Chapter 27: Diseases of the NMJ and Skeletal Muscle Flashcards
Disorders of NMJs present with what?
Painless muscle weakness
Myastheina Gravis is associated with autoantibodies against what?
- ACh receptors on post-synaptic membrane (85% cases)
- Muscle-specific receptor tyrosine kinase (15%)
There is a strong association with tht AChR autoantibodies seen in Myathenia Gravis and which abnormalities?
Thymic abnormalities: Thymoma and Thymic hyperplasia
Myasthenia gravis patients with AChR autoantibodies usually present with what signs/sx’s?
- Fluctuating weakness that worsens with exertion and over course of day
- Diplopia** and **ptosis due to involvement of extra-ocular muscles
What electrophysiologic findings help distinguish Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome?
- M.G. = Diminished muscle responses after repeated stimulation
- L.E.M.S = Increased muscle response after repeated stimulation
What is 1st line tx for Myasthenia Gravis and what other tx’s can be used to control the sx’s?
- 1st line = Acetylcholinesterase inhibitors
- Plasmapheresis and immunosuppressives (glucocorticoids, cyclosporine, rituximab) –> ↓ autoAb titers
Lambert-Eaton Myasthenic Syndrome is an autoimmune disorder due to what?
Antibodies block ACh release by inhibiting pre-synaptic Ca2+ channel
50% of Lambert-Eaton Myasthenic Syndrome cases are associated with what underlying condition?
Malignancy; most often small-cell carcinoma of lung
Pt’s with Lambert-Eaton Myasthenic Syndrome typically present with what sx’s?
Weakness of the extremities and autonomic dysfunction
Type II fiber atrophy with sparing of type I fibers is seen with what?
Prolonged corticosteroid therapy or disuse
Clusters or groups of atrophic skeletal muscle fibers are seen in which disorders?
Neurogenic diseases
Regenerating myofibers are rich in what and stain how in H&E stained sections; characteristic nuclei and nucleoli that are seen?
- RNA and stain basophilic
- Enlarged nuclei and prominent nucleoli
Which autoantibody type in Dermatomyositis is associated with prominent Gottron papules and heliotrope rash?
Anti-Mi2 antibodies
Which autoantibody type in Dermatomyositis is associated with interstitial lung disease, non-erosive arthritis, and a rash known as “mechanic’s hands?”
Anti-Jo1 antibodies
Which autoantibody type in Dermatomyositis is associated with paraneoplastic and juvenile cases?
Anti-P155/P140 antibodies
Myofiber atrophy accentuated at the periphery of fascicles known as perfascicular atrophy is seen with what disorder?
Dermatomyositis
Biopsies and immunohistochemical studies of muscle and skin in Dermatomyositis will show deposition of what?
Complement MAC (C5b-9) within capillary beds + infiltrate rich in CD4+ T helper cells
What are the signs and sx’s of dermatomyositis and some complications which may be seen?
- Slow onset symmetric muscle weakness often w/ myalgias affecting the proximal ms. 1st
- 10% of pt’s have dysphagia and another 10% with interstitial lung disease —> can cause death
- Cardiac involvement = common, rarely leads to failure
What is the most common inflammatory myopathy in children and average age of onset?
Juvenile Dermatomyositis; average age 7 y/o
Juvenile Dermatomyositis is more likely to have what findings compared to the adult-type; how does this affect prognosis?
Calcinosis and lipodystrophy; have a better prognosis
Various rashes have been described in Dermatomyositis, but which 2 are the most characteristic?
- Heliotrope rash: Lilac colored discoloration of upper eyelids assoc. w/ periorbital edema
- Gottron papules: scaling erythematous eruption or dusky patches over knuckles, elbows and knees
Which inflammatory myopathy is more associated with perimysial infiltration vs. endomysial infilatration?
- Dermatomyositis = perimysial (CD4+ T cells)
- Polymyositis and Inclusion body myositis = endomysial (CD8+ T cells)
When is the onset of Polymyositis and what are the signs/sx’s; how is it distinguished from Dermatomyositis?
- Adult onset w/ myalgia and weakness; NO cutaneous features
- Symmetrical proximal muscle involvement
When does Inclusion Body Myositis typically present?
- Disease of late adulthood; typically >50 y/o
- Most common cause of inflammatory myopathy in pt’s >65 y/o
What are the typical signs/sx’s of Inclusion Body Myositis?
- Slowly progressive muscle weakness most severe in quadriceps and distal upper extremities; asymmetric
- Dysphagia is not uncommon
What are 4 morphological changes that are specific for Inclusion Body Myositis?
- Abnormal cytoplasmic inclusions, “rimmed vacuoles”
- Tubulofilamentous inclusions in myofibers
- Cytoplasmic inclusions containing beta-amyloid, TDP-43, and ubiquitin
- Endomysial fibrosis and fatty replacement
What is the first-line tx for inflammatory myopathies (i.e., dermatomyositis and polymyositis)?
Corticosteroids
Which drugs are associated with slowly progressive muscle weakness which predominantly affects type I fibers?
Chloroquine and hydroxychloroquine
Ullrich congenital muscular dystophy (UCMD) is due to mutations in what; what is a morphological hallmark?
- Mutations in one of thre collagen VI alpha genes
- Hallmark: mismatched expression of normally co-localized matrix proteins perlecan and collagen VI
How do the type of mutations of Dystrophin differ between Duchenne and Becker muscular dystrophy?
- Duchenne: deletions or frame shift mutations –> total absence
- Becker: synthesis of a truncated version, which retains some function
What will immunohistochemical staining for dystrophin show in Duchenne vs. Becker muscular dystrophy?
- Duchenne: absence of normal sarcolemmal staining pattern
- Becker: shows reduced staining
What morphological changes are seen with disease progression in Duchenne and Becker muscular dystrophy?
Muscle tissue is replaced by collagen and fat cells = Fatty replacement or change”
Where does weakness associated with Duchenne muscular dystrophy begin and how does it progress?
- Begins in pelvic girdles —> extends to shoulder girdles
- Pseudohypertrophy of calves often present
- Wheel-chair bound around age 9.5
Which lab value can aid in the diagnosis of Duchenne and Becker muscular dystrophy?↑↑
↑↑↑ CK
What is a key feature of Myotonic Dystrophy?
Myotonia: sustained involuntary contraction of a group of muscles; can be elicited by percussion on thenar eminence
Myotonic dystrophy is caused by what?
Expansions of CTG triplet repeats in 3’-noncoding region of DMPK gene
How does Myotonic Dystrophy present signs and sx’s?
Gait, then atrophy of facial muscles = ptosis and “hatchet face,” frontal balding, cataracts, cardiomyopathy
What is the triad of findings seen with Emery-Dreifuss Muscular Dystrophy?
1) Slowly progressive humeroperoneal weakness
2) Cardiomyopathy w/ conduction defects
3) Early contractures of the achilles, spine, and elbows
Emery-Dreifuss Muscular Dystrophy is due to mutations in genes that encode what and what is the inheritance of EMD1 and EMD2?
- Genes that encode nuclear lamina proteins
- X-linked = EMD1
- Autosomal dominant = EMD2
Carnitine palmitoyltransferase II deficiency is associated with what pattern of muscle damage?
- Episodic muscle damage with exercise and fasting
- Defect in transport of FFAs —> mitochondria
Milder deficiencies of acid maltase lead to what type of myopathy in adults?
Myopathy preferentially involving respiratory and truncal muscles
Skeletal muscle involvement in Mitochondrial Myopathies can manifest with what findings; involvement of what is common and can be a clue to the diagnosis?
- Weakness + ↑ CKorrhabdomyolysis
- Extraocular muscle involvement = common and clue to dx
- Chronic progressive external opthalmoplegia = common feature
Morphologically what is the most consistent pathologic change seen in skeletal muscle of the Mitochondrial Myopathies; which stain can be used?
- Abnormal aggregates of mitochondria under the sarcolemma producing appearance of “ragged red fibers”
- Trimchrome stain*
Which syndrome due to deletions or duplications in mtDNA is characterized by ophthalmoplegia, pigmentary degeneration of the retina, and complete heart block?
Kearns-Sayre syndrome
Point mutations in mtDNA can lead to which two mitochondrial myopathies?
- Myoclonic epilepsy w/ ragged red fibers
- Leber hereditary optic neuropathy
Wernig-Hoffman (SMA type 1) is due to destruction of what and what is the presentation?
- Destruction of anterior horn cells in the spinal cord
- Onset at birth, floppy baby, death <3 yo
- Muscle weakness of truncal and extremity ms. initially; followed by chewing, swallowing and breathing difficulties
What are the characteristic morphological changes seen with Spinal Muscular Atrophy (SMA)?
Large zones of severely atrophic myofibers mixed with scattered normal sized fibers or hypertrophied myofibers, found individually or in small groups
Missense mutations in CACNA1S (subunit of muscle Ca2+ channel) are the most common cause of what?
Hypokalmemic paralysis
RYR1 mutations are associated with what?
Malignant hyperthermia –> hypermetabolic state: tachycardia + tachypnea + muscle spasms and later hyperpyrexia
