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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
Copyright © Momentum Press®, LLC, 2018.

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First published in 2018 by


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Abstract
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 c­ ategorized 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 d ­ evelopment,
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.

Keywords
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
Contents
Acknowledgments....................................................................................ix
Introduction...........................................................................................xi
Chapter 1 Symptoms and Diagnosis...................................................1
Chapter 2 Causes and Contributing Factors.....................................13
Chapter 3 Treatment and Therapy....................................................37
Chapter 4 Future Prospects...............................................................43
Conclusion............................................................................................49
Glossary................................................................................................51
Bibliography..........................................................................................61
About the Author...................................................................................65
Index....................................................................................................67
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 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.
Introduction
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 d ­ evelopmental milestones
such as crawling, standing, and walking on a typical t­ imeline. 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 m ­ uscles 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, r­ espiratory 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 U ­ niversity. The ­inspirational story of Joe
Akmakjian caught the attention of the M ­ uscular Dystrophy A ­ ssociation
(MDA), which named him the 2007–2008 MDA State A ­ mbassador 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
xii INTRODUCTION

to adulthood, gain more i­ ndependence, and ­fulfill their p ­ ersonal 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 i­ nherited.
Chapter 3 presents available treatments for children and adults with MD,
including hormone treatments for muscle strength, heart m ­ edications,
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 e­ valuates
­prospects for curing MD by the correction of genetic defects or the
­delivery of therapeutic genes to patients.
CHAPTER 1

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 m­ uscles 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
2 MUSCULAR DYSTROPHY

Table 1.1  The nine most common types of MD


Type Occurrence Age of onset Muscles affected
Duchenne MD 20 in 100,000 2–5 years Hips, thighs, shoulders,
(DMD) males calves, heart
Myotonic dystrophy 11 in 100,000 Infancy to Face, neck, arms, hands,
(DM) adulthood hips, calves, heart
Becker MD (BMD) 4 in 100,000 5–15 years Hips, thighs, shoulders,
males calves, heart
Facioscapulohumer- 4 in 100,000 Adolescence to Face, shoulders, upper
al MD (FSHD) adulthood arms, hips, calves
Congenital MD 2 in 100,000 Birth or infancy Neck, arms, trunk, legs
(CMD)
Limb-girdle MD 2 in 100,000 Childhood to Shoulders, hips, heart
(LGMD) adulthood
Emery–Dreifuss MD 1 in 100,000 5–15 years Upper arms, calves, heart
(EDMD)
Distal myopathy 1 in 100,000 Childhood to Lower arms, hands, calves,
adulthood feet
Oculopharyngeal 1 in 100,000 40 years or later Eyelids, throat
MD (OPMD)

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 a­ mbulation. 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 p ­ ermanent 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
Symptoms and Diagnosis 3

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 i­ ntellectual 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
4 MUSCULAR DYSTROPHY

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 p ­ eople,
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.
Symptoms and Diagnosis 5

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 m ­ obility
aid, such as a wheelchair. Early signs of shoulder muscle weakness are
6 MUSCULAR DYSTROPHY

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
Symptoms and Diagnosis 7

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 n­ euromuscular 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
8 MUSCULAR DYSTROPHY

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 o­ bservations
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
Symptoms and Diagnosis 9

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 p ­ erform
­microscopic examination of the muscle to distinguish among several causes
of muscle dysfunction, including metabolic diseases, p ­ arasitic ­infections,
diseases of the blood vessels, neuromuscular diseases, and MD. The choice
of tissue taken with a muscle biopsy is sometimes guided by u ­ ltrasound
­imaging, which can reveal muscle atrophy. A ­ nother 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 c­ reatine 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 c­ reatine kinase levels in the blood that are over 100 times higher than
normal. E ­ lectromyography (EMG) is also used for the diagnosis of MD.
EMG involves insertion of an electrode needle into a m ­ uscle 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
it useful for following the progression of muscle disease. A diagnosis of MD
is 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,
10 MUSCULAR DYSTROPHY

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 m ­ uscles
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 b­ reathing at an abnor-
mally slow rate, and hypercapnia, which is an elevated level of carbon
Symptoms and Diagnosis 11

dioxide in the blood. MD can also reduce the efficiency of coughing,


with the consequence of respiratory infections due to the i­ nability 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. D ­ isruption 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 a­ ssociated 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
12 MUSCULAR DYSTROPHY

weakening of the tongue muscles that ­position a food mass to enter the
esophagus, with the result that s­ wallowing ­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 a­ ppetite,
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 p ­ ractical
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 m ­ edian 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 s­ tandard
­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 d ­ isability 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 a­ ssociated 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 e­ nvironment
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.
Index
AAV. See Adeno-associated virus Centers for Disease Control and
Actin, 13 Prevention (CDC), 38
Action potential, 14 Centromere, 16
Adaptive behavior, 12 Cervical collar, 39–40
Adeno-associated virus (AAV), 47 Chorionic villus sampling (CVS), 32
Air stacking, 40 Chromosomes, 16
Alisporovir, 45 CMD. See Congenital muscular
Alleles, 26 dystrophy
Allogeneic, 46 Codons, 17
Alternative splicing, 17 Cognition, 12
Ambulation, 2 Collagen alpha-1(VI) chain, 22–23
Amniocentesis, 32 Conduction disorder, 10
Angiotensin-converting-enzyme Congenital muscular dystrophy
(ACE) inhibitors, 38 (CMD), 5
Antiarrhythmic drugs, 38 Continuous positive airway pressure
Anticoagulants, 38 (CPAP) ventilator, 41
Antimineralocorticoid diuretics, 38 Contractures, 2
Antisense oligonucleotide, 43 Copy number variations (CNVs), 19
Arrhythmia, 10 Corticosteroids, 37
Ataluren, 44 COX-inhibiting nitric oxide donors, 38
ATP, 13 Creatine kinase, 9
Atria, 10 CRISPR/Cas, 48
Autosomal dominant pattern, 26 CRISPR/Cpf1, 48
Autosomal recessive, 26 Cryopreservation, 33–34
Autosomes, 16 Cytoskeleton, 24

Becker muscular dystrophy (BMD), 3 Deflazacort, 37–38


Beta blockers, 38 Deletion, 19
Blastomere biopsy, 33 DGC. See Dystrophin–glycoprotein
BMD. See Becker muscular dystrophy complex
Diploid, 16
Calpain, 23 Distal muscles, 6
Cardiac arrest, 10 Distal muscular dystrophy. See Distal
Cardiac muscle, 13 myopathy
Cardiac pacemaker cells, 14–15 Distal myopathy, 6
Cardiomyopathy, 10 DMD. See Duchenne muscular
Carrier, 26 dystrophy
Caveolae, 24 DNA
Caveolinopathies, 24 methylation of CpG islands, 22
CDC. See Centers for Disease Control microarrays, 30
and Prevention replication, 18
Cell-free fetal DNA (cffDNA), 32 sequencing, 30
68 INDEX

Dominant alleles, 26 Genetic testing, for MD, 30–32


Double homeobox protein 4 Genome editing, 48
(DUX4), 22 Genome-editing gene therapy
Duchenne muscular dystrophy method, 48
(DMD), 1 Genome-wide association study
Dysferlin, 25 (GWAS), 34
Dysphagia, 11–12 Genotype, 26
Dystroglycan complex, 14 Glossopharyngeal breathing, 40
Dystrophia myotonica, 3 Golden Retriever muscular dystrophy
Dystrophin, 14 (GRMD), 36
Dystrophin–glycoprotein complex Gower’s sign, 2
(DGC), 14
Dystrophy, xii Haploid, 16
Heterozygous, 26
EDMD. See Emery–Dreifuss Homozygous dominant, 26
muscular dystrophy Homozygous recessive, 26
Electromyography (EMG), 9 Human genome, 16
Emery–Dreifuss muscular dystrophy Hypercapnia, 10–11
(EDMD), 6 Hypotonia, 5
Epigenetic process, 22 Hypoventilation, 10
Esophagus, 11
Eteplirsen, 43 In vitro fertilization (IVF), 33
European Medicines Agency Induced pluripotent stem cells, 46
(EMA), 44 Insertion, 19
Exome sequencing, 31 Insufflation–exsufflation
Exon skipping, 43 ventilator, 40
Exons, 16 Intellectual disability, 3
Extracellular matrix, 14 Intelligence quotient (IQ), 12
Intermittent positive pressure
Facioscapulohumeral muscular ventilator, 41
dystrophy (FSHD), 4 Intrapulmonary percussive
Fibrosis, 45 ventilator, 40
Floppy baby syndrome. See Introns, 16
Hypotonia Isoforms, 18
Fluorescent in situ hybridization
(FISH), 31 Karyotype, 31
Four-and-a-half LIM domains protein Kyphosis, 11
1 (FHL1), 24
Frameshift mutation, 19 Laminin, 14
FSHD. See Facioscapulohumeral Laminopathies, 23
muscular dystrophy LGMD. See Limb-girdle muscular
dystrophy
Gastrostomy, 41 Limb girdle, 5
Gene expression, 16 Limb-girdle muscular dystrophy
Gene modifiers, 34 (LGMD), 5
Gene therapy, for MD, 46–48 LMNA genes, 23
Genes, 16 Lordosis, 11
Genetic code, 18 LTBP4 gene, 35
INDEX
69

Magnetic resonance imaging Nonsense readthrough, 44


(MRI), 9 Nuclear lamina, 23
Maternal blood screening, 32 Nusinersen, 44
MD. See Muscular dystrophy
mdx mouse, 35 Oculopharyngeal muscular dystrophy
Mendel, Gregor, 26 (OPMD), 7
Messenger RNA (mRNA), 17 OPMD. See Oculopharyngeal
Microdystrophin genes, 47 muscular dystrophy
Missense mutations, 18 Orthoses, 39
Mitochondria, 45 Oxidative stress, 45
Monogenic disorders, 34
Muscular dystrophy (MD) PABPN1. See Polyadenylate-binding
contributing factors, 34–36 protein 1
diagnosis of, 8–9 PCR. See Polymerase chain reaction
drug treatment for, 37–39 Pedigree analysis, 31
experimental drugs for, 43–45 Pelvic girdle, 5
gene mutations, 16–25 Peristalsis, 11
gene therapy for, 46–48 PGD. See Preimplantation genetic
genetic testing, 30–32 diagnosis
health complications of, 9–12 Phenotype, 26
hereditary information, 26–30 Pluripotent, 45
muscles function, 13–15 Point mutation, 18
nine most common types of, 2 Poly(A) tail, 17
physical therapy, 39–41 Polyadenylate-binding protein 1
preimplantation genetic diagnosis (PABPN1), 25
of, 33–34 Polymerase chain reaction (PCR), 30
stem cell therapy for, 45–46 Prednisone, 37
symptoms of, 1–8 Preimplantation genetic diagnosis
Mutagens, 18 (PGD), 33
Mutations, 18 Prenatal diagnostic testing, 32
Myoblasts, 46 Prodrug, 38
Myofibrils, 13 Promoter, 16
Myopathy, 1 Proximal muscles, 5
Myosatellite cells, 46 Pseudohypertrophy, 1
Myosin, 13 Pulmonary aspiration, 7
Myotonia, 3 Punnett square, 26
Myotonic dystrophy (DM), 3
Myotonin–protein kinase (MT-PK), 21 Recessive alleles, 26
Regenerative medicine, 45
Nasal intermittent positive pressure Restrictive lung disease, 10
ventilation (NIPPV), 41 RNA polymerase, 16
Neurons, 19 RNA splicing, 17
NIPPV. See Nasal intermittent
positive pressure ventilation Sarcoglycan complex, 14
Noncoding RNA molecules, 22 Sarcolemma, 14
Noninvasive prenatal diagnosis Sarcomeres, 13
(NIPD), 32 Scapular winging, 4
Nonsense mutation, 18–19 Scoliosis, 3
70 INDEX

Sex chromosomes, 16 Totipotent, 33


Sex-linked MD, 28 Trachea, 11
Shoulder girdle, 5 Tracheostomy, 41
Simvastatin, 45 Transcription, 16
Single nucleotide polymorphisms, 34 factor, 21
Skeletal muscle, 13 Translation, 17
Sleep apnea, 11 Trans-splicing, 47
SMA. See Spinal muscular atrophy TREAT-NMD DMD Global
Smooth muscle, 11 Database, 20
Spinal muscular atrophy (SMA), xi, 7 Trinucleotide repeats, 21
Spliceopathy, 21 Trophectoderm biopsy, 33
Spontaneous mutations, 18
Stem cells, 45 U7 snRNA, 47–48
therapy, for MD, 45–46 Ultrasound imaging, 9
Synapses, 19 Utrophin, 35
Syntrophin complex, 14
Ventricles, 10
Tamoxifen, 45
Tendons, 14 Whole-genome sequencing, 31
Tetranucleotide repeats, 22
Thick filaments, 13 X inactivation, 22
Thin filaments, 13 X-linked recessive, 29
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
• Down Syndrome: One Smart Cookie by Todd T. Eckahl

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