often affected in adult-onset DM1. A person with DM1 might find it difficult to ungrasp a pencil, loosen their grip on a baseball, or let go of a steering wheel. Health complications of adult-onset DM1 include cataracts, speech impairment, eating problems, recurrent respiratory infections, gastrointestinal prob- lems, intellectual disability, daytime sleepiness, and diabetic symptoms. Males with DM1 usually have more severe symptoms than females with the same disease. The life expectancy for people with DM varies consider- ably. Many people with DM have a normal life expectancy, but congenital forms of DM can cause death in infancy or childhood. Facioscapulohumeral muscular dystrophy (FSHD) is named for its effects on the muscles of the face (facio-), the shoulder blades (scapulo-), and the upper arms (humeral). FSHD occurs in about 1 in 25,000 people, and although its onset is usually in adolescence or adulthood, a rare form also occurs with onset in infancy. The two types of this disease, FSHD1 and FSHD2, have different genetic causes. The first muscles to be affected by both types are those of the face, shoulders, and arms, but muscle weakness will spread to the lower legs and the hips. The effects of FSHD are often unequal on one side of the body compared to the other. The severity of symptoms ranges widely, and they appear gradually over years. Some people develop leg muscle weakness that takes away their independent ambulation and requires them to use a wheelchair, but others only experience effects in their arms. Progressive weakening of shoulder muscles often leads to scapular winging, which means that the shoulder blades stick out from the back. Some people with FSHD only have weakness of the muscles surrounding their eyes or their mouths, and others have such mild symptoms that they are unaware of their disease. Health complication of FSHD include scoliosis, minor hearing loss, and vision problems. Most people with FSHD have a normal lifespan.



Congenital muscular dystrophy (CMD) refers to any of more than 30 genetic diseases that cause muscle weakness at birth or in infancy, followed by muscle wasting. CMD is caused by a small number of related molecular and cellular malfunctions. The collective occurrence of CMD has been estimated to be about 1 in 50,000 infants, but this estimate is ex- pected to rise with increased awareness and improved diagnosis, especially genetic diagnosis. CMD causes hypotonia, also known as floppy baby syndrome, which is the occurrence of weak muscles throughout the body. Infants with hypotonia seem “floppy” because of their weak muscles and are often delayed in meeting developmental milestones such as rolling over, sitting up, crawling, and walking. For some infants, hypotonia in the mouth and throat makes it difficult for them to drink breast milk or formula, which leads to poor weight gain. The rate of progression and severity of muscle weakness and wasting varies among CMD types. In many cases, muscle function gradually worsens, but in others it stabilizes and sometimes improves. The most common muscles affected by CMD are those of the neck, arms, trunk, and legs. Common health complica- tions of CMD include heart problems, respiratory disease, scoliosis, and eating problems. The life expectancy of people with CMD varies widely. Some CMD forms cause death in infancy or childhood, whereas others do not alter normal life expectancy. Limb-girdle muscular dystrophy (LGMD) is a group of muscular diseases that have different genetic causes but which share effects on the muscles attached to the bones of the limb girdle, which includes the shoulder girdle and the pelvic girdle. LGMD causes weakening and wasting of the shoulder and hip muscles that are used to move the arms and the legs. These muscles are called proximal muscles because they are close to the midline of the body. Occurring in about 1 in 50,000 people, LGMD first presents itself at various ages from childhood to adulthood, progresses at varying rates, and varies widely in symptom severity. The early signs of hip muscle weakness caused by LGMD include swaying from side to side while walking, walking on the balls of the feet, having trouble climbing stairs, and having trouble standing up from a seated position. For some people with LGMD, these symptoms advance to the point where they lose independent ambulation and require a mobility aid, such as a wheelchair. Early signs of shoulder muscle weakness are



difficulty raising the arms above the head, trouble lifting objects with outstretched arms, and problems with tasks that require arm extension, such as eating. Progressive weakening of shoulder muscles often leads to scapular winging. Sometimes LGMD affects other muscles, such as those of the hands, feet, and lower legs. LGMD can cause contractures of the muscles of the joints in the arms and legs, pseudohypertrophy of the calf muscles, and scoliosis. Although the most important health complica- tions of LGMD are heart problem and respiratory problems, people with LGMD usually have a normal life expectancy. Emery–Dreifuss muscular dystrophy (EDMD) occurs in about 1 in 100,000 people. Its onset is most often between childhood and adolescence, when muscles of the shoulders, upper arms, and lower legs begin to weaken. Early signs of the disease include walking on the toes, adopting an abnormal waddling gait, having trouble bending the arms or raising them above the head, and adopting an unusual gait. Joint deformities often develop from contractures, resulting in stiffness and limitations of arm and leg mobility. As EDMD progresses, its effects on leg muscles often worsen to the point where people are no longer able to walk without assistance, and sometimes lose independent ambulation. Weakening of the heart often occurs in adolescence or adulthood, which reduces the life expectancy for people with EDMD to between 40 and 60 years. Other health complications of EDMD include contractures and breathing problems. Distal myopathy, also known as distal muscular dystrophy, is a general name for a group of genetic diseases that are characterized by progressive weakening and wasting of the distal muscles, which include the muscles of the lower arms, hands, calves, and feet. Distal myopathy is rare, occurring in about 1 in 100,000 people. The age of onset for distal myopathy types ranges from childhood to adulthood. Early symp- toms include noticeable weakness of the ankles, which causes an unsteady gait, and weakness of the wrists and fingers, which limits dexterity and affects the ability to grasp objects. The progression of symptoms for dif- ferent forms of distal myopathy varies, but most of them limit the range of motion of the arms and affect the ability to walk without assistance. Some forms of distal myopathy cause weakness of the vocal cords, caus- ing the voice to be weak and breathy at first, and later to be hoarse and



nasal. Some distal myopathy patients experience weakness in muscles of the throat, which results in eating problems. The most important health complications of distal myopathy are heart disease and respiratory prob- lems. Other health complications might include speech problems, eating problems, and recurrent respiratory infections. People with distal myopa- thy usually have a normal life expectancy. Oculopharyngeal muscular dystrophy (OPMD) occurs in about 1 in 100,000 people, and symptoms first appear in adulthood, typically at the age of 40 years or later. OPMD is named for its effects on the muscles that control the eyelids (oculo-), and the muscles of the throat (pharyngeal). The earliest sign of the disease is droopy eyelids. As the disease progresses, it affects muscles in the throat, which causes people to have trouble swallowing food at first, and trouble drinking liquids later. Weakening of the tongue frequently occurs, which adds to the eating difficulties and affects speech. In the later stages of OPMD, leg and hip muscles can be affected, requiring the use of a cane or a walker. Health complications of OPMD include weight loss from eating problems, and pneumonia from the pulmonary aspiration of food, liquids, or saliva into the lungs. The life expectancy for people with OPMD is normal. The disease that Joe Akmakjian was born with, SMA type 2, is not considered to be a type of MD, but it is closely related. SMA type 2 is distinct from MD because the underlying cause is not weakening and loss of muscles, but loss of the nerve cells in the spinal cord and brain that control muscles. The name of the disease reflects the loss of nerves in the spine that leads to muscle atrophy. SMA type 2 is a neuromuscular disease that affects proximal muscles, such as those of the shoulders, upper arms, hips, and thighs. There are five types of SMA that can be distinguished by age of onset and severity of symptoms, and the overall occurrence of them is 1 in 10,000 births. The symptoms of SMA type 0 can be noticed in the later stages of pregnancy as an abnormally inactive fetus. Babies born with SMA type 0 cannot breathe or swallow on their own and usually die within 6 months. SMA type 1 is the most common form of SMA and causes muscle weakness, movement deficiencies, and feeding problems in infants. Severe respiratory problems cause most infants with SMA type 1 to die within 1 year. SMA type 1 is the most common genetic cause of infant mortality. SMA type 2 causes breathing problems, respiratory



infections, scoliosis, contractures, and loss of independent ambulation. People with SMA type 2 have an estimated life expectancy of early adult- hood. SMA type 3 and SMA type 4 affect ambulation but are less severe and have little effect on life expectancy.

How Is Muscular Dystrophy Diagnosed?

Diagnosis of MD begins with a physical examination during which a clinician looks for telltale physical symptoms that merit further inves- tigation. A newborn infant is checked for hypotonia, or floppy baby syndrome, which is caused several types of MD. At 9 months, a child is assessed for their ability to roll over, sit up without support, crawl, and grasp objects. At 18 months, children are expected to be able to stand, walk on their own, and manipulate objects with their hands. The absence of any of these motor skills might be explained by MD. A child who shows the characteristic movements of Gower’s sign, walks by swaying from side to side, plants their feet unevenly on either their toes or their heels, or has trouble keeping their balance might have MD, and is recommended for further diagnostic testing. The observation of pseudohypertrophy of mus- cles such as those of the calves can also contribute to a diagnosis of MD in young children. For an older child or an adult, having trouble standing up from a seated position can be part of a MD diagnosis. The standing posture of an older child or adult can also reveal characteristic signs of muscle weakness to a trained observer. Swaying from side to side while walking and walking on the balls of the feet are telltale symptoms of some types of MD. Reports from the patient or their caregivers about difficul- ties in climbing stairs, jumping, or running also contribute to a diagnosis of MD. Sometimes a patient is asked to perform exercises so observations can be made about muscle strength and respiratory function. Difficulties that adolescents or adults have with moving their arms or using their hands with dexterity can lead to the diagnosis of some types of MD, whereas muscle weakness in the face or the throat provides early evidence of other types. Physical examinations can uncover stiffness of joints or joint deformities that have resulted from excessive muscle contractures caused by MD. Observation of droopy eyelids, weakness of other muscles in the face, or difficulties with speaking also can contribute to a diagnosis



of MD. A physical examination for the diagnosis of MD is accompanied by inquiries about the medical and family histories of the patient. For patients who display physical signs of MD, additional tests are performed to confirm or reject the diagnosis of MD. A common test is

a muscle biopsy, which usually involves local anesthesia and the removal

of a small amount of muscle tissue with a needle. Muscle biopsies can be also be performed surgically with general anesthesia. Pathologists perform

microscopic examination of the muscle to distinguish among several causes of muscle dysfunction, including metabolic diseases, parasitic infections, diseases of the blood vessels, neuromuscular diseases, and MD. The choice of tissue taken with a muscle biopsy is sometimes guided by ultrasound imaging, which can reveal muscle atrophy. Another common diagnos- tic tool for MD is an enzyme test. Blood is drawn and sent to a clinical

laboratory to check for an abnormally high level of creatine kinase, which is released when muscle tissue deteriorates, but does not cause health problems on its own. A creatine kinase level 3 times higher than normal

is reason for concern about the presence of MD. Some types of MD pro-

duce creatine kinase levels in the blood that are over 100 times higher than normal. Electromyography (EMG) is also used for the diagnosis of MD. EMG involves insertion of an electrode needle into a muscle to measure changes in electrical activity that occur during rest, slight contraction, forceful contraction, and relaxation. The trace of electrical activity is an electromyogram, and subtle changes in its height and shape can be used to differentiate among a variety of nerve and muscle diseases. Because it can reveal the shape and volume of muscles, magnetic resonance imaging (MRI) is very useful for the diagnosis of MD. The ability of MRI to detect inflammation of muscle tissue before symptoms appear facilitates early

detection of muscle deterioration, and its ability to distinguish muscle tissue from fat or connective tissue that replaces it during muscle wasting makes


useful for following the progression of muscle disease. A diagnosis of MD


often confirmed with genetic testing, which is described in Chapter 2.

Health Complications of Muscular Dystrophies

The primary symptoms for all types of MD come from the progres- sive weakening and atrophy of voluntary muscles, but most MD types,



including DMD, BMD, DM, LGMD, EDMD, FSHD, and CMD, also affect involuntary heart muscle, leading to life-threatening health com- plications. The earliest manifestation of MD-associated heart disease is often cardiomyopathy, which makes it increasingly difficult for the heart to circulate blood throughout the body, and can generate breathing prob- lems, fainting, chest pain, fatigue, swelling of the hands and feet, and a bloated abdomen. The progression of heart disease in MD patients often leads to a conduction disorder. Conduction is the process by which a pair of electrical signals travels down the heart to simultaneously and evenly contract on both sides. A conduction disorder slows down one of these two pathways so that one half of the heart contracts before the other. People with a conduction disorder can be asymptomatic for years, but the condition often worsens progressively to produce chest pain, faintness, palpitations, breathing difficulty, and fatigue. Conduction disorders can also lead to arrhythmia, during which the heart beats too quickly, too slowly, or irregularly. The cause of arrhythmia is failed coordination of muscle contraction in the two upper chambers of the heart, the atria, or its two lower chambers, the ventricles. Arrhythmia can occur subtly without symptoms, or can cause chest pain, dizziness, fainting, sweating, palpitations, and shortness of breath. Extreme arrhythmia can result in sudden cardiac arrest, which is the second leading cause of death for people with MD, after respiratory failure. MD-associated weakening and wasting of the voluntary and invol- untary muscles used for breathing frequently leads to respiratory disease. Respiratory disease is a common health complication associated with most types of MD, including DMD, BMD, DM, LGMD, EDMD, distal my- opathy, and some types of CMD. The cause of MD-associated respiratory disease is progressive weakening of the muscles that enable the exchange of air in the lungs for the support of cellular metabolism throughout the body. Breathing is a delicate balance between the strength of the muscles used for the inhalation and exhalation of air and the elasticity of the muscles of the chest wall. Different types of MD affect these muscles in characteristic ways, which results in a variety of respiratory problems. Among these are restrictive lung disease, during which a patient cannot fully inflate the lungs, hypoventilation, which is breathing at an abnor- mally slow rate, and hypercapnia, which is an elevated level of carbon



dioxide in the blood. MD can also reduce the efficiency of coughing, with the consequence of respiratory infections due to the inability to clear microbes from the lungs. Many MD patients have sleep apnea, which means they repeatedly stop breathing during sleep. Sleep apnea can be fatal. Early symptoms of respiratory disease include headaches, fatigue, chest pain, and sleep problems. The progression of lung disease can lead to respiratory failure, which is the leading cause of death among people with MD. For most types of MD, progressive wasting and weakening of muscles throughout the body spreads to the muscles of the back that position and flex the column of vertebrae surrounding the spinal cord. Disruption of the balance of strength among these muscles alters the normal shape of the spine, which is straight in the left-to-right dimension but has three gradual curves front to back. Scoliosis is an abnormal curvature of the spine from side to side, and it is a common health complication associated with most types of MD. Some people with MD also develop kyphosis, which is excessive outward curvature of the upper spine, or lordosis, which is exaggerated inward curvature of the lower spine. Abnormal curvature of the spine causes symptoms such as back pain, muscle spasms, and back stiffness. As curvature worsens, some MD patients struggle to walk or stand upright, whereas others have difficulty sitting upright without assis- tance. Because abnormal spinal curvature changes the shape of the chest cavity, it also exacerbates MD-associated respiratory disease. Many types of MD cause health complications associated with swallowing. The purpose of swallowing is to cause solids or liquids to enter the digestive system through the esophagus instead of passing into the airways via the trachea, where they can obstruct breathing or cause a lung infection. Swallowing involves using powerful jaw muscles to chew food into a rounded mass, positioning the mass with the tongue and throat muscles to the opening of the esophagus, and pushing the mass to- ward the stomach with peristalsis, a series of involuntary contractions of smooth muscle surrounding the esophagus. The disruption of swallowing is a health complication called dysphagia. One way that MD causes dys- phagia is weakening of the jaw muscles needed for chewing. Dysphagia means children and adults with MD take longer to eat their food, and in extreme cases, they need to eat food that is easier to chew. MD also causes



weakening of the tongue muscles that position a food mass to enter the esophagus, with the result that swallowing becomes difficult and painful. Dysphagia often results in incomplete clearing of a food mass from the throat, and when breathing happens, some of it can be aspirated into the airways. Choking and coughing result as the body attempts to clear the airways. Long-term consequences of dysphagia include loss of appetite, weight loss, and an increased occurrence of respiratory infections. Some types of MD are associated with intellectual disability, which occurs when there are deficits in cognition, the ability to reason, think, and learn, and adaptive behavior, the conceptual, social, and practical adaptive skills needed for a productive and independent life. The most common measure of cognitive ability is the intelligence quotient (IQ), which quantifies the results of standardized tests. The median IQ score

for children or adults of a given age is set at 100, and the range of 85 to 115 includes all IQ scores within one standard deviation of the median. Because the range of 70 to 130 contains all the scores within two standard deviations, 96 percent of all IQ scores fall within this range. About

2 percent of people have an IQ below 70 and are considered to have

intellectual disability if they also have significant deficits in functional skills. The average IQ score among boys with DMD is about 85. Approximately 30 percent of boys with DMD have an IQ below 70 and

3 percent have an IQ less than 50. A similar distribution of IQ scores

has been found among people with myotonic dystrophy. Intellectual disability is also associated with some types of CMD. The occurrence of intellectual disability in children with MD affects their ability to achieve physical, emotional, and cognitive developmental milestones, to gain independence in caring for themselves, to adjust to the social environment of school, and to learn. Behavioral problems often arise from a failure to understand personal relationship and social norms. Adults with MD who also have intellectual disability often have problems with communication, independent living, interpersonal relationships, and employment.


AAV. See Adeno-associated virus Actin, 13 Action potential, 14 Adaptive behavior, 12 Adeno-associated virus (AAV), 47 Air stacking, 40 Alisporovir, 45 Alleles, 26 Allogeneic, 46 Alternative splicing, 17 Ambulation, 2 Amniocentesis, 32 Angiotensin-converting-enzyme (ACE) inhibitors, 38 Antiarrhythmic drugs, 38 Anticoagulants, 38 Antimineralocorticoid diuretics, 38 Antisense oligonucleotide, 43 Arrhythmia, 10 Ataluren, 44 ATP, 13 Atria, 10 Autosomal dominant pattern, 26 Autosomal recessive, 26 Autosomes, 16

Becker muscular dystrophy (BMD), 3 Beta blockers, 38 Blastomere biopsy, 33 BMD. See Becker muscular dystrophy

Calpain, 23 Cardiac arrest, 10 Cardiac muscle, 13 Cardiac pacemaker cells, 14–15 Cardiomyopathy, 10 Carrier, 26 Caveolae, 24 Caveolinopathies, 24 CDC. See Centers for Disease Control and Prevention Cell-free fetal DNA (cffDNA), 32

Centers for Disease Control and Prevention (CDC), 38 Centromere, 16 Cervical collar, 39–40 Chorionic villus sampling (CVS), 32 Chromosomes, 16 CMD. See Congenital muscular dystrophy Codons, 17 Cognition, 12 Collagen alpha-1(VI) chain, 22–23 Conduction disorder, 10 Congenital muscular dystrophy (CMD), 5 Continuous positive airway pressure (CPAP) ventilator, 41 Contractures, 2 Copy number variations (CNVs), 19 Corticosteroids, 37 COX-inhibiting nitric oxide donors, 38 Creatine kinase, 9 CRISPR/Cas, 48 CRISPR/Cpf1, 48 Cryopreservation, 33–34 Cytoskeleton, 24

Deflazacort, 37–38 Deletion, 19 DGC. See Dystrophin–glycoprotein complex Diploid, 16 Distal muscles, 6 Distal muscular dystrophy. See Distal myopathy Distal myopathy, 6 DMD. See Duchenne muscular dystrophy

DNA methylation of CpG islands, 22 microarrays, 30 replication, 18 sequencing, 30



Dominant alleles, 26 Double homeobox protein 4 (DUX4), 22 Duchenne muscular dystrophy (DMD), 1 Dysferlin, 25 Dysphagia, 11–12 Dystroglycan complex, 14 Dystrophia myotonica, 3 Dystrophin, 14

Genetic testing, for MD, 30–32 Genome editing, 48 Genome-editing gene therapy method, 48 Genome-wide association study (GWAS), 34 Genotype, 26 Glossopharyngeal breathing, 40 Golden Retriever muscular dystrophy

Dystrophin–glycoprotein complex (DGC), 14 Dystrophy, xii

EDMD. See Emery–Dreifuss muscular dystrophy Electromyography (EMG), 9 Emery–Dreifuss muscular dystrophy (EDMD), 6 Epigenetic process, 22 Esophagus, 11 Eteplirsen, 43 European Medicines Agency (EMA), 44 Exome sequencing, 31 Exon skipping, 43 Exons, 16 Extracellular matrix, 14

Facioscapulohumeral muscular dystrophy (FSHD), 4 Fibrosis, 45 Floppy baby syndrome. See Hypotonia Fluorescent in situ hybridization (FISH), 31

Gastrostomy, 41

(GRMD), 36 Gower’s sign, 2

Haploid, 16 Heterozygous, 26 Homozygous dominant, 26 Homozygous recessive, 26 Human genome, 16 Hypercapnia, 10–11 Hypotonia, 5 Hypoventilation, 10

In vitro fertilization (IVF), 33 Induced pluripotent stem cells, 46 Insertion, 19 Insufflation–exsufflation ventilator, 40 Intellectual disability, 3 Intelligence quotient (IQ), 12 Intermittent positive pressure ventilator, 41 Intrapulmonary percussive ventilator, 40 Introns, 16 Isoforms, 18

Karyotype, 31

Four-and-a-half LIM domains protein

Kyphosis, 11

1 (FHL1), 24 Frameshift mutation, 19 FSHD. See Facioscapulohumeral muscular dystrophy

Gene expression, 16 Gene modifiers, 34 Gene therapy, for MD, 46–48 Genes, 16 Genetic code, 18

Laminin, 14 Laminopathies, 23 LGMD. See Limb-girdle muscular dystrophy Limb girdle, 5 Limb-girdle muscular dystrophy (LGMD), 5 LMNA genes, 23 Lordosis, 11 LTBP4 gene, 35

Magnetic resonance imaging (MRI), 9 Maternal blood screening, 32 MD. See Muscular dystrophy mdx mouse, 35 Mendel, Gregor, 26 Messenger RNA (mRNA), 17 Microdystrophin genes, 47 Missense mutations, 18 Mitochondria, 45 Monogenic disorders, 34 Muscular dystrophy (MD) contributing factors, 34–36 diagnosis of, 8–9 drug treatment for, 37–39 experimental drugs for, 43–45 gene mutations, 16–25 gene therapy for, 46–48 genetic testing, 30–32 health complications of, 9–12 hereditary information, 26–30 muscles function, 13–15 nine most common types of, 2 physical therapy, 39–41 preimplantation genetic diagnosis of, 33–34 stem cell therapy for, 45–46 symptoms of, 1–8 Mutagens, 18 Mutations, 18 Myoblasts, 46 Myofibrils, 13 Myopathy, 1 Myosatellite cells, 46 Myosin, 13 Myotonia, 3 Myotonic dystrophy (DM), 3 Myotonin–protein kinase (MT-PK), 21

Nasal intermittent positive pressure ventilation (NIPPV), 41 Neurons, 19 NIPPV. See Nasal intermittent positive pressure ventilation Noncoding RNA molecules, 22 Noninvasive prenatal diagnosis (NIPD), 32 Nonsense mutation, 18–19



Nonsense readthrough, 44 Nuclear lamina, 23 Nusinersen, 44

Oculopharyngeal muscular dystrophy (OPMD), 7 OPMD. See Oculopharyngeal muscular dystrophy Orthoses, 39 Oxidative stress, 45

PABPN1. See Polyadenylate-binding protein 1 PCR. See Polymerase chain reaction Pedigree analysis, 31 Pelvic girdle, 5 Peristalsis, 11 PGD. See Preimplantation genetic diagnosis Phenotype, 26 Pluripotent, 45 Point mutation, 18 Poly(A) tail, 17 Polyadenylate-binding protein 1 (PABPN1), 25 Polymerase chain reaction (PCR), 30 Prednisone, 37 Preimplantation genetic diagnosis (PGD), 33 Prenatal diagnostic testing, 32 Prodrug, 38 Promoter, 16 Proximal muscles, 5 Pseudohypertrophy, 1 Pulmonary aspiration, 7 Punnett square, 26

Recessive alleles, 26 Regenerative medicine, 45 Restrictive lung disease, 10 RNA polymerase, 16 RNA splicing, 17

Sarcoglycan complex, 14 Sarcolemma, 14 Sarcomeres, 13 Scapular winging, 4 Scoliosis, 3



Sex chromosomes, 16 Sex-linked MD, 28 Shoulder girdle, 5 Simvastatin, 45 Single nucleotide polymorphisms, 34 Skeletal muscle, 13 Sleep apnea, 11 SMA. See Spinal muscular atrophy Smooth muscle, 11 Spinal muscular atrophy (SMA), xi, 7 Spliceopathy, 21 Spontaneous mutations, 18 Stem cells, 45 therapy, for MD, 45–46 Synapses, 19 Syntrophin complex, 14

Tamoxifen, 45 Tendons, 14 Tetranucleotide repeats, 22 Thick filaments, 13 Thin filaments, 13

Totipotent, 33 Trachea, 11 Tracheostomy, 41 Transcription, 16 factor, 21 Translation, 17 Trans-splicing, 47 TREAT-NMD DMD Global Database, 20 Trinucleotide repeats, 21 Trophectoderm biopsy, 33

U7 snRNA, 47–48 Ultrasound imaging, 9 Utrophin, 35

Ventricles, 10

Whole-genome sequencing, 31

X inactivation, 22 X-linked recessive, 29


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

Down Syndrome: One Smart Cookie by Todd T. Eckahl

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