Dystrophies, Inflammatory myopathies & endocrine myopathies

Classification of Myopathies

A. Hereditary Muscular dystrophies Congenital myopathies Myotonias and channelopathies Metabolic myopathies Mitochondrial myopathies B. Acquired Inflammatory myopathies Endocrine myopathies Drug induced/ toxic myopathies Myopathies associated with systemic illness

Muscular Dystrophies Definition: Group of genetically determined,

progressive degenerative disorders of muscle

History: 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”.

Classification of Muscular dystrophies Age of onset:

A. Early childhood: Duchenne muscular dystrophy

B. Childhood/ adolescence: Becker

Landouzy-Dejerine (FSH)

Emery-Dreifuss

Limb-girdle (Erb)

C. Adult: Oculopharyngeal, myotonic dystrophy (Steinert)

Classification of Muscular dystrophies

Genetic: Chromosome Protein

A. Sex linked: (X-linked)

Duchenne (Xp21) Dystrophin

Becker (Xp21) Dystrophin

Emery-Dreifuss (Xq28) Emerin

B. Autosomal dominant :

Facioscapulohumeral (4q35) ? oculopharyngeal (14q11) Protein 2

myotonic dystrophy (19) DMPK

C. Variable inheritance: Limb-girdle type (Erb)

Dystrophinopathies -Duchenne’s and Becker

Duchenne’s Muscular dystrophy (DMD) X linked recessive 1:3500 male newborns Usual onset between 3 and 5 years

Clinical features Proximal muscles and neck flexors involved early Calf hypertrophy, Gower’s sign Contractures in tendoachilles, scoliosis, cardiomyopathy Slow progression and wheelchair bound by age 12 Death common by age 20 due to respiratory cause Lab features: CPK elevated, EMG, Biopsy Identifiable Xp21 mutation with absence of dystrophin

Duchenne’s…pathology

Scattered groups of necrotic and regenerating fibres

Hypertrophied fibres Small round fibres Perimysial and endomysial proliferation Muscle fibre loss and fat replacement Dystrophin deficiency demonstrated by

immunohistochemical staining

Duchenne’s…molecular pathology

Duchenne’s dystrophy is caused by the absence or deficiency of dystrophin protein which is the product of Xp21 gene locus

It 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 matrix

The 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

Duchenne’s Treatment

Supportive care: Use of leg braces, passive exercises, scoliosis if more than 35 degrees treated surgically

Corticosteroids: Prednisolone and deflazocort found to be useful

Prednisolone at a dose of 0.75mg/kg prolongs ambulation by 3 to 4 years

Gene replacement therapy in the future

Inflammatory myopathies

Definition: Heterogenous group of disorders characterised by inflammation in the skeletal muscles with resultant muscle fiber damage and subsequent clinical weakness

These are relatively uncommon about 1 in 100000

Classification of Inflammatory myopathies

Idiopathic: Dermatomyositis Polymyositis Connective tissue disease: Scleroderma, SLE, RA Inclusion body myositis Miscellaneous: Eosinophilic myositis, Sarcoid myopathy

Infectious: Viral myositides: Influenza, HIV and other Parasitic myositis: Trichinosis, toxoplasmosis, cysticercosis Bacterial myositis Fungal mysositis

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 IBM

Diagnosis confirmed by elevated CPK and biopsy. DM is humorally mediated whereas PM is cell mediated muscle injury

Treatment with steroids, immuno suppresants and I.V immunoglobulins in PM and DM.

Endocrine myopathies

Hyperthyroidism: Proximal weakness; periodic paralysis. CPK is usually normal. Type 1 and 2 fibre atrophy

Hypothyroidism: 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 atrophy Hypoparathyroidism: mild weakness, tetany

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, cramps Diabetes when uncontrolled can produce diabetic muscle

infarction especially in the thighs and can manifest as a painful swelling. CPK is normal.

Myotonic dystrophy

Laboratory features: CPK mildly elevated EMG: myotonic discharges “dive bomber” Genetic screening: CTG repeat on chromosome

19 on leukocyte DNATreatment:

Supportive care Phenytoin, procainamide and mexiletine for

myotonia

Myotonic dystrophy

Systemic features Ocular : Cataract, ptosis, retinal degeneration Cardiac:Conduction disease, arryhtmias,cardiomyopathy Gastrointestinal: Dysphagia, colonic dysmotility,

megacolon Endocrine: Diabetes due to insulin resistance, testicular

atrophy, abnormal GH release Immune: reduced serum immunoglobulins Miscellaneous: Frontal balding, cranial hyperostosis

Myotonic dystrophy

This is the most common inherited muscle disorder affecting adults

Autosomal dominant 15 cases per 100000 live births and M:F is 1:1 Varies 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 19

The classical form usually present in adolescence or early adulthood

The most frequent symptoms are muscle weakness and stiffness affecting the distal limbs and myotonia