2 Classification of Myopathies A. HereditaryMuscular dystrophiesCongenital myopathiesMyotonias and channelopathiesMetabolic myopathiesMitochondrial myopathiesB. AcquiredInflammatory myopathiesEndocrine myopathiesDrug induced/ toxic myopathiesMyopathies associated with systemic illness
3 Muscular DystrophiesDefinition: Group of genetically determined, progressive degenerative disorders of muscleHistory: Distinction between myopathic and neuropathic disease was made only in the later half of the 19th century.Duchenne in 1855 first described a progressive muscular atrophy of childhood and was termed “hypertrophic paraplegia of infancy”.Erb in 1891 was the first to recognize the group of diseases due to primary degeneration of muscle and called it “muscular dystrophies”.
4 Classification of Muscular dystrophies Age of onset:A. Early childhood: Duchenne muscular dystrophyB. Childhood/ adolescence: BeckerLandouzy-Dejerine (FSH)Emery-DreifussLimb-girdle (Erb)C. Adult: Oculopharyngeal, myotonic dystrophy (Steinert)
5 Classification of Muscular dystrophies Genetic: Chromosome ProteinA. Sex linked: (X-linked)Duchenne (Xp21) DystrophinBecker (Xp21) DystrophinEmery-Dreifuss (Xq28) EmerinB. Autosomal dominant :Facioscapulohumeral (4q35) ? oculopharyngeal (14q11) Protein 2myotonic dystrophy (19) DMPKC. Variable inheritance: Limb-girdle type (Erb)
6 Dystrophinopathies -Duchenne’s and Becker Duchenne’s Muscular dystrophy (DMD)X linked recessive1:3500 male newbornsUsual onset between 3 and 5 yearsClinical featuresProximal muscles and neck flexors involved earlyCalf hypertrophy, Gower’s signContractures in tendoachilles, scoliosis, cardiomyopathySlow progression and wheelchair bound by age 12Death common by age 20 due to respiratory causeLab features: CPK elevated, EMG, BiopsyIdentifiable Xp21 mutation with absence of dystrophin
8 Duchenne’s…pathology Scattered groups of necrotic and regenerating fibresHypertrophied fibresSmall round fibresPerimysial and endomysial proliferationMuscle fibre loss and fat replacementDystrophin deficiency demonstrated by immunohistochemical staining
10 Duchenne’s…molecular pathology Duchenne’s dystrophy is caused by the absence or deficiency of dystrophin protein which is the product of Xp21 gene locusIt is part of the dystrophin-glycoprotein complex (DGC) which is a group of membrane-associated proteins that span the muscle sarcolemma and provide linkage and stability between the intracellular and cytoskeleton and the extracellular matrixThe postulate is that absence of this protein results in tears in the membrane due to weakening of the sarcolemma with a resulting calcium leak into the muscle fibre initiating a cascade of events leading to muscle fibre necrosis
11 Duchenne’s TreatmentSupportive care: Use of leg braces, passive exercises, scoliosis if more than 35 degrees treated surgicallyCorticosteroids: Prednisolone and deflazocort found to be usefulPrednisolone at a dose of 0.75mg/kg prolongs ambulation by 3 to 4 yearsGene replacement therapy in the future
12 Inflammatory myopathies Definition: Heterogenous group of disorders characterised by inflammation in the skeletal muscles with resultant muscle fiber damage and subsequent clinical weaknessThese are relatively uncommon about 1 in
13 Classification of Inflammatory myopathies Idiopathic:DermatomyositisPolymyositisConnective tissue disease: Scleroderma, SLE, RAInclusion body myositisMiscellaneous: Eosinophilic myositis, Sarcoid myopathyInfectious:Viral myositides: Influenza, HIV and otherParasitic myositis: Trichinosis, toxoplasmosis, cysticercosisBacterial myositisFungal mysositis
14 Inflammatory myopathies Clinical features:Weakness affects neck flexors, pectoral and pelvic girdle muscles in dermatomyositis (DM) and polymyositis (PM). Distal muscles involved in inclusion body myositis (IBM)Cardiac and smooth muscle may be involved. Dysphagia is a common symptom in DM, PM and IBMDiagnosis confirmed by elevated CPK and biopsy. DM is humorally mediated whereas PM is cell mediated muscle injuryTreatment with steroids, immuno suppresants and I.V immunoglobulins in PM and DM.
16 Endocrine myopathiesHyperthyroidism: Proximal weakness; periodic paralysis. CPK is usually normal. Type 1 and 2 fibre atrophyHypothyroidism: Proximal weakness, muscle hypertrophy, cramps, myalgia. Ankle jerks may demonstrate delayed relaxation. Myoedema which is a painless mounding of the muscle when it is percussed. CPK usually elevated.Hyperparathyroidism: Proximal weakness and atrophyHypoparathyroidism: mild weakness, tetany
17 Endocrine myopathy…contd Hypercortisolism/ steroid myopathy: Women more prone to develop exogenous steroid induced myopathy. Usually when prednisone dosage is > 30mg/ day. Fluorinated steroids like triamcinolone> betamethasone> dexamethasone greater propensity. Proximal muscle weakness. Serum CPK , EMG is normal. Biopsy shows preferential atrophy of Type 2 fibres.Hypocortisolism: Generalised weakness, fatigue, crampsDiabetes when uncontrolled can produce diabetic muscle infarction especially in the thighs and can manifest as a painful swelling. CPK is normal.
18 Myotonic dystrophy Laboratory features: CPK mildly elevated EMG: myotonic discharges “dive bomber”Genetic screening: CTG repeat on chromosome 19 on leukocyte DNATreatment:Supportive carePhenytoin, procainamide and mexiletine for myotonia
20 Myotonic dystrophyThis is the most common inherited muscle disorder affecting adultsAutosomal dominant15 cases per live births and M:F is 1:1Varies from a mild late onset form of the disease to a severe congenital disorder. Severity depends on the number of CTG repeats in the DMPK gene on chromosome 19The classical form usually present in adolescence or early adulthoodThe most frequent symptoms are muscle weakness and stiffness affecting the distal limbs and myotonia