MYASTHENIC SYNDROMES
* Mutations identified in AChR subunits
1. Myasthenia Gravis: Autoimmune
- Clinical Features
- Weakness: Extraocular, Bulbar & Generalized
- Fatigue
- Differential Diagnosis
- Post-Synaptic dysfunction
- Reduced # Acetylcholine Receptors (AChRs)
- Damage to Post-synaptic Membrane
- Diagnostic Testing
- Associated Disorders
- Thymoma in patients older than 30
- Thyroid: Hyper- & Hypofunction
- Medications
- Treatment: AChE inhibitors & Immunosuppression
2. Myasthenic Syndrome (Lambert-Eaton; LEMS): Autoimmune
- Clinical features
- Weakness: Proximal; Improves with brief sustained exercise
- Extraocular muscles rarely involved
- Sensory neuropathy
- Autonomic neuropathy
- Dry mouth & eyes
- Impotence: Males
- Associated CNS syndromes: Ataxia; Encephalopathy
- Treatment: 3,4 diaminopyridine & Immunosuppression
- Presynaptic disorder: Reduced Calcium Channels
- Serum Antibody
- IgG vs P/Q-type Voltage Gated Calcium Channel (Conotoxin w-MVIIC binding; CACNB2)
- Cancer + LEMS: 100%
- No cancer: 91%
- False positives: Hypergammaglobulinemia; Chronic liver disorders; Infections
- Normal: < 3%
- Electrophysiology
- Increment with rapid (50 Hz) RNS or sustained muscle contraction
- Decrement on slow (5 Hz) RNS
- Small CMAP amplitude
- Ca++ channel blockade: P most common; Q often; N minority of cases
- Tumor: Small Cell Lung Cancer
3. Familial Infantile
Chromosome 17p; Recessive
- Clinical features
- Onset: Birth or early childhood
- Weakness: Fluctuating Ptosis; Crises; Respiratory
- Improvement with age
- No myopathy; Normal tendon reflexes
- Treatment
- AChE inhibitors
- ? 3,4 diaminopyridine
- Electrophysiology
- Decrement on 2 to 3 Hz RNS only in weak muscles, after exercise
- Stimulus evokes single CMAP
- Low end-plate potential (EPP) quantal content
- Presynaptic disorder
- Small synaptic vesicles
- ? Reduced acetylcholine resynthesis or repackaging
- Candidate gene: Synaptobrevin 2
4. Paucity of Synaptic Vesicles and Reduced Quantal Release: Congenital
- Clinical features
- Onset: Birth
- Weakness: Bulbar & Limb
- Treatment: AChE inhibitors
- Electrophysiology
- Decrement on RNS
- Reduced EPP quantal release
- Presynaptic defect: Reduced # of Synaptic Vesicles
5. Endplate Acetylcholinesterase (AChE) Deficiency
Autosomal Recessive
- Clinical features
- Onset: Birth to 2 years
- Weakness: Extraocular, Facial & Proximal trunk
- Slow pupillary response to light
- Scoliosis
- Reduced tendon reflexes
- No response to AChE inhibitors
- Synaptic loss of acetylcholinesterase; small presynaptic terminals
- Electrophysiology
- Decrement in all muscles; Not corrected by edrophonium
- Repetitive CMAP response to single stimulus
- Pathology
- AChE deficiency at neuromuscular junctions
- Small motor nerve terminals
- Simplified post-synaptic folds at some NMJs
6. Slow Acetylcholine Receptor (AChR) Channel Syndromes
Autosomal Dominant
- Multiple mutations identified
- a
, b , & e subunits of AChR
- Most in ion pore transmembrane domain (M2) of AChR subunits
- Produce slow AChR ion channel closure
- Also abnormal reopening of AChR
- Reduced # & density of AChR at NMJs
- Enhanced agonist binding affinity of AChR
- Increased AChR channel openings during ACh occupancy
- Decreased desensitization of mutant AChR by ACh
- Most severe with missense introduction of phenylalanine (eL269F or aV249F)
- Other: aT254I; bL262M; eT264P; bV266M
- Other a mutations
- M1 transmembrane domain (aN217K)
Moderate weakness & fatigability
Slows rate of channel closing
Allows multiple reopenings per activation episode
- Extracellular, near ACh binding site (aG153S)
Decreased rate of dissociation of ACh from AChR
Repeated openings with normal open time
Mildest clinical syndrome
? Stabilizes open state
- M2 domain: aV249F: Not facing channel lumen
Increased channel openings in absence of ACh
Prolonged opening in presence of ACh
Increased Ach affinity or AChR in closed state
Enhanced steady-state desensitization
Defects produce cationic overload & degeneration of junctional folds
- Extracellular between M2 & M3: aS269I
? alters coupling between ACh binding & channel gating
- ß subunit: Near channel gate (bL262M)
- More severe weakness
- Increased folding of postsynaptic membrane & # of AChRs
- Clinical features
- Onset: Infant to Adult
- Ophthalmoplegia
- Weakness & Wasting
- Cervical, Scapular, Finger Extensors
- Upper limbs> Lower
- Slow progression
- No response to AChE inhibitors
- Electrophysiology
- Decrement in weak muscles
- Repetitive CMAP response to single stimulus
- Postsynaptic recordings: Slow closure of AChR ion channel
- Pathology
- Type I fiber predominance
- Endplate myopathy with neighboring autophagic vacuoles
- Reduced nerve terminal area
- Treatment
- Quinidine Sulfate: 200 mg tid po
- Serum concentrations: 0.7-2.4 mg/ml.
7. Mutations of epsilon subunit of AChR
Autosomal Recessive
- Genetics
- Most patients compound heterozygotes
- Each patient with one null & one missense mutation
- AChR dysfunction & phenotype correlates with missense mutation
- AChR changes
- Clinical features
- Onset: Congenital
- Weakness: Generalized
- Electrophysiology: Decrement on RNS
- Pathology
- Post-synaptic folding: Normal
- Endplate morphology: Multiple small regions
8. AChR Deficiency and Short Channel Open Time
? Autosomal Recessive; More common in males
- Clinical features
- Onset < 2 years
- Weakness: Extraocular, Facial & Generalized
- Course: Benign; Weakness persists into adulthood
- Response to AChE Inhibitors
- Electrophysiology
- Decrement in facial muscles
- No exhaustion phenomenon
- Short open time of AChR channel
- Muscle
- Postsynaptic reduction in # of AChRs
- Elongated neuromuscular junctions
9. Abnormal ACh-AChR Interaction: Low-affinity, fast-channel syndrome
Autosomal Recessive
Point mutation in e subunit of AChR
- AChR changes
- Mutations in e subunit: P121L; G-8R (Signal peptide); S143L (Glycosylation site)
- P121l mutation causes abnormal AChR # & function
- Reduced affinity of AChR for ACh
- Affinity is mainly reduced in open & desensitized states of AChR
- Decreased rate, # & time of AChR channel openings
- Clinical features
- Congenital
- Weakness: Generalized
- Postsynaptic defect in AChR
- Decrement on RNS
- NMJ anatomy: Normal
- ? response to AChE inhibitors, or 3,4-diaminopyridine
- NMJ morphology: Normal
10. High Conductance & Fast Closure of AChRs: Congenital
- Weakness: Ocular, Neck and patchy Limb
- Postsynaptic defect in AChR channel kinetics
- Decrement in hand muscles post-exercise
- Little response to AChE inhibitors
11. Familial Limb-Girdle Myasthenia
Autosomal Recessive/ Sporadic
- Clinical features
- Onset: Teens
- Weakness: Limb-Girdle; Symmetric; fatiguable
- Normal extra-ocular muscles
- Response to AChE inhibitors
- Decrement on RNS
- Muscle pathology: Tubular aggergates
12. Other Congenital Syndromes
- Reduction in # of AChR at Neuromuscular Junctions
- e
subunit nonsense mutations
Reduced AChR expression
Normal channel function
No channel function
- Other frameshifting mutations
- Many patients are heteroallelic
- Expression of g AChR (immature) @ NMJs: ? compensatory
- Reduction in # of AChR at Neuromuscular Junctions and
Paucity of Secondary Synaptic Clefts
- Presynaptic defects in ACh synthesis, mobilization or storage
- Congenital MG syndrome resembling LEMS
13. Familial immune MG
Autosomal recessive
14. Congenital MG with facial malformations
15.
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8/20/97
Presynaptic