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Muscular Dystrophies Muscular Dystrophies Dr Meriel McEntagart St George’s Medical Genetics Unit Learning Objectives Meaning of term “muscular dystrophy” Pros and cons of clinical versus molecular classification of muscular dystrophies Have an appreciation of why such a large number of genes share the common feature of dystrophic muscle Treatment options for muscular dystrophies MUSCULAR DYSTROPHIES Overview of inherited muscle disease Common pathology and classification of muscular dystrophies Duchenne/Becker muscular dystrophy & genetic counselling Facioscapulohumeral MD Limb girdle MD Congenital MD Other rarer types Common pathology Skeletal muscle Cardiac muscle Respiratory muscle Additional clinical features CNS involvement Musculoskeletal involvement Eye abnormalities Skin changes Common pathology Elevated serum creatine kinase Myopathic electrophysiology Muscle biopsy finding Dystrophic process affecting muscle fibres Rounding up of fibres Splitting of fibres Regenerative fibres Accumulation of connective tissue Fat infiltration Signs of inflammation Immunohistochemistry to distinguish subtypes Classification Muscular Dystrophies Phenotype ie Clinical Distribution muscle involvement Proximal eg Limb girdle MD Distal eg Tibial MD Generalised eg Congenital MD Genotype ie Molecular According to gene involved Allelic disorders different phenotypes Clinical Classification Muscular Dystrophies Duchenne/Becker Muscular Dystrophy Limb Girdle Muscular Dystrophy LGMD1A,B,C… autosomal dominant LGMD2A,B,C… autosomal recessive Congenital Muscular Dystrophy MDC1A,B,C… Distal Muscular Dystrophy Muscular Dystrophy with contractures Emery-Dreifuss XLR, AD Bethlem myopathy Facio-scapulo-humeral MD Myotonic MD Other rare Molecular classification MD Dystrophinopathies DMD/BMD cardiomyopathy Laminopathies EDMD, LGMD, Cardiomyopathy,(Lipodystrophy, CMT) Dystroglycanopathies CMD and LGMD Sarcoglycanopathies LGMD2 Dysferlinopathies LGMD and distal MD Collagenopathies LGMD and CMD DMD pedigree 5y 3y 5 m Dystrophin DMD 70% Duplications or deletions of whole exons Point mutations Out of frame mutations BMD Duplications/deletions of whole exons Point mutations In frame mutations Produce some dystrophin with residual function Limb girdle muscular dystrophies Examples • Sarcoglycanopathies • Dystroglycanopathies • Dysferlinopathy Muscular Dystrophy Congenital Classical CMD (Merosin deficient/laminin alpha 2) Hypotonia +/- contractures White matter changes MRI brain Intellect normal Fukuyama CMD Mental retardation Structural brain abnormality Muscle-eye-brain MD Mental retardation Hydrocephalus Ocular abnormalities eg myopia, glaucoma, retinal or optic atrophy Walker-Warburg MD Mental retardation Lissencephaly II “smooth brain” Ocular malformations Muscle-eye-brain and Walker-Warburg FKRP Distal myopathies Adult onset • late • early Examples • Myofibrillar myopathies • Welander • Nonaka Nuclear envelope protein neuromuscular diseases Emery–Dreifuss muscular dystrophy (XL & AD) Emery Dreifuss muscular dystrophy Onset usually childhood • rare after 20 years Contractures Cardiac conduction defects/ cardiomyopathy Humeral/peroneal muscle wasting Genes • Emerin (XL) • Lamin A/C (AD) Collagen VI related muscle disorders Bethlem myopathy (AD) and Ullrich congenital MD (AD & de novo dominant) Ullrich CMD FSH MD Autosomal dominant FSHD gene? Contraction of macrosatellite repeat D4Z4 in subtelomeric region 4q35 FSHD patients 1-10 units, controls 11-100 10-30% FSHD de novo contraction of D4Z4 repeat Contractions on specific 4q haplotypes pathogenic thus contraction itself not sufficient to cause the disease Molecular mechanism underlying the myopathy unknown ?alteration in transcriptional characteristics of 4q subtelomere Myotonic Dystrophy Myotonic Dystrophy Multisystem disorder Muscle weakness distal + Myotonia Respiratory failure Cardiac arrhythmias Cataracts Diabetes mellitus Hypogonadism Anaesthetic risks Two types DM1 (most common) CTG expansion 3’UTR DMPK gene ch 19 DM2 untranslated CCTG expansion intron 1 ZNF9 ch 3 Triplet repeat disorder DM1 Risk congenital myotonic dystrophy on maternal transmission in DM1 Mode of action mutations DM1&2? Hypothesis that RNA pathogenesis causes multisystem clinical features RNA gain of function Splicing alterations Cardiac troponin T (cTNT) Insulin Recepton (IR) Muscle specific Chloride Channel (Clc-1) Tau CNS Myotubularin MTMR1 in congenital DM1 muscle Treatment of muscular dystrophies Supportive with physiotherapy and occupational therapy Steroids in DMD Gene therapy with viral vectors Antisense oligomers to convert out-of-frame to in-frame ie DMD to BMD phenotype “molecular patch” PTC124 a small organic molecule can force the translation machinary to ignore premature termination codons TREAT NMD http://www.treat-nmd.eu/ Disease information Patient Registries Research Industry Biobanks The End Muscle-eye-brain POMGnT1 Muscle-eye-brain 1p32 Distal Myopathies Late adult onset Type 1 AD Welander 2p13 Type 2 AD Markesbery-Griggs/Udd Titin Early adult onset Type 1 AR Nonaka (Familial IBM) GNE Type 2 AR Miyoshi (LGMD2B) Dysferlin Type 3 AD Laing MYH7 Myofibrillar myopathies Myotilin ZASP Desmin αBcrystallin Collagen VI related muscle disorders Genes involved COL6A1, COL6A2, COL6A3 Bethlem myopathy AD Mild proximal myopathy Contractures long finger flexors, wrists, elbows, ankles Skin features eg follicular hyperkeratosis, keloid formation, cigarette paper scars Ullrich congential MD AR and de novo AD Early onset muscle weakness Proximal joint contractures later spine, achilles and finger flexors Distal joint laxity Normal intelligence May never walk independently Respiratory failure second decade Skin changes as per Bethlem myopathy Nuclear envelope protein neuromuscular diseases XLR and AD Emery-Dreifuss MD Early contractures Achilles,elbows,spine Muscle wasting humeral and peroneal Cardiac conduction defect/cardiomyopathy Usually present by 30y Onset usually in childhood rare after 20y CK usually elevated but may be normal XL Emerin gene AD Lamin A/C gene .
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