Muscular Dystrophies in Childhood

Muscular Dystrophies
In Childhood
Dr Alpana SK
Dept of Pediatrics

Dr Alpana SK, www.peditips.com

What is muscular dystrophy?
 Increasing weakness and loss of muscle
mass and function until the patient is
confined to a wheelchair
 A problem with the synthesis of proteins in
the muscle fibers causes deterioration
 Four forms of the disease are recognized,
based on:
 Pattern of inheritance
 Age when symptoms are first noted
 Distribution of the muscles first involved

 Dystrophinopathy: disorders involving
dystrophin
 Duchenne MD and Becker MD are the
muscular disorders – the two most common
and severe dystrophies
 Dystrophin is a very large gene on the X-
chromosome, ubiquitous in the human body
 Dystrophin-Associated Protein (DAP) Complex
– composed of the extracellular,
transmembrane, and intracellular components

Classification of types of MD
Heritable MDs include the following:
 Sex-linked MDs
 Duchenne
 Becker
 Emery-Dreifuss
 Autosomal dominant MDs
 Facioscapulohumeral
 Distal
 Ocular
 Oculopharyngeal
 Autosomal recessive MD –
limb-girdle form

What is Duchenne’s Muscular
Dystrophy?
 The disease is characterized
 Early onset often before school years
 By progressive muscular deterioration and
death by 14 to 18 years of age
 A defect of a large gene on the X

Prevalence of DMD
 Affects one in
3500 to 5000
newborn males
 1/3 of these with
previous family
history.
 2/3 sporadic

What is the pattern of
inheritance?
X-linked recessive inheritance

Duchenne Muscular Dystrophy
Inheritance.
 Mother carries the recessive gene and
passes it to her child
 Trait is usually expressed in
males only

 The gene for dystrophin
production sits on the X
chromosome.
 Dystrophin is a cytosolic
protein associated with
the external membrane
of skeletal, cardiac and
smooth muscle cells and
of some neurons
 If a normal gene for
dystrophin is present,
then the protein will be
made.
 If the gene is missing
or altered, dystrophin
may not be produced at
all or only in abnormal
forms, resulting in
Duchenne muscular
dystrophy
Xp21 band is
responsible for
dystrophin
production

In Duchenne muscular dystrophy (DMD) patients with a deletion of exons 45–54, an
out-of-frame transcript is generated in which exon 44 is spliced to exon 55. Owing
to the frame shift, a stop codon occurs in exon 55, which prematurely aborts
dystrophin synthesis. b | Using an exon-internal antisense oligonucleotide (AON) in
exon 44, the skipping of this exon can be induced in cultured muscle cells.
Accordingly, the transcript is back in-frame and a Becker muscular dystrophy
(BMD)-like dystrophin can be synthesized

 In the Duchenne muscular dystrophy, the attachment of muscle fibers
to their surrounding endomysium (extracellular matrix) becomes
weakened due to mutations in the dystrophin gene.
(Image courtesy of the National Cancer Institute)

What are the symptoms?
 difficulty in walking at about the age
of four years
 increased size in calf muscles
 Loss of the ability to walk at about
the age of 11
 Death at about the age of 18 or later,
usually because of respiratory failure.

Symptoms of DMD
 Awkward gait (patients tend to walk on their forefeet, because of an
increased calve tonus)
 Frequent falls
 Progressive difficulty walking , Eventual loss of ability to walk (usually
by the age of 12)
 Difficulty with motor skills (running, hopping, jumping)
 Fatigue
 Higher risk of behaviour and learning difficulties.
 Skeletal deformities (including scoliosis in some cases)
 Muscle deformities of tongue and calf muscles. The enlarged muscle
tissue is eventually replaced by fat and connective tissue, hence the
term pseudohypertrophy.
 of heels and legs, rendering them unusable because the muscle
fibers shorten and fibrosis occurs in connective tissue

Posture changes during progression of Duchenne muscular
dystrophy.

Possible Complications
 Deformities
 Permanent, progressive disability
 Decreased mobility
 Decreased ability for self-care
 Mental impairment (varies, usually minimal)
 Pneumonia or other respiratory infections
 Respiratory failure
 Cardiomyopathy
 Congestive heart failure (rare)
 Heart arrhythmias (rare)

Diagnosing Muscular Dystrophy
 Detailed patient and family history (3 generation pedigree)
Determine the source of the muscle weakness (nerve or muscle
 Laboratory tests:
 Serum CK is very elevated
 Troponin I is elevated above normal but not to levels in cardiac
ischemia
 Liver enzymes show high AST & ALT
 Muscle biopsy - Endomysial fibrosis Variable fiber size: Small
fibers rounded Dystrophic muscle Hypercontracted (opaque)
muscle fibers
 Myopathic grouping
 Muscle fiber degeneration & regeneration
 Muscle fiber internal architecture: Normal or immature
 Dystrophin: Absent staining
 Other membrane proteins: Sarcoglycans and Aquaporin 4 are
reduced

Diagnosing Muscular Dystrophy
 CPK test
In DMD patients CPK leaks out of the muscle cell
into the bloodstream, so a high level (nearly 50 to
100 times more) confirms that there is muscle
damage. Affected individuals may have a value as
high as 15,000 to 35,000iu/l (normal = 60iu/l).
 DNA test
The dystrophin gene is composed of 79 exons, and
DNA testing and analysis can usually identify the
specific type of mutation and the exon or exons
that are affected. DNA testing confirms the
diagnosis in most cases.[3]

a. Hematoxylin and eosin
staining of control tissue
b. Hematoxylin and eosin
staining of DMD patient,
which shows abnormal
variation in fiber size,
degenerating and
regenerating fibers,
immune cell infiltration,
and increased fibrosis
c. Immunofluorescence
analysis of dystrophin in
control tissue biopsy
d. Immunofluorescence
analysis of dystrophin in a
young DMD patient
biopsy, illustrating the
loss of sarcolemmal
staining in DMD

Prenatal tests
 If one or both parents are 'carriers' of a particular
condition there is a risk that their unborn child will be
affected by that condition. 'Prenatal tests' are carried out
during pregnancy, to try to find out if the fetus (unborn
child) is affected.
 The tests are only available for some neuromuscular
disorders. Different types of prenatal tests can be carried
out after about 10 weeks of pregnancy.
 Chorion villus sampling (CVS) - 10-12 weeks
amniocentesis - 14-16 weeks,
placental biopsy and foetal blood sampling - 18 weeks.
Women and/or couples need to consider carefully which test to
have and to discuss this with their genetic counselor.
 Earlier testing would allow early termination which would
probably be less traumatic for the couple, but it carries a
slightly higher risk of miscarriage than later testing (about
2%, as opposed to 0.5%).

Approach to Diagnosis of Childhood Muscular Dystrophy
No Deletion
Detected
Diagnosis of Dystrophinopathy (DMD or BMD)
Deletion Not
Informative
for Severity
Deletion Informative
for Severity.
Positive Family History
Deletion
Detected
DNA Analysis
for Dystrophin
Gene Abnormality
Male
Abnormal
Dystrophin
Merosin and
Adhalin Analysis
Normal
Dystrophin
Muscle Biopsy
Female
Elevated
Muscular Dystrophy
Unlikely
Normal
CK
Muscular Weakness

Therapy
 Rehabilitation Therapy:
 Physical
 Occupational
 Respiratory
 Promising Therapies:
 Pharmacologic Therapy
 Cell Therapy
 Gene Transfer Therapy
 Newer Targets

Treatment
 There is no known cure for Duchenne muscular
dystrophy
 Treatment is generally aimed at control of
symptoms to maximize the quality of life.
 Corticosteroids such as prednisone and
deflazacort increase energy and strength and
defer severity of some symptoms.
 Mild, non-jarring physical activity such as
swimming is encouraged. Inactivity (such as bed
rest) can worsen the muscle disease.

Treatment
 Physical therapy is helpful to maintain muscle strength,
flexibility, and function.
 Orthopedic appliances (such as braces and wheelchairs) may
improve mobility and the ability for self-care. Form-fitting
removable leg braces that hold the ankle in place during
sleep can defer the onset of contractures.
 Appropriate respiratory support as the disease progresses
is important
 Idebenone is a new drug currently being actively researched
and is expected to be approved in the US and Europe by
Santhera Pharmaceuticals. Meanwhile it is sold in the US as
a nutritional products mainly by Cognitive Nutrition.
www.cognitivenutrition.com/ The effective dose is 450 mg
daily.

Advances in Gene Therapy(3)
 Researches have developed "minigenes," which
carry instructions for a slightly smaller version of
dystrophin, that can fit inside a virus. Utrophin..
Is similar to dystrophin and can be engineered.
 Researchers have also created the so-called
gutted virus, a virus that has had its own genes
removed so that it is carrying only the dystrophin
gene

Prognosis
 Duchenne muscular dystrophy eventually affects
all voluntary muscles and involves the heart and
respioratory muscles in later stages.
 Survival is rare beyond the early 30s,although
recent advancements in medicine are extending
the lives of those afflicted.
 Death in Duchenne muscular dystrophy most
commonly results from pulmonary insufficiency,
respiratory infections.
 In about 10% of cases, death is due to cardiac
dysfunction..

Congenital Muscular Dystrophy
 Presentation: neonatal onset of severe
weakness, delayed motor milestones,
contractures
 Merosin negative/CMD A1
 White matter hypodensities on brain scan but
normal mental capacity
 Diagnosis by muscle biopsy
immunohistochemistry showing loss of α2-
laminin (AR-chromosome 6q22-23)

Neuronal Migration Disorders
 With neuronal migration disorders get
mental retardation, brain malformations,
and clinical eye involvement
 Fukuyama’s muscular dystrophy – affects
fukutin protein (AR – chromosome 9q31)
 Muscle-eye-brain disease – affects
POMGnT1, (AR – chromosome 1p32-34)
 Walker Warburg – affects POMT1 (AR)
 Glycosyltransferases are also important in
neuronal development

Myotonic Muscular Dystrophy or
Steinert’s disease
 Presentation – adult with multiple systems affected
 Primarily distal and facial weakness
 Facial features: frontal balding in men, ptosis, low-
set ears, hatchet jaw, dysarthria, swan neck, ^
shaped upper lip
 Myotonia: worse in cold weather, after age 20
 Heart: conduction block – evaluate syncope
 Smooth muscle: constipation, care with swallowing,
gallstones, problems with childbirth, BP lability
 Brain: learning disabilities, increased sleep
requirement
 Ophthalmology: cataracts
 Endocrine: insulin resistance, hypothyroidism,
testicular atrophy

FascioScapularHumeral Muscular
Dystrophy
 Presentation:
 Facial weakness with trouble blowing up a balloon,
sipping through a straw, whistling, trouble closing
the eyes at night, scapular winging that may be
asymmetric, pain
 May have absence of pectoralis, biceps, or
brachioradialis
 Also affected: mild high pitched hearing loss, retinal
abnormalities, mental retardation in early onset
 Genetics/Testing
 Southern blot testing available (chromosome 4q35)
for decrease in repeats normally present
 Muscle biopsy may show lymphocytic infiltrates

Limb Girdle Muscular Dystrophy
 Presentation: variable age of onset with
weakness and wasting of the limb-girdle
 May have calf hypertrophy, involvement of
scapular muscle and deltoid in
sarcoglycanopathies
 Many types involve dysfunctional sarcoglycans
– transmembrane proteins of the DAP that
interact with cytoplasmic proteins
 Table 2 – types of LGMD

Oculopharyngeal Muscular
Dystrophy
 Presentation: mid-adult with ptosis, facial
muscle weakness with difficulty swallowing,
proximal muscle weakness, may have
extraocular muscle weakness, more common
in French-Canadian and Hispanic population
 Genetics
 Muscle biopsy shows filamentous nuclear inclusions
and ubiquitin containing vacuoles
 Affects poly A binding protein 2 (PABP2) by
expansion of a GCG repeat without anticipation
seen – Southern blot (chromosome 14q11-13)

Emery-Dreifuss Muscular Dystrophy
Scapuloperoneal MD
 Presentation: stiff joints, shoulder and upper
arm weakness, calf weakness, cardiac
conduction defects and arrhythmias,
contractures
 Genetics
 X-linked type affects emerin
 Diagnose by protein analysis of leukocytes or skin
fibroblasts
 DNA testing available (chromosome Xq28)
 AD affects lamin A or lamin C (chromosome 1q21)
 Nuclear membrane proteins

Distal Muscular Dystrophy
 Presentation: weakness in forearms, hands, and lower legs
 clinically similar to a neuropathy but NCV normal
 Muscle biopsy with autophagocytic vacuoles/ inclusion
bodies
 Table 3 – Types of DMD
Welander distal myopathy AD/2p13 hands first
Anterior tibial/Markesbery-
Griggs/Udd
AD/2q31-33
Nonaka/Inclusion body myopathy 2 AR/9p13 Rimmed vacuoles, inclusion
bodies, affects GNE
Gowers/Laing distal myopathy AD/14q11
Miyoshi myopathy AR/2p13 Affects dysferlin
Distal myopathy with vocal cord and
pharyngeal weakness
AD/5

Myopathies
 Central core disease:
 Ryanodine receptor, Ca channel that mediates
excitation/contraction coupling, (AD – chromosome 19q13)
 Associated with Malignant Hyperthermia
 Myotubular myopathy
 Myotubularin, important in myogenesis (Xq28)
 Nemaline Myopathy
 Caused by many defects, disorder of thin filaments
 Rod-like stuctures on muscle biopsy
 Inflammatory
 Juvenile Dermatomyositis
 Inclusion Body Myositis (usually distal)
 Adult Polymyositis (associated with malignancy)

Therapy
 Contracture prevention
 Stretching exercises and postural
changing
 Stretch the most contracture prone
groups (gastrocnemius, hip flexors,
iliotibial bands, hamstrings)
 AFO at night to supplement

 Strengthening/conditioning/endurance
 Goal is to maintain or improve muscle strength
and maximize functional ability – slight
improvement is possible
 Additional goal is to avoid muscular damage by
overwork or injury
 No eccentric contraction or delayed soreness
 Voluntary active exercise such as
swimming/hydrotherapy or cycling in ambulatory
children currently recommended

 Mobility aids
 Walking orthoses – KAFO
 Standing frames, standing wheelchairs, swivel
walker occasionally used
 Walkers where arm strength less affected
 Transfer board
 Wheelchair – power needed for independence
 Plan for indoor lift, van with lift, roll in shower
 Improving daily activities of daily living
 Physical and Occupational Therapy – teaching
modified techniques
 Antigravity orthoses are being developed to assist in
daily living activities
 Splinting and therapy to prevent hand contractures

 Surgery
 note the risk inherent to surgery – malignant
hyperthermia
 Palliative vs. rehabilitative
 Tendon releases
 Achilles
 Need KAFO to walk post-op
 Relieves pain and allow shoe wear
 Hamstring and iliotibial band
 Relieves hip and knee pain or contracture
 Allows better gait compensation

 Scoliosis – spine stabilization
 Bracing is not effective with progressive
neuromuscular disease
 Timely correction of scoliosis is important
for patient comfort and respiratory ability
 Spine and scapular stabilization may aid
function of arms
 Ophthalmology
 Deficient eye closure oculomaxillofacial MD
and FSH MD may require artificial tears or
tarsorrhaphy
 Treatment for cataracts in Myotonic MD

 Respiratory
 Patients with morning headache, nightmares,
excessive daytime somnolence, mental
dullness, difficulty concentrating, increased
colds, coughing, or pneumonia should undergo
evaluation
 Influenza vaccine and pneumococcal vaccine
 In-exsufflator for airway clearance, cough assist
 Pulmonologist, pulmonary function testing

 Assisted noninvasive ventilation
 Oxygen alone does not ventilate!
 Positive pressure ventilation vs. volume ventilation
with pressure limit
 Assisted ventilation with tracheostomy
 Talk to patient about degree of desired intervention
when respiratory status first starts to decline and
before an acute event
 The goal is home ventilation
 Cardiology
 EKG – pacemaker for conduction defects and
arrhythmias
 Echocardiogram – afterload reduction, digoxin for
cardiomyopathy

 Nutrition/GI
 Overweight and underweight are
common problems
 Overweight impairs mobility
 Underweight decreases strength & health
 Protein and calorie supplements
 Assess for dysphagia
 Intestinal hypomotility in DMD, CMD,
and myotonic dystrophy can require a
bowel regimen to prevent constipation

 Osteopenia/Osteoporosis
 Begins before walking stops, fractures may end
walking
 Worsened by steroids
 Calcium supplements, Miacalcin may help
 Psychology/Neuropsychological
 Education – aid in planning
 Special education may not be needed with
accomodation and modifications
 Progressive loss of function affects patient and
family

Muscular Dystrophies in Childhood

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