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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 Types of MD o Duchenne* (DMD) Most common hereditary neuromuscular disease X-linked recessive Abnormal gene Xp21 Absent or nonfunctional dystrophin gene 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 Lordotic posture Leg pain Complications Contractures Nonambulatory Frequent respiratory infections Dilated cardiomyopathy 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 Clinical presenation Later with less severe symptoms Nonambulatory by 27 Cardiomyopathy may be present to skeletal symptoms Prognosis Life expectancy 40s DMD/BMD diagnostics Laboratory Test o Extremely elevated creatine kinase (CK): eventual decrease to normal as muscle dies Electromyogram (EMG) o Nonspecific myopathic features (small polyphasic potentials) 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 DNA sequencing from peripheral blood of Xp21 o Emery-Dreifuss (EDMD) Scapuloperoneal or Scapulohumeral or Humeroperoneal muscular dystrophy 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 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 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) 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 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 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 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 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 Diagnostics DNA testing main method to confirm the diagnosis o D4Z4 gene on 4q35 Suportive tx Cosmetic surgery improves facial muscle expression Scapular fixation may help if symptomatic Pain control (up to 80%) 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 Clinical Diagnosis (ptosis, dysphagia, +FH) Genetic testing for PABPN11/4q11-q13 if needed Supportive Treatment Blepharoplasty for ptosis Cricopharyngeal myotomy temporarily improves swallowing 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) 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 Adult form (DM2 only): typically present with proximal muscle weakness Typically diagnosis in 4th decade 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 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 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 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 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 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