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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.
10 9 8 7 6 5 4 3 2 1
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
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
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
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
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
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