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