Dr. Urmila Banik Unit of Pathology Faculty of Medicine

Denervation atrophy Spinal Muscular Atrophy (Motor Neuron Disease) Muscular Dystrophies X-linked Muscular Dystrophy (Duchenne Muscular Dystrophy & Becker Muscular Dystrophy) Myotonic Dystrophy Types of skeletal muscle diseases

Channelopathies (Ion Channel Myopathies) Congenital Myopathies Myopathies associated with inborn errors of metabolism Inflammatory Myopathies Dermatomyositis Polymyositis Toxic Myopathies Thyrotoxic Myopathy Ethanol Myopathy Drug induced Myopathy Types of skeletal muscle diseases

Diseases of the Neuromuscular Junction Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome Tumors Rhabdomyoma Rhabdomyosarcoma Types of skeletal muscle diseases

X linked Muscular Dystrophy Duchenne Muscular Dystrophy (DMD) Becker Muscular Dystrophy (BMD) Myasthenia Gravis Rhabdomyosarcoma Today we are going to talk about

DMD Most severe & common form 1/3500 live male births Clinically evident by age 5 →relentless progression BMD Less common Less severe X-linked Muscular Dystrophy X linked Muscular Dystrophy

Pathogenesis & Molecular genetics Dystrophin Cytoplasmic protein Located adjacent to sarcollemmal membrane Forming strong mechanical link to cytoplasmic actin

X linked Muscular Dystrophy Dystrophin form interface between cytoskeletal proteins & group of trans membrane protein having interactions with ECM Transfers force of contraction to connective tissue

Dystrophin Interacts with dystrobrevin & syntrophins that form link to nNOS & Caveolin X linked Muscular Dystrophy

The role of this complex of proteins has been proposed to be the basis of myocyte degeneration that occurs in the absence of dystrophin or various other proteins that interact with dystrophin

Xp21 region DMD gene→dystrophin (427kD) Deletions mostly; frame shift & point mutations 2/3 rd familial; rest new mutations X linked Muscular Dystrophy

Female carriers & affected Males who survive up to adulthood have risk of Dilated Cardio-Myopathy X linked Muscular Dystrophy Female: carriers; asymptomatic often ↑ S. creatine Kinase minimal histologic changes in muscle biopsy Male: affected

Variation in fiber diameter (small; enlarged; fiber splitting) X linked Muscular Dystrophy M/E

↑ Internalized nuclei Degeneration, Necrosis, Phagocytosis Regeneration Proliferation of endomysial connective tissue Late stage: almost total replacement by fat & connective tissue X linked Muscular Dystrophy

Western blot DMD minimal/no dystrophin BMD Altered dystrophin size (abnormal MW)

Cardiac involvement Interstitial fibrosis; Subendocardium DMD Enlarged round hyaline fibers that have lost their normal cross striation are seen; believed to be hyper contracted; rarely found in BMD X linked Muscular Dystrophy

DMD Boys normal at birth, walking delayed Clumsiness & inability to keep up with peers ***** Weakness: pelvic girdle→shoulder girdle Pseudohypertrophy (lower leg muscle enlargement with weakness) X linked Muscular Dystrophy Clinical Course

HF, arrhythmia Cognitive impairment Mental retardation Death: Respiratory insufficiency Pulmonary infection Cardiac decompensation X linked Muscular Dystrophy

BMD Later stage than DMD Onset: late childhood/adolescence Slower & variable rate of progression Many have nearly normal life span Cardiac involvement : frequent X linked Muscular Dystrophy

Gene therapy is being studied for these patients & is still in experimental stage

Myasthenia Gravis Diseases of the Neuromuscular Junction Muscle disease Best defined forms of autoimmune disease Characteristic temporal & anatomic patterns as well as drug response

Diseases of the Neuromuscular Junction Prevalence: 3/100,000 <40: female predominance ≥40: equal prevalence 65%: thymic hyperplasia 15%: thymoma

Pathogenesis ↑ internalization and degradation of receptors Diseases of the Neuromuscular Junction complement fixation and direct injury to post synaptic membrane (−) binding of ACh Autoantibodies against AChR lead to loss of functional AChR at the NMJ by:

Diseases of the Neuromuscular Junction Sensory & autonomic functions are not affected

Diseases of the Neuromuscular Junction M/E Light microscopy: Muscle biopsy usually unrevealing Severe cases: disuse changes with type 2 fiber atrophy may be found IFM: Immune complexes & MAC (C5-C9) along post synaptic membrane

Diseases of the Neuromuscular Junction Clinical Course Weakness begins with extraocular muscles Drooping eyelids (ptosis) Double vision (diplopia) Seek medical attention

Generalized weakness Fluctuating weakness days, hours, minutes intercurrent medical conditions can lead to exacerbations Diseases of the Neuromuscular Junction

Improvement in strength in response to anticholinesterase agents Most useful test on clinical examination

Diseases of the Neuromuscular Junction Respiratory compromise major cause of mortality 95% survive > 5yrs due to improved Rx & better ventilatory support Rx: Anticholinesterase drugs Prednisone Plasmapheresis Thymic resection

Rhabdomyosarcoma Skeletal muscle tumor Most common soft tissue sarcoma of childhood & adolescence (usually <20yrs) Any anatomic location; extremities, head & neck, genitourinary system

Skeletal muscle tumor Histological subclassification Embryonal: (60%) children (<10 yrs) Alveolar: (20%) early to mid adolescence Pleomorphic: (Rare) adults

M/E Skeletal muscle tumor Rhabdomyoblast Eccentric eosinophilic granular cytoplasm rich in thick & thin filaments May be round or elongate(tadpole /strap cells)

Skeletal muscle tumor IHC Ab to myogenic markers (Desmin, MYOD1 and myogenin)

Skeletal muscle tumor Embryonal RMS Types: Sarcoma botryoides Spindle cell & anaplastic variant Soft gray infiltrative mass

Nasal cavity, orbit, middle ear, prostate, paratesticular region Sarcoma Botryoides: walls of hollow mucosal lined structures (nasopharynx, CBD, bladder, vagina) Where the tumor abouts the mucosa of an organ they form a submucosal zone of hypercellulartity ( Cambium Layer ) Skeletal muscle tumor

Tumor cells mimic skeletal muscle at various stages of embryogenesis Sheets of both round & spindled cells in myxoid stroma

Deep musculature of extremities Alveolar Fibrous septae dividing cells in clusters of aggregates creating crude resemblance to pulmonary alveolae In the center cells become dyscohesive; peripheral ones are attached to septae Skeletal muscle tumor

Pleomorphic Numerous large sometimes multinucleated bizzare eosinophillic tumor cells Can resemble other pleomorphic sarcomas histologically

Skeletal muscle tumor Clinical Course Aggressive neoplasm Rx: Surgery Chemotherapy with/without radiotherapy

Prognosis Histologic type & location influence survival: Botryoid : best Anaplastic embryonal, pleomorphic & alveolar: fatal Skeletal muscle tumor