Fascioscapulohumeral Muscular Dystrophy
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autosomal dominant.
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type 1A: deletions from D4Z4 on 4q35.
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type 1B: mutated FSHMD1B.
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morphology: dystropic myopathy with inflammatory infiltrates in muscle.
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presentation: age 10-30yrs, weakness of muscles of face, neck, shoulder girdle.
Oculopharyngeal Muscular Dystrophy
- autosomal dominant
- mutated PABP-2 gene.
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morphology; dystrophic myopathy with rimmed vacuoles in type 1 fibers.
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presentation: onset in mid adult life, ptosis and weakness of extraocular muscles, difficulty swallowing.
Emery-Dreifuss Muscular Dystrophy
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X-linked.
- mutated emerin (EMD1) gene
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morphology: mild myopathic changes, absent emerin.
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presentation: onset 10-20yrs, prominent contractures especially at elbows and ankles.
Congenital Muscular Dystrophies
- autosomal recessive
- three types: MDC1A = type 1a, merosin deficient (laminin alpha 2 gene).
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MDC1B = type 1b, 1q42.
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MDC1c = type 1c, fukutin related protein gene.
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morphology: variable fiber size, extensive endomysial fibrosis.
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presentation: neonatal hypotonia, respiratory insufficiency, delayed motor milestones.
- MDC1B = type 1b, 1q42.
- MDC1c = type 1c, fukutin related protein gene.
Congenital Muscular Dystrophy with CNS Manifestations
- aka Fukuyama type.
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autosomal recessive.
- mutated fukutin.
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morphology: variable muscle fiber size and endomysial fibrosis, CNS malformations (polymicrogyria)
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presentation: neonatal hypotonia and mental retardation.
Congenital Muscular Dystrophy with CNS and Ocular Manifestations
- aka Walker-Warburg type.
- mutated POMT1, POMT2.
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morphology: variable muscle fiber size and endomysial fibrosis, CNS and ocular malformations
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presentation: neonatal hypotonia and mental retardation with cerebral and ocular malformations.
Lipid Myopathies
- abnormalities of carnitine transport system or deficiency of mitochondrial dehydrogenase enzyme systems ⇒ block fatty acid catabolism, muscle lipid accumulation.
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limited ATP generation when exercising ⇒ pain, tightness, myoglobinuria.
- can have cardiomyopathies and fatty liver.
Mitochondrial Myopathies
- oxidative phosphorylation diseases.
- from mutations in nuclear and mitochondrial genes.
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morphology: aggregates of abnormal mitochondria ⇒ irregular muscle fiber contour (ragged red fibers),
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↑ # and abnormalities in shape and size of mitochondria.
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may contain paracrystalline arrays (parking lot inclusions) or alterations in cristae structure.
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presentation: young adults, proximal muscle weakness, severe eye muscle dysfunction. neurologic symptoms, lactic acidosis, cardiomyopathy.
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from mtDNA mutation have maternal inheritance.
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from pt mutations in mtDNA ⇒ myoclonic epilepsy, Leber hereditary optic neuropathy, MELAS.
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from deletions or duplications of mtDNA ⇒ chronic progressive external ophthalmoplegia or Kearns-Sayer syndrome.
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from mutated nuclear DNA = X-linked or autosomal dominant/recessive. subacute necrotizing encephalopathy, exertional myoglobinuria, X-linked cardioskeletal myopathy.
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↑ # and abnormalities in shape and size of mitochondria.
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may contain paracrystalline arrays (parking lot inclusions) or alterations in cristae structure.
presentation: young adults, proximal muscle weakness, severe eye muscle dysfunction. neurologic symptoms, lactic acidosis, cardiomyopathy.
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from mtDNA mutation have maternal inheritance.
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from pt mutations in mtDNA ⇒ myoclonic epilepsy, Leber hereditary optic neuropathy, MELAS.
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from deletions or duplications of mtDNA ⇒ chronic progressive external ophthalmoplegia or Kearns-Sayer syndrome.
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from mutated nuclear DNA = X-linked or autosomal dominant/recessive. subacute necrotizing encephalopathy, exertional myoglobinuria, X-linked cardioskeletal myopathy.
Central Core Disease
- autosomal dominant
- mutation RYR1 gene.
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morphology: cytoplasmic cores slightly eosinophilic and distinct from sarcoplasm. in type I fibers on NADH stain.
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presentation: early onset hypotonia, nonprogressive weakness, skeletal deformities, sometimes malignant hyperthermia.
Nemaline Myopathy
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autosomal dominant or recessive.
- dominant = NEM1-TPM3 gene (tropomysin 3)
- recessive = NEM2-NEB gene (nebulin)
- dominant or recessive = ACTA1 gene (skeletal muscle actin alpha 1)
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morphology: aggregates of nemaline rods (subsarcolemmal spindle-shaped particles), in type I fibers, from alpha-actinin in Z-band. see on Gomori stain.
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presentation: weakness, hypotonia, delayed motor development in childhood (sometimes adults).
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nonprogressive.
- involves proximal limb muscles most.
- can have skeletal abnormalities.
- dominant = NEM1-TPM3 gene (tropomysin 3)
- recessive = NEM2-NEB gene (nebulin)
- dominant or recessive = ACTA1 gene (skeletal muscle actin alpha 1)
- nonprogressive.
- involves proximal limb muscles most.
- can have skeletal abnormalities.
Myotubular Myopathy
- aka centronuclear.
- X-linked, autosomal dominant, autosomal recessive.
- X-linked = MTM1 gene.
- autosomal dominant = MYF6 gene
- autosomal recessive = unknown.
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morphology: abundance of centrally located nuclei involving majority of muscle fibers, in type I fibers with small diameter, can be in type II fibers.
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presentation: X-linked: infancy with hypotonia, poor prognosis.
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autosomal = limb weakness, slowly progressive.
- recessive = intermediate in severity and prognosis.
- X-linked = MTM1 gene.
- autosomal dominant = MYF6 gene
- autosomal recessive = unknown.
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autosomal = limb weakness, slowly progressive.
- recessive = intermediate in severity and prognosis.
Dermatomyositis
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lilac discoloration of upper eyelids and periorbital edema before or with weakness.
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Grotton lesions = scaling, erythematous patches over knuckles, elbows, knees.
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slow onset muscle weakness, bilaterally symmetric, proximal muscles first.
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dysphagia in 1/3.
- may have interstitial lung disease, vasculitis, myocarditis.
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25% have cancer.
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juvenile pts: GI symptoms, 1/3 have calcinosis.
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targets capillaries.
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morphology: perivascular inflammatory infiltrates, scattered necrotic muscle fibers and muscle fiber atrophy at periphery of fascicles from hypoperfusion.
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tx: immunosuppression.
- dysphagia in 1/3.
Polymyositis
- in adults.
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cytotoxic T cell driven myocyte damage
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autoAb against tRNA synthetases.
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slow onset muscle weakness, bilaterally symmetric, proximal muscles first.
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morphology: endomysial inflammation, scattered necrotic muscle fibers, no vascular injury (perifascicular atrophy)
- tx: immunosuppression.
Inclusion Body Myositis
- starts with distal muscle involvement (extensors of knee, flexors of wrist).
- can be asymmetric.
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insidious onset, age > 50 yrs.
- CD8+ T cells present but immunosuppression not effective.
- intracellular deposits of beta-amyloid and hyperphosphorylated tau = abnormal protein folding.
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morphology: endomysial inflammatory infiltrates, rimmed vacuoles (clear cytoplasm with thin rim basophilic material), contain amyloid.
Thyrotoxic Myopathy
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proximal muscle weakness, can precede clinical thyroid dysfunction.
- myofiber necrosis, regeneration, interstitial lymphocytosis.
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hypothyroidism: muscle cramping and slow movements from fiber atrophy, ↑ # internal nuclei, glycogen aggregates.
Ethanol Myopathy
- binge drinking ⇒ acute toxic syndrome of rhabdomyolysis with myoglobulinemia.
- can cause renal failure.
Drug-Induced Myopathies
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Cushing syndrome or corticosteroids ⇒ proximal muscles weakness and atrophy in type II fibers
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chloroquine ⇒ proximal myopathy with autophagic membrane-bound vacuoles and intracellular curvilinear lamellar bodies.
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Statin-induced myopathy in 1-2%.
Myasthenia Gravis
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autoAb against skeletal muscle Ach receptors.
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women < 40 yrs. m=f in elderly.
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pathogenesis: AchR autoAb ⇒ complement fixation and direct postsynaptic membrane damage, accelerate internalization and down-regulation of AchR, or block Ach binding.
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morphology: LM unremarkable, junctional folds reduced or gone at NMJ, ↓ AchR expression.
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Presentation: easy fatigability, ptosis, and diplopia. worsen with repeated stimulation.
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thymic hyperplasia in 65%.
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thymomas in 15%.
- thymic resection can improve it.
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tx: anticholinesterase agents, prednisone, plasmapheresis.
- thymic hyperplasia in 65%.
- thymomas in 15%.
- thymic resection can improve it.
Lambert-Eaton Myasthenic Syndrome