Disorders of the NMJ and Skeletal Muscle

Question 1

In general terms, describe how the NMJ works.

Answer 1

1. depolarization of the nerve terminal leads to activation of the VG calcium channels, leading to an influex of calcium into the presynaptic bouton
2. this triggers a release of ACh via exocytosis
3. the ACh diffuses across the cleft and binds to the ACh receptors
4. triggers an inward sodium current leading to depolarization of the muscle endplate
5. triggers the activation of voltage-dependent sodium channels in the troughs of the endplate folds
6. results in muscle contraction

Question 2

What are the antibodies in myasthenia gravis directed against?

Answer 2

post-synaptic nicotinic acetylcholine receptors

but also Muscle Specific Kinase and Lipoprotein-related protein 4

Question 3

Describe the bimodal distribution of MG incidence.

Answer 3

there’s a peak in the 20s-30s and a second peak in the 70s-80s

Question 4

Early-onset MG is more often associated with what? Late-onset MG?

Answer 4

Early-onset more associated with thymic hyperplasia

Late-onset more associated with thymoma

Question 5

Describe the typical presentation of MG.

Answer 5

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

Question 6

What does myasthenic crisis entail?

Answer 6

MG affecting the diaphragm

Question 7

Describe the Edorphonium/Tensilon test for MG.

Answer 7

Tension is an anti-acetylcholinesterase agent - you give it IV and observe the patient for improvement in muscle strength

Question 8

What will repetitive nerve stimulation show in MG?

Answer 8

decremental response (compound muscle action potential response amplitude that falls with successive nerve stimulation)

Question 9

What is the most sensitive clinical test for MG and what’s the characteristic result?

Answer 9

single-fiber electomyograpy with increased jitter (a measure of the variability of NMJ transmission)

Question 10

How is MG treated?

Answer 10

acetylcholinesterase inhibitors, especially pyridostigmine
steroids
immunosuppressive therapy

thymectomy if there’s a thymoma

Question 11

What is the antibody against in Lambert-Eaton?

Answer 11

presynaptic P/Q type- voltage gated calcium channel

Question 12

LE is usually associated with what cancer?

Answer 12

Small-cell lung cancer

Question 13

Describe the typical presentation of LE.

Answer 13

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

Question 14

What will LE show on slow repetitive nerve stimulation? How about with fast repetitive nerve stimulation?

Answer 14

with slow: a decremental response

with fast: an incremental response

Question 15

What medication is the most effective for improving muscle strength in patients with LE?

Answer 15

3,4-diaminopyridine (and may be more effective if used in conjunction with pyridostigmine)

Question 16

What is the mutation in Duchenne musclaar dystrophy and Becker muscular dystrophy?

Answer 16

mutations of the dystrophin gene on the X-chromosome

Question 17

How do Duchenne’s and Becker’s present?

Answer 17

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

Question 18

Is the CK level normal or elevated in Duchenne’s?

Answer 18

elevated - if it’s normal, Duchenne’s is likely not the diagnosis

Question 19

What is the treatment for Duchenne’s and Becker’s?

Answer 19

glucocorticoids are recommended for all

Question 20

What characterizes the limb-girdle muscular dystrophies?

Answer 20

shoulder and hip girdle weakness with relative sparing of the extraocular, pharyngeal and facial muscles

Question 21

Myotonic Dystrophy is the most common inherited skeletal muscle disorder affecting adults. What are the two mutations?

Answer 21

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)

Question 22

Describe the typical presentation of myotonic dystrophy.

Answer 22

Usually weakness and stiffness of DISTAL muscles

action and percussion myotonia are present

proximal weakness develops later in the disease

Question 23

What are some of the systemic findings in myotonic dystrophy?

Answer 23

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

Question 24

Is the CK normal or elevated in myotonic dystrophy?

Answer 24

usually normal, but may be mildly elevated

Question 25

Fascioscapulohumeral muscular dystrophy is the third most common muscular dystrophy after Duchenne’s and myotonic. What’s the genetic defect?

Answer 25

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

Question 26

Describe the typical presentation of Fascioscapulohumeral muscular dystrophy.

Answer 26

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

Question 27

What muscular dystrophy presents with joint contractures (often elbow, ankle and c-spine) PRIOR to the onset of weakness and atrophy?

Answer 27

Emery-Dreifuss Muscular Dystrophy

Question 28

What are the genetic defects in Emery-Dreifuss?

Answer 28

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

Question 29

What is the distribution of weakness in Emery-Dreifuss?

Answer 29

humeroperoneal (biceps, triceps, peroneal and tibial muscles)

Question 30

What is the main cause of morbidity and mortality in Emery-Dreifuss?

Answer 30

cardiac conduction defects - often need pacemakers

Question 31

How will muscular channelopathies present?

Answer 31

with intermittent attacks of weakness (usually in relation to potassium concentrations)

Question 32

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?

Answer 32

lactate and pyruvate

Question 33

What will muscle biopsy show in the mitochondrial myopathies?

Answer 33

ragged red fibers

Question 34

What are the three noninfectious immune-mediated inflammatory myopathies?

Answer 34

polymyositis
dermatomyositis
inclusion body myositis

Question 35

Is the weakness in polymyositis and dermatomyositis proximal or distal? How about in inclusion body?

Answer 35

PM and DM weakness is proximal and symmetric

IBM can be either proximal or distal and is asymmetric

Question 36

Describe the rash associated with dermatomyositis.

Answer 36

purplish discoloration of the eyelids (heliotrope) and popular erythematous scaly lesions over the knuckles called Gottron patches

Question 37

What are some of the extramuscular manifestations in dermatomyositis?

Answer 37

cardiac conduction defects, myocarditis, CHF

interstitial lung disease (esp with anti-jo-1 antibodies)

Question 38

What will muscle biopsy show in polymyositis?

Answer 38

endomysial inflammation with invasion of non-necrotic muscle fibers with CD8+ T cells

Question 39

What will muscle biopsy show in inclusion body myositis?

Answer 39

endomysial inflammation with basophilic rimmed vacuoles

Question 40

What is the mainstay of treatment for the inflammatory myopathies?

Answer 40

corticosteroids for dermatomyositis and polymyositis, but they don’t work in inclusion body