Download Muscular Dystrophy criteria Dystropy = “abnormal growth

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Muscular Dystrophy criteria
o Dystropy = “abnormal growth”
o Obligatory Criteria
 Primary myopathy
 Genetic basis
 Progressive
 Degenerative with death of muscle fibers occurs at some stage in the
disease
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Types of MD
o Duchenne* (DMD)
 Most common hereditary neuromuscular disease
 X-linked recessive
 Abnormal gene Xp21
 Absent or nonfunctional dystrophin gene
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Clinical presentation
 Weakness progressing proximal to distal, and lower to upper
o Hip girdle muscles at 2-3 years
o Gower’s sign at 3-6 years
o Trendelenburg gait (gluteus medius lurch) at 3-6 years
o Wheelchair bound by 12 years
 Hyporeflexia/areflexia progressing proximal to distal
 Pseudohypertrophy of calves
 Achilles shortening leads to toe walking
 IQ impairment +/- learning disabilities
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Lordotic posture
Leg pain
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Complications
 Contractures
 Nonambulatory
 Frequent respiratory infections
 Dilated cardiomyopathy
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Prognosis
 Death in late teens or 20s
o Becker Muscular Dystrophy (BMD)
 Genetically the same as Duchenne
 Later onset
 Milder clinical course
 X-linked recessive
 Abnormal gene Xp21
 Partially functional dystrophin
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Clinical presenation
 Later with less severe symptoms
 Nonambulatory by 27
 Cardiomyopathy may be present to skeletal symptoms
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Prognosis
 Life expectancy 40s
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DMD/BMD diagnostics
 Laboratory Test
o Extremely elevated creatine kinase (CK): eventual
decrease to normal as muscle dies
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Electromyogram (EMG)
o Nonspecific myopathic features (small polyphasic
potentials)
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Muscle biopsy (rules out neurogenic disease)
o Nonspecific myopathic changes (muscle fiber degeneration
and regeneration with replacement with connective tissue
and fat, and inflammatory cells)
o Differentiate DMD vs BMD by quantitative dystrophin
expression
o DMD <5% dystrophin expressed on Western blot
o Intermediate phenotype 5-20%
o BMD 20-50% dystrophin expression
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DNA sequencing from peripheral blood of Xp21
o Emery-Dreifuss (EDMD)
 Scapuloperoneal or Scapulohumeral or Humeroperoneal muscular
dystrophy
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Genetics: nuclear membrane protein
 X-linked recessive form Xq28
o Defect in EDMD1 gene coding for emerin, a protein
expressed at the inner nuclear membrane
o Emerin stabilizes the nuclear membrane during muscle
contraction
 Autosomal Dominant form at 1q21.2
o EDMD2 linked to mutations in coding for lamin-A/C
expressed on the nuclear lamina
o Later clinical presentation
 Autosomal Recessive form ( very rare) 1q21.2
o EDMD3 also linked to mutations in coding for lamin-A/C
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Clincal features
 Onset of symptoms 5-15 years
 Slow progression of scapulo-humero-peroneal muscle
weakness/wasting
 Rare facial weakness
 Early contractures of elbows and ankles
 Normal intellectual function
 Severe cardiomyopathy often the cause of death
o Associated with AV conduction abnormalities
o Due to suddenly fatal ventricular fibrillation
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Diagnosis
 ECG: AV block, atrial arrhythmias
 Muscle biopsy: Lack of emerin in myocyte nuclei (X link form)
 DNA testing of emerin gene (X link form)
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Mange with pacer for heart and cardiomyopathy meds
o Limb-Girdle (LGMD)
 Progressive hereditary myopathies of hip and shoulder girdle
 Heterogenous group with16 different genetic forms
 Several mutations affect proteins critical to the structural integrity of the
muscle cell membrane (sarcoglycanopathies)
 Autosomal Recessive (LGMD2A-N)
o most forms
 Autosomal dominant (LGMD1A-H)
o Benign course with little impairment
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Clinical manifestation
 Typically presents in middle to late childhood with progressive hip
and shoulder girdle weakness and atrophy
o Childhood onset mostly pelvic girdle distribution (may
mimic DMD and BMD)
o Adult onset usually both hip and shoulder involvement
o Preferentially affects the biceps
 Lordosis
o Gluteal weakness>> back pain
 Decreased deep tendon reflexes
 Slowly progressive
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Diagnostics
 Default diagnosis of LGMD made on clinical criteria
 Muscle biopsy
o Usually nonspecific evidence of muscular dystrophy
o Muscle biopsy immunohistochemistry for specific proteins
may be needed if genetic testing unrevealing
o dystrophin, dysferlin, lamin A/C
 Genetic testing first to try to define specific gene mutations
o LGMD2A-N and LGMD1A-H
o MUST rule out DMD/BMD
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Prognosis
 Wheelchair bound by 30
 Mid-late adulthood life span
 Death due to cardiopulmonary complications
o Facioscapulohumeral (FSHMD)
 Autosomal dominant
 Deletions in D4Z4 gene on 4q35 locus predominantly
 Genetic anticipation often seen
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Clinical presenation
 Weakness and atrophy in facial and shoulder girdle muscles
 Upper lip rounded and protrudes (resembles pucker)
o Pharyngeal and tongue muscles spared
 Prominent scapular winging
o Wasted biceps & triceps with relative sparing of deltoid
 Asymmetry of weakness is common
 Inability to close eyes in sleep
 Hearing loss and retinal vasculopathy
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Diagnostics
 DNA testing main method to confirm the diagnosis
o D4Z4 gene on 4q35
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Suportive tx
 Cosmetic surgery improves facial muscle expression
 Scapular fixation may help if symptomatic
 Pain control (up to 80%)
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Prognosis
 Lifespan not significantly affected
 20% eventually wheelchair bound
 Monitoring for pulmonary, ophthalmologic and hearing
complications
o Occulopharyngeal (OPMD)
 Ocular and pharyngeal involvement
 Autosomal dominant
 GCG repeat expansion in PABPN1 @ 14q11-q13
 Presents with
 Ptosis may eventually occlude vision
 Dysarthria
 Dysphagia may cause weight loss and death
 Progressive weakness of extraoccular muscles
 Onset: middle age
 Asymmetric weakness of levator palpebrae muscles
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Clinical Diagnosis (ptosis, dysphagia, +FH)
 Genetic testing for PABPN11/4q11-q13 if needed
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Supportive Treatment
 Blepharoplasty for ptosis
 Cricopharyngeal myotomy temporarily improves swallowing
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o Distal
 Diverse collection of diseases characterized by weakness that starts
distally
 Hands/forearms
 Lower legs/feet
 +/- gradual progression to proximal muscles
 Variable presentation
 Diagnostics
 Nearly 20 types each with a different gene locus
o Many of the genes code for sarcomere proteins
o AD, AR or sporadic
 Muscle biopsy to differentiate from neurogenic disease
o Degeneration and loss of muscle fibers
o Replacement by fibrous and fatty connective tissue
o +/- rimmed vacuoles
 Genetic testing for specific genes and/or proteins
o Myotonic (MMD)
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Congenital form (DM1 only): infants born to mothers with symptomatic
DM
 hypotonia
 poor feeding often requires G-tube
 respiratory failure often requires ventilation
 Clubfoot +/- extensive congenital contractures
 Cognitive deficits typically do not progress
Juvenile form (DM1/DM2): typically reflect non-skeletal muscle
involvement
 Cognitive deficiency
 Dysarthria
 Hearing
 Poor coordination
 Cardiac arrhythmias precipitated by exercise
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Adult form (DM2 only): typically present with proximal muscle
weakness
 Typically diagnosis in 4th decade
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Autosomal dominant
Classic Myotonic Dystrophy (DM1) @19q13.3
 Cytosine-thymine-guanine (CTG) trinucleotide expansion of
dystrophia myotonica protein kinase gene (DMPK)
o Anticipation (increased expansion→earlier onset and more
severe)
DM2 @ 3q 21.3
 CCTG tetranucleotide expansion located in zinc finger protein 9
gene (ZNF9)
o No correlation between size of expansion and severity
DM3 @ 15q21-q24
 Inheritance overwhelmingly maternal
Diagnosis
 Labs
o Increased CK and GGT (not specific but may raise
suspicion)
o Decreased IgG and IgM
o FSH elevated and testosterone low
 EMG can demonstrate myotonia (if not seen clinically)
 DNA analysis showing abnormal expansion of the CTG/CCTG
repeat is definitive
 Diagnosis can often be made by clinical presentation, labs and
FH alone.
Management primarily supportive
 Myotonia can be treated with medication
o Not useful if functional disability is caused by weakness
 Monitoring for cardiac, immune, and endocrine complications
o ECG at least annually
o Thyroid testing
o Glucose tolerance testing
Prognosis
 Mean age of death in 50’s
o Earlier death with earlier onset/more severe disease
o Life span only mildly reduced in DM2
 Mortality from respiratory complications and arrhythmias
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o Congenital (CMD)
 Encompasses several distinct rare diseases with the common characteristic
of:
 Severe hypotonia and weakness at birth
 Follows a slow or nonprogressive clinical course
 Autosomal recessive
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Types
 Merosin deficient: LAMA2 coding for merosin @ 6q22-23
o Severe CMD
o demyelination of the cerebral hemispheres typically w/o
structural CNS anomalies
o Muscle bx stain shows absent/decreased merosin
 Ullrich type: defect in collagen VI gene
o elbow contractures
o hyperextensible distal joints
 Dystroglycanopathies (6 different genes)
 Severe cardiomyopathy
 Brain malformations and developmental delay
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Clinical manifestation
 Diffuse hypotonia and weakness
 Contractures/Arthrogryposis at birth and progress
 Mental and neurological status highly variable
o Associated with cerebral malformations
o Cognitive impairment
o Reflexes decreased or absent
 Cardiac involvement (ranges from absent to severe)
 Retinal degeneration
 Variable severity
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Diagnostics
 Labs
o CK moderately elevated
 EMG
o Myopathic features
 DNA testing for known genes
 Muscle biopsy may help with diagnosis
o Proliferation of endomysial collagen envelops individual
muscle fibers at birth
o Staining for merosin
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Management
 Cardiac evaluation for all infants with CMD
o routine monitoring if at risk for cardiac involvement
 Eye evaluation at birth
o Monitor for retinal degeneration
 Brain imaging
 EEG to detect seizures
 Supportive
Muscular Dystrophy management overview
o Anticipate issues with anesthesia
o Cardiac
 ECG and/or ECHO to evaluate heart involvement
 Monitor cardiac status
 Treat cardiac complications
o Pulmonary
 Monitor respiratory status
 Prompt treatment of respiratory infections
 Progressive support with cough assist machines, CPAP, tracheostomy and
ventilation
o Orthopedic
 Physical therapy to improve mobility and avoid contractures
 ? light exercise may be beneficial
 Mechanical aids (bracing, wheelchairs) to increase mobility
 Surgical intervention if necessary (scoliosis, scapular winging)
o Multidisciplinary supportive therapy
 Monitor nutritional status/weight since risk for obesity
 Social and emotional support