Download Muscular Dystrophy

Muscular Dystrophy
Beyond Duchenne
Ann Bubenzer
Objectives
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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
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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 con’t
Physical exam reveals hypotonic infant
with high arched palate. Physical exam is
otherwise normal.
Laboratory such as CBC and electrolytes
are normal.
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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.
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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.
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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 can’t let go
easily.
History and Physical Exam in the
Newborn and Office
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History
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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
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Family History
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Include enough of family tree to pick up
autosomal recessive disorders and X-linked
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
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School functioning/cognitive development
Cardiac function/arrhythmias/syncope
Respiratory
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Physical exam findings
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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
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Tone: resistance to passive movement
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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
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Covers all muscular dystrophies and myopathies
Multisystem diseases : ALS or Friedreich Ataxia
Neuropathy : HSMN, CMTD
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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
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Creatine kinase :
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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
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Muscle biopsy
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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
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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
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Genetic analysis
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PCR for specific known defects
Southern blot for nucleotide repeats
Electromyography
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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
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Heart – cardiomyopathy
Respiratory
Intellect - 30 % with impairment IQ <75
Testing
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Immunostaining with absence of dystrophin
PCR testing available for common mutations (X21.2)
Becker Muscular Dystrophy
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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
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Presentation: neonatal onset of severe
weakness, delayed motor milestones,
contractures
Merosin negative/CMD A1
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White matter hypodensities on brain scan
but normal mental capacity
Diagnosis by muscle biopsy
immunohistochemistry showing loss of α2laminin (AR-chromosome 6q22-23)
Neuronal Migration Disorders
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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
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
Steinert’s disease
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Presentation – adult with multiple systems affected
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Primarily distal and facial weakness
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Facial features: frontal balding in men, ptosis, lowset ears, hatchet jaw, dysarthria, swan neck, ^
shaped upper lip
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Myotonia: worse in cold weather, after age 20
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Heart: conduction block – evaluate syncope
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Smooth muscle: constipation, care with swallowing,
gallstones, problems with childbirth, BP lability
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Brain: learning disabilities, increased sleep
requirement
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Ophthalmology: cataracts
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Endocrine: insulin resistance, hypothyroidism,
testicular atrophy
Genetics:
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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:
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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
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Southern blot testing available (chromosome 4q35)
for decrease in repeats normally present
Muscle biopsy may show lymphocytic infiltrates
Limb Girdle Muscular Dystrophy
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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
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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
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X-linked type affects emerin
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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
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Presentation: weakness in forearms, hands, and lower legs
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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/2q31-33
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
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Central core disease:
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Myotubular myopathy
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Myotubularin, important in myogenesis (Xq28)
Nemaline Myopathy
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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
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Juvenile Dermatomyositis
Inclusion Body Myositis (usually distal)
Adult Polymyositis (associated with malignancy)
Treatment - Medications
Steroids
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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
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Genetic therapies
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Repairing the mutated sequences
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Replacing the mutated sequences
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Using cell’s 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
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Utrophin in DMD
Therapy
Contracture prevention
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Stretching exercises and postural
changing
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Stretch the most contracture prone
groups (gastrocnemius, hip flexors,
iliotibial bands, hamstrings)
AFO at night to supplement
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Strengthening/conditioning/endurance
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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
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No eccentric contraction or delayed soreness
Voluntary active exercise such as
swimming/hydrotherapy or cycling in
ambulatory children currently recommended
Mobility aids
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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
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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.com
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Surgery
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note the risk inherent to surgery –
malignant hyperthermia
Palliative vs. rehabilitative
Tendon releases
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Achilles
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Need KAFO to walk post-op
Relieves pain and allow shoe wear
Hamstring and iliotibial band
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Relieves hip and knee pain or contracture
Allows better gait compensation
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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
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Ophthalmology
 Deficient
eye closure oculomaxillofacial MD
and FSH MD may require artificial tears or
tarsorrhaphy
 Treatment for cataracts in Myotonic MD
Respiratory
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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
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Assisted noninvasive ventilation
Oxygen alone does not ventilate!
 Positive pressure ventilation vs. volume ventilation
with pressure limit
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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
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Cardiology
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EKG – pacemaker for conduction defects and
arrhythmias
Echocardiogram – afterload reduction, digoxin
for cardiomyopathy
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Nutrition/GI
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Overweight and underweight are
common problems
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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
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Osteopenia/Osteoporosis
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Begins before walking stops, fractures may
end walking
Worsened by steroids
Calcium supplements, Miacalcin may help
Psychology/Neuropsychological
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Education – aid in planning
Special education may not be needed with
accomodation and modifications
Progressive loss of function affects patient
and family
Thank you
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My family
Dr. Vikki Stefans
Dr. Robert Warren