Muscular Diseases Flashcards
Becker’s Muscular Dystrophy
X linked Recessive
Gene: truncated Dystrophin (Xp21) 2.5Mb gene
Loss of function makes cell membrane fragile in both skeletal and cardiac muscle
Proximal Muscle weakness
Fiber damage with compensatory hypertrophy
Muscle atrophy, fibrosis and fat infiltration
Death from respiratory failure or heart failure
Diagnosis: Elevated muscle enzymes in plasma (CK)
Histology: Central nuclei, variable fiber size, fatty
Genetic analysis: dystrophin stain (some dystrophin)
Duchenne’s Muscular Dystrophy
X linked Recessive
Gene: absent Dystrophin (Xp21) 2.5 Mb gene
Loss of function makes cell membrane fragile in both skeletal and cardiac muscle
Dytrophin deficiency: Normally anchors actin to membrane glycoprotein and attached to sarcoglycans-I/M band associated possible role in maintaining membrane integrity w/contraction
Proximal Muscle weakness
Normal milestones at birth-walking delayed and is clumsy and unable to keep up with peers
Weakness/wasting of pelvic muscle leads to Gowers sign
Waddling gait-wheelchair by 12
Fiber damage with compensatory hypertrophy
Muscle atrophy, fibrosis and fat infiltration
Death from respiratory failure or heart failure
Diagnosis: Elevated muscle enzymes in plasma (CK)
Histology: Central nuclei, variable fiber size, fatty
Genetic analysis: dystrophin stain (no dystrophin)
Myotonia
Involuntary spasm or rigidity of a muscle subsequent to a voluntary contraction or irritation
Myotonia Congenita: rare, genetically variable mutation of muscle (ClCl chloride channel)
Myotonic Dystrophies: defective splicing of muscle ClCl channel mRNA caused by nuclear accumulation of CUG or CCUG repeat RNA
Myasthenia Gravis
Autoimmunity to Ach receptors in NMJ
Blockade of receptors leads to receptor internalization and degradation and damage to motor end plate by complement
Decreases motor end plate potential
Leads to fatigue without soreness or burning (no lactic acidosis)
Acquired early/mid life
Associated with thymoma and thymic hyperplasia
Diagnosed by presence of antibodies or from positive effect of Ach esterase inhibition (Tensilon test/edrophonium test)
Characterized by episodic muscle weakness, particularly eyelids and ocular muscles, weakness worse with use and at end of the day
Death due to respiratory failure
Treatment: AChE inhibitors (treat OD with Scopolamine)
Polymyositis
Proximal weakness, develops over weeks and months, elevated CK
Most often involves shoulders
Can’t climb stairs or comb hair
Average age of onset at 37, females more
Pathology: non specific lymphocytic (CD8) invastion of muscle fibers, necrotic fibers invade endomysium
Pathogenesis: cell-mediated immune response against muscle fibers (increased expression of MHC)
Findings: increased CK, +ANA, +anti-jo-1, +anti-SRP, +anti-Mi-2-antibodies
Muscle biopsy: inflammation and necrosis regeneration and fibrosis of muscle fibers
Treatment: corticosteroid
Dermatomyositis
Proximal weakness over weeks to months
Elevated CK, often facial rash
most common inflammatory myopathy in children
Clinical: malar rash, gottron papules on MCP, PIPs and DIPs, heliotrope rash, cracked fingers
increased risk of occult malignancy
Pathology: perifasicular atrophy, perimysial-perivascular inflammation
Pathogenesis: humoral-mediated microangiopathy in muscle vessels with ischemic necrosis of muscle fibers (CD4 invasion of perimysium)
Adult cases can be paraneoplastic
Findings: increased CK, +ANA, +anti-jo-1, +anti-SRP, +anti-Mi-2-antibodies
Muscle biopsy: inflammation and necrosis regeneration and fibrosis of muscle fibers
Treatment: corticosteroid
Mitochondrial Diseases
Multi-sytsem disorder due to respiratory chain defects, variable phenotypes even if identical genotype
Generalized weakness, progressive external ophtalmoplegia is common
Pathology: Ragged red fibers on trichome, Ragged blue fibers on SDH, mitochrondrial paracrystalline inclusions (sensitive not specific) (parking lots)
COX negative ragged red fibers suggest mitochondrial gene defects
COX positive ragged red fibers suggest mitochondrial proliferation
Pathogensis:
Nuclear gene defects: Autosomal
Mutations in genes encoded by nuclear DNA
Leigh’s syndrome (subacute necrotizing encephalopathy), X-linked cardioskeletal myopathy (Barth syndrome), exertional myoglobinuria
Point mutations in genes encoded by nuclear DNA
Mitochondrial gene defects: maternal inheritance
myoclonic epilepsy with ragged red fibers (MERRF)
Leber hereditary optic neuropathy (LHON)
Mitochondrial enchepalopmyopathy with lactic acidosis and stoke-like episodes (MELAS)
Deletions or duplications in mtDNA
Chronic progressive external ophthalmoplegia
Kearns-Sayre syndrome-myopathy with ophthalmoplegia, pigmentary degeneration of retina, complete heart block
Treatment: no effective therapy, nutrition based treatments, variable survival
Pompe’s disease
Glycogen Storage Disease
Clinical: infantile hypotonia, progressive weakness, cardiomegaly, and hepatomegaly, large tongue failure to thrive
Autosomal recessive
Deficient in lysosomal alpha-1,4-glucosidase (acid maltase)
Failure to show rise of serum lactate after exercise due to block of glycolysis
Pathology: vacuolar myopathy with glycogen accumulation within muscle fibers
Strong PAS staining (+ glycogen)
Strong acid phosphatase staining
EM show increased cytoplasmic and membrane bound glycogen
Prognosis/Treatment: variable prognosis:
Pompe’s diesease usually fatal before age 2 (cardiorespiratory failure)
Expensive enzyme replacement therapy
McArdle disease
Glycogen Storage disease
Autosomal recessive
Increase glycogen in muscle but cannot break it down leading to painful muscle cramps, myoglobinuria (red urine) with strenuous exercise and arrhythmia from electrolyte abnormalities
Deficiency in skeletal muscle glycogen phosphorylase (myophosphorylase)
Failure to show rise of serum lactate after exercise due to block of glycolysis
Have fixed mild myopathy but ned to prevent renal failure due to myoglobinuria
Oral sucrose before exercise is beneficial
Werdnig-Hoffman
Age: birth to first 4 months
Location: degeneration of LMNs
Pathogenesis: mutations in SMN1 gene encode a truncated protein
Presentation: expected LMN dysfunction, muscle weakness, hypotonia, muscle wasting and tongue fasciculations “floppy baby”
Gross pathology: atrophy of ventral horns and nerve roots
Microscopic pathology: loss of motor neurons in spinal cord ventral hour and brainstem motor nuclei, muscle biopsy shows neurogenic atrophy
Poliomyelitis
Infects anterior horn neurons in spinal cord causing motor defects and flaccid paralysis
Post polio syndrome can occur after the initial infection up to 20 years later
Fibromyalgia
Etiology unknown
Pathogenesis: proposed amplification of central integration of sensory stimuli
Coexisting affective disorder in 50% of patients (depression or psychosis)
Features: widesperead pain, Fatigue, non restorative sleep, stiffness,, parasthesias, could have headaches and abdominal pain
Pain is more sever in morning and exacerbated by exercise
Criteria: must include left sided pain, right sided pain, pain above wasit, pain below waist, axial skeletal pain and include number of painful areas (symmetrical tender spots 11 of 18)
Evaluation includes somatic symptoms of fatigue
Treatment: Analgesics-NSAIDS, Tramadol, Tricyclic antidepressant, SSRI, Gabapentin
Improve sleep
Relaxation techniques
Stretching and aerobic conditioning
Statin induced myopathy
HMG-CoA reductase inhibitors
1.5% of people on statins develop this
It is unrelated to dose or statin subtype
Proximal muscle weakness
Within weeks to months after starting a statin
CK is increased
Steroid myopathies
Atrophy is predominantly of Type II fibers leadign to proximal muscle weakness and atrophy without pain
Lower extremities more involved
Normal CK
Lambert-Eaton syndrome
Similar presentation to myasthenia gravis
Can distinguish clinically because patients are not repsonsive to choinesterase inhibitors and elecrophysiologic studies show enhanced neurotransmission with repeat stimulation also patients have hyporeflexia or areflexia
Proximal muscles are involved, eyes are usually spared
Pathogenesis: more related to decreased presynaptic function. Autoimmunity to presynaptic calcium channels is possible cause
Most commonly a paraneoplastic syndrome secondary to small cell carcinoma in the lung
Resolves with resection of tumor
Weakness improves throughout the day
Dry mouth, impotence,
Diplopia, ptosis, dysarthia and/or dysphagia due to CN involvement
