Disorders of the NMJ and Skeletal Muscle Flashcards
In general terms, describe how the NMJ works.
- depolarization of the nerve terminal leads to activation of the VG calcium channels, leading to an influex of calcium into the presynaptic bouton
- this triggers a release of ACh via exocytosis
- the ACh diffuses across the cleft and binds to the ACh receptors
- triggers an inward sodium current leading to depolarization of the muscle endplate
- triggers the activation of voltage-dependent sodium channels in the troughs of the endplate folds
- results in muscle contraction
What are the antibodies in myasthenia gravis directed against?
post-synaptic nicotinic acetylcholine receptors
but also Muscle Specific Kinase and Lipoprotein-related protein 4
Describe the bimodal distribution of MG incidence.
there’s a peak in the 20s-30s and a second peak in the 70s-80s
Early-onset MG is more often associated with what? Late-onset MG?
Early-onset more associated with thymic hyperplasia
Late-onset more associated with thymoma
Describe the typical presentation of MG.
fatigable muscle weakness
ocular involvement is the most common, manifesting as ptosis and diplopia
bulbar weakness manifests as dysarthria and dysphagia
limb weakness is usually proximal and symmetric
What does myasthenic crisis entail?
MG affecting the diaphragm
Describe the Edorphonium/Tensilon test for MG.
Tension is an anti-acetylcholinesterase agent - you give it IV and observe the patient for improvement in muscle strength
What will repetitive nerve stimulation show in MG?
decremental response (compound muscle action potential response amplitude that falls with successive nerve stimulation)
What is the most sensitive clinical test for MG and what’s the characteristic result?
single-fiber electomyograpy with increased jitter (a measure of the variability of NMJ transmission)
How is MG treated?
acetylcholinesterase inhibitors, especially pyridostigmine
steroids
immunosuppressive therapy
thymectomy if there’s a thymoma
What is the antibody against in Lambert-Eaton?
presynaptic P/Q type- voltage gated calcium channel
LE is usually associated with what cancer?
Small-cell lung cancer
Describe the typical presentation of LE.
fatigable proximal weakness (bulbar and ocular symptoms are rare) with autonomic complaints like dry eyes, dry mouth and impotence
the characteristic finding is muscle facilitation: with brief intense exercise, muscle strength increases, but fatigue develops with sustained activity
What will LE show on slow repetitive nerve stimulation? How about with fast repetitive nerve stimulation?
with slow: a decremental response
with fast: an incremental response
What medication is the most effective for improving muscle strength in patients with LE?
3,4-diaminopyridine (and may be more effective if used in conjunction with pyridostigmine)
What is the mutation in Duchenne musclaar dystrophy and Becker muscular dystrophy?
mutations of the dystrophin gene on the X-chromosome
How do Duchenne’s and Becker’s present?
proximal weakness in young boys
Positive Gowers’ sign, pseudohypertrophy of the calf muscles
usually wheel-chair bound by age 12 in Duchenne’s, death usually around 20 2/2 respiratory insufficiency and aspiration
Is the CK level normal or elevated in Duchenne’s?
elevated - if it’s normal, Duchenne’s is likely not the diagnosis
What is the treatment for Duchenne’s and Becker’s?
glucocorticoids are recommended for all
What characterizes the limb-girdle muscular dystrophies?
shoulder and hip girdle weakness with relative sparing of the extraocular, pharyngeal and facial muscles
Myotonic Dystrophy is the most common inherited skeletal muscle disorder affecting adults. What are the two mutations?
autosomal dominant
either an unstable CTG expansion in the CMPK gene or a CCTG expansion in the XNF9 gene
(pathophysiology results from disordered RNA processing)
Describe the typical presentation of myotonic dystrophy.
Usually weakness and stiffness of DISTAL muscles
action and percussion myotonia are present
proximal weakness develops later in the disease
What are some of the systemic findings in myotonic dystrophy?
cataracts, ptosis, arrhythmias, dysphagia, insulin resistance, testicular atrophy and frontal balding
changes in affect, personality and motivation in addition to cognitive dysfunction are also commonly observed
Is the CK normal or elevated in myotonic dystrophy?
usually normal, but may be mildly elevated
Fascioscapulohumeral muscular dystrophy is the third most common muscular dystrophy after Duchenne’s and myotonic. What’s the genetic defect?
loss of several pieces of DNA (the D4Z4 repeats) of the tip of chromosome 4, which leads to an upregulation of the double homeobox-4 gene
Describe the typical presentation of Fascioscapulohumeral muscular dystrophy.
it’s in the name…
you get weakness in the face (facio), scapula, and upper arm, usually asymmetric
will descend to involve the legs over time
What muscular dystrophy presents with joint contractures (often elbow, ankle and c-spine) PRIOR to the onset of weakness and atrophy?
Emery-Dreifuss Muscular Dystrophy
What are the genetic defects in Emery-Dreifuss?
the Emerin gene on the X-chromosome is most common
also autosomal dominant forms from mutations in the lamin A and lamin C genes on chromosome 1
What is the distribution of weakness in Emery-Dreifuss?
humeroperoneal (biceps, triceps, peroneal and tibial muscles)
What is the main cause of morbidity and mortality in Emery-Dreifuss?
cardiac conduction defects - often need pacemakers
How will muscular channelopathies present?
with intermittent attacks of weakness (usually in relation to potassium concentrations)
There are a ton of mitochondrial myopathies, usually accompanied by other systemic manifestations like seizure, stroke, migraine, diabetes, etc. What will be elevated in the serum?
lactate and pyruvate
What will muscle biopsy show in the mitochondrial myopathies?
ragged red fibers
What are the three noninfectious immune-mediated inflammatory myopathies?
polymyositis
dermatomyositis
inclusion body myositis
Is the weakness in polymyositis and dermatomyositis proximal or distal? How about in inclusion body?
PM and DM weakness is proximal and symmetric
IBM can be either proximal or distal and is asymmetric
Describe the rash associated with dermatomyositis.
purplish discoloration of the eyelids (heliotrope) and popular erythematous scaly lesions over the knuckles called Gottron patches
What are some of the extramuscular manifestations in dermatomyositis?
cardiac conduction defects, myocarditis, CHF
interstitial lung disease (esp with anti-jo-1 antibodies)
What will muscle biopsy show in polymyositis?
endomysial inflammation with invasion of non-necrotic muscle fibers with CD8+ T cells
What will muscle biopsy show in inclusion body myositis?
endomysial inflammation with basophilic rimmed vacuoles
What is the mainstay of treatment for the inflammatory myopathies?
corticosteroids for dermatomyositis and polymyositis, but they don’t work in inclusion body
