Muscular Dystrophy

Muscular Dystrophy
Beyond Duchenne
Ann Bubenzer
Objectives
Recognize patients that require referral

for diagnosis and management of
muscular disorders.
Perform the history and physical exam to
screen for neuromuscular disorder for
patients of all ages.
Describe current methods of diagnostic
testing for neuromuscular disorders.
Discuss current therapy and treatment
options available and the affect on
prognosis
Presentations of patients with

neuromuscular disorders
Case 1
Called to evaluate newborn infant with
hypotonia. Pregnancy complicated
only by flu-like illness in 2nd trimester
and question of decreased strength of
fetal movements compared to first
pregnancy. Labor and delivery
complicated by precipitous delivery.
Case 1 cont
Physical exam reveals hypotonic
infant with high arched palate.
Physical exam is otherwise normal.
Laboratory such as CBC and
electrolytes are normal.
Case 2
4 year old presents to clinic with chief
complaint of toe walking and falling.
The parents also state that he has
trouble with stairs and running. Sat
alone at 8 months, walking by 15
months.
On physical exam he demonstrates
walking up legs with hands in order to
rise from seated position on floor.
Calves are prominent.
Case 3
14 y/o with difficulty lifting arms
above head. On review of symptoms,
this adolescent states he has never
been able to blow up a balloon.
On physical exam, scapular winging
is noted.
Case 4
Infant presents with narrow facies, ^
shaped upper lip, and respiratory
distress after birth. Poor feeder
requiring OG tube assistance.
Mother has similar facial features.
When you shake her hand, she cant
let go easily.
History and Physical Exam in

the Newborn and Office
History
Newborn floppy infant, term or preterm,

poor head control, poor feeding,
prolonged labor, maternal complications
Childhood development delay in sitting,
standing, walking, toe walking, difficulty
stair climbing or running
Teen or adult difficulty in self-care,
swallowing, athletic/endurance activity
Family History
Include enough of family tree to pick up

autosomal recessive disorders and Xlinked or AD disorders with variable
penetrance
Many x-linked or AD represent new
mutations
Past diagnoses in older family members
may not be accurate
Review of Systems
School functioning/cognitive development

Cardiac function/arrhythmias/syncope
Respiratory
Physical exam findings
Muscle mass: signs of wasting or

hypertrophy/pseudohypertrophy
Muscle strength: power generation of
force against resistance or gravity
Observe reaching, getting up from floor
Observe trunk and head/neck control
Test specific proximal groups position so
against gravity
Tone: resistance to passive movement
Note hyper vs. hypotonia in weak areas
Deep tendon reflexes: normal or decreased

Normal sensation: remember
proprioception
Joint contracture: reduced passive range of
motion not due to tone
What is Muscular Dystrophy?

(MD)
Muscular Dystrophy: group of genetic
disorders that are characterized by
progressive loss of muscle integrity, wasting,
and weakness. Characterized by
degeneration and regeneration of muscle
fibers (in contrast with static or structural
myopathies)
Muscular Dystrophy Association
Covers all muscular dystrophies and myopathies

Multisystem diseases : ALS or Friedreich Ataxia
Neuropathy : HSMN, CMTD
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 Xchromosome, ubiquitous in the human body
Dystrophin-Associated Protein (DAP)
Complex composed of the extracellular,
transmembrane, and intracellular
components
The Lancet Neurology

Volume 2 Number 5 May 2003
Copyright 2003 Elsevier
General Diagnostic Testing
Creatine kinase :
Aids in narrowing the differential diagnosis

if greatly elevated (50 times normal)
Increased in DMD, BMD, polymyositis, and
rhabdomyolysis
Nonspecific if mildly elevated 2-3x normal
Lower late in MD course due to severely
reduced muscle mass
Not helpful for carrier detection
Muscle biopsy
Dystrophic changes include necrosis,

degeneration, regeneration, fibrosis and
fatty infiltration, sometimes mild
inflammation
Specific diseases may have inflammation,
intracellular vacuoles, rods, and other
inclusions on biopsy
Biochemical muscle protein analysis
Useful for specific identified protein that is

missing and many specific mutations may
cause the same deficiency
Immunohistochemical protein staining
Western blot quantitates percent of
normal protein present
Genetic analysis
PCR for specific known defects

Southern blot for nucleotide repeats
Electromyography
Useful if diagnosis not clear (biopsy has

mixed features)
Differentiates neuropathic vs. myopathic
Characteristic myotonic discharges in
adults with myotonia dive bomber
sound
Perform after the CK
Duchenne Muscular
Dystrophy
Presentation: 3-5 y/o with

pseudohypertrophy of calf muscles, frequent
falls, slow running, and waddling gait
Prevalence of 1:3500
Other organs affected
Heart cardiomyopathy
Respiratory
Intellect - 30 % with impairment IQ <75
Testing
Immunostaining with absence of dystrophin

PCR testing available for common mutations
(X21.2)
Becker Muscular Dystrophy
Slowly progressive form with same

gene affected as Duchenne MD
Muscle biopsy immunostaining for
dystrophin with patchy staining
Disorder of function or decreased
amount of dystrophin rather than
absence of the protein
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
2-laminin (AR-chromosome 6q22-23)
Neuronal Migration
Disorders
With neuronal migration disorders get

mental retardation, brain malformations,
and clinical eye involvement
Fukuyamas 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
Other Merosin Positive CMD

Disorder
Protein
Associated signs Inheri-tance
Chromosome
Rigid Spine
Disease
SEPN1
(selenoprotein)
Slowly
progressive
Spine
contractures
AR
1p36
Ullrich CMD
COL6A2
Rapidly
progressive
Joint
hyperlaxity
AR
21q22
Bethlem
myopathy
Type VI
collagen
subunits
Slowly
progressive
Myopathy?
AD
21q22 and 2q37
Integrin a7
deficiency
Integrin a7
AR
12q13
CMD 1C
Fukutin-related Rapidly
protein
progressive
Cardiomyopathy
AR
19q13
Myotonic Muscular Dystrophy

or Steinerts 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
Genetics:
Mothers can have adult or congenital onset

offspring; fathers can have adult onset offspring
Parents may not be aware of own diagnosis
Myotonin gene is affected as well as adjacent
transcription factor gene SIX 5 by CTG repeat in
noncoding region of chromosome 19q13.3, and
anticipation seen with increased repeats
Muscle biopsy with internalized nuclei, type 1
fiber atrophy, ring fibers, and sarcoplasmic
masses
Congenital: severe form, initial respiratory

distress after birth with ventilatory
requirement or apnea, feeding difficulty,
mental retardation, club feet, scoliosis,
strabismus
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
Type
Protein
Chromosome
Inheritance
1A
Myotilin
5q22-34
AD
1B
Laminin A/C
1q21
AD/allelic to EDMD
1C
Caveolin-3
3p25
AD
7q
AD
1D
2A
Calpain-3
15q15-21
AR
2B
Dysferlin
2p13
AR/allelic to Myoshi
Myopathy
2C
Gamma
sarcoglycan
13q12
AR
2D
Alpha sarcoglycan
17q12-21
AR
2E
Beta sarcoglycan
4q12
AR
2F
Delta sarcoglycan
5q33-34
AR
2G
Telethonin
17q11-12
AR
9Q33
AR
19q13
AR/allelic to CMD 1C
2H
2I
Fukutin-related
protein
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
Anterior tibial/MarkesberyGriggs/Udd
AD/2q3133
Nonaka/Inclusion body
myopathy 2
AR/9p13
Gowers/Laing distal myopathy
AD/14q11
Miyoshi myopathy
AR/2p13
Distal myopathy with vocal cord

and pharyngeal weakness
AD/5
hands first
Rimmed vacuoles,
inclusion bodies, affects
GNE
Affects dysferlin
Myopathies
Central core disease:
Myotubular myopathy
Myotubularin, important in myogenesis (Xq28)
Nemaline Myopathy
Ryanodine receptor, Ca channel that mediates

excitation/contraction coupling, (AD chromosome
19q13)
Associated with Malignant Hyperthermia
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)
Treatment - Medications
Steroids
Briefly increase strength, slow progression in

dystrophinopathy for walking, arm use, and
respiratory function
Weekend or 15-20/month as well as
prednisolone/deflazacort may minimize SE
Dilantin and Tegretol raise the repolarization

threshold and improve myotonia
Methylphenidate improves daytime
somnolence in DM
Albuterol may help in FSH MD
Creatine and glutamine may help delay
progression/improve energy in youngest
with DMD
Treatment future therapies
Genetic therapies
Repairing the mutated sequences
Replacing the mutated sequences
Using cells own repair mechanisms but adding template

Gentamicin trial for relaxation in stop codon recognition
for DMD has not worked
Inserting truncated genes or whole gene with vector
Upregulation of similar functioning

proteins
Utrophin in DMD
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/enduranc
e
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
comfysplints.co
m
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
Thank you
My family
Dr. Vikki Stefans
Dr. Robert Warren

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Muscular Dystrophy

Recognize patients that require referral

Presentations of patients with

History and Physical Exam in

Newborn floppy infant, term or preterm,

Include enough of family tree to pick up

School functioning/cognitive development

Physical exam findings

Muscle mass: signs of wasting or

Tone: resistance to passive movement

Note hyper vs. hypotonia in weak areas

Deep tendon reflexes: normal or decreased

What is Muscular Dystrophy?

Covers all muscular dystrophies and myopathies

Dystrophinopathy: disorders involving

The Lancet Neurology

General Diagnostic Testing

Aids in narrowing the differential diagnosis

Dystrophic changes include necrosis,

Biochemical muscle protein analysis

Useful for specific identified protein that is

PCR for specific known defects

Useful if diagnosis not clear (biopsy has

Presentation: 3-5 y/o with

Immunostaining with absence of dystrophin

Becker Muscular Dystrophy

Slowly progressive form with same

Presentation: neonatal onset of

White matter hypodensities on brain

With neuronal migration disorders get

Other Merosin Positive CMD

Associated signs Inheri-tance

21q22 and 2q37

Myotonic Muscular Dystrophy

Presentation adult with multiple systems affected

Primarily distal and facial weakness

Facial features: frontal balding in men, ptosis,

Myotonia: worse in cold weather, after age 20

Heart: conduction block evaluate syncope

Smooth muscle: constipation, care with

Brain: learning disabilities, increased sleep

Endocrine: insulin resistance, hypothyroidism,

Mothers can have adult or congenital onset

Congenital: severe form, initial respiratory

Facial weakness with trouble blowing up a

Southern blot testing available (chromosome

Limb Girdle Muscular

Presentation: variable age of onset with

Muscle biopsy shows filamentous nuclear

X-linked type affects emerin

Diagnose by protein analysis of leukocytes or skin

AD affects lamin A or lamin C (chromosome

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

Gowers/Laing distal myopathy

Distal myopathy with vocal cord

Central core disease:

Myotubularin, important in myogenesis (Xq28)