Myasthenia Gravis & Neuromuscular Junction (NMJ) Disorders

BASIC CONCEPTS   Acetylcholine receptors (AChRs)   AChR structure   AChR subunit mutations: α; β; e; δ   Neuromuscular junction (NMJ)     Normal     Presynaptic     Postsynaptic ACQUIRED NMJ DISORDERS   Botulism   Myasthenia gravis     Autoimmune myasthenia gravis     Childhood MG     Drug-induced MG     Neonatal: Transient MG     Ocular     Anti-MuSK antibody positive     Anti-AChR-antibody-negative     Thymoma     Domestic animals   Myasthenic syndrome (Lambert-Eaton)   Snake venom toxins Synaptic and Post-synaptic molecules at the NMJ

CONGENITAL & FAMILIAL NMJ DISORDERS2   Congenital MG syndromes: General     Clinical features     Molecular localization     AChRs: Kinetic abnormalities   Presynaptic defects     Congenital MG + Episodic apnea (Familial infantile): ChAT; 10q11     Paucity of synaptic vesicles & Reduced quantal release     Congenital Lambert-Eaton-like     Episodic ataxia 2: CACNA1A; 19p13     Reduced quantal release   Synaptic basal lamina defects     Acetylcholinesterase (AChE) deficiency at NMJs: ColQ; 3p25     Laminin β2 (LAMB2) deficiency: 3p21   Postsynaptic defects: AChR disorders; α, β, δ, e subunits     Kinetic abnormalities in AChR function       Reduced Numbers of AChRs at NMJs           Slow AChR channel syndromes: Increased Response to ACh                 Delayed channel closure: AChR mutations                 Repeated channel reopenings: AChR mutations           Fast-channel syndromes: Reduced Response to ACh                 Mode-switching kinetics disorder: AChR e subunit                 Gating abnormality: AChR α or e subunit                 Arthrogryposis: AChR δ subunit           Also see: e subunit disorders       Normal numbers of AChRs at NMJs: Reduced Response to ACh               Fast-channel syndrome: Low ACh-affinity of AChR; AChR e subunit               Fast-channel syndrome: Reduced channel openings; AChR α subunit               High conductance & Fast closure of AChRs       Increased Numbers of AChRs at NMJs               Slow AChR channel syndrome: AChR subunit βL262M     No kinetic abnormalities in AChR function         Reduced Numbers of AChRs at NMJs                 AChR mutations                     Usually: e subunit: 17p13                     Rarely other subunits: α; 2q24, β; 17p12, δ; 2q33     Arthrogryposis syndromes         Recurrent congenital MG: Maternal antibodies vs fetal AChRs         Multiple pterygium syndrome (Escobar): AChR γ-subunit mutations   Postsynaptic defects: Other     Agrin: 1pter     MuSK: 9q31     Plectin deficiency: Plectin; 8q24     Rapsyn: 11p11     Weakness + Episodic apnea & Bulbar dysfunction: SCN4A; 17q35     Limb-girdle MG; Familial: Dok-7; 4p16     Limb-girdle MG + Tubular aggregates     Lethal congenital myopathy: Contactin-1; 12q11   Other hereditary MG syndromes     Congenital MG       Benign congenital MG & Facial malformations: Rapsyn       Congenital + Acquired MG       Other     Familial immune

Posey & Spiller Fatigue (Ptosis) in a patient with MG

Repetitive nerve stimulation: Decrement

Myasthenia Gravis: Autoimmune

• Clinical Features
  • Weakness
    • Extraocular
    • Bulbar
    • Generalized
    • Distal
  • Fatigue
  • Onset age
    • Childhood
    • Adult: Early & Late peaks
• Differential Diagnosis
• Pathophysiology: Post-Synaptic changes
  • Reduced number of Acetylcholine Receptors (AChRs)
  • Damage to Post-synaptic Membrane
  • Small NMJs
• Diagnostic Testing
  • Tensilon
  • Serum Antibodies
    • IgG vs AChR
    • IgG vs MuSK
    • Anti-Striational
      • Thymoma associations
      • Titin
      • Ryanodine receptor
    • Other
  • Repetitive Nerve Stimulation (RNS): Decrement
    • Test proximal & facial muscles
  • Single fiber EMG: Increased jitter
• Variants
  • Adult onset
    • Early
    • Late
  • Childhood onset
    • Arthrogryposis: Recurrent Congenital
    • Neonatal: Transient
  • Ocular
  • Drug-induced
  • Anti-AChR-Ab-Negative: No anti-AChR antibodies
  • Focal weakness
    • Ocular
    • Distal: Hands > Feet
    • Respiratory failure
    • Bulbar
  • Slow channel syndrome: Acquired
  • Brachio-cervical inflammatory myopathies
  • Hereditary component to immune MG
    • MG + Thymic hyperplasia
    • Familial immune MG
  • Animals
• Associations
  • Genetic & HLA types
  • Medications
  • Pregnancy
  • Systemic disorders
  • Thymic pathology
    • Thymoma: Patients older than 30
    • Hyperplasia
  • Thyroid: Hyper- & Hypofunction
• Treatment
  • AChE inhibitors & Immunosuppression
  • Immune disorders: Treatment strategies

Myasthenic Syndrome (Lambert-Eaton; LEMS): Autoimmune

Antibodies Clinical features Electrophysiology Epidemiology Neoplasms Subgroups Treatment Also see   Congenital LEMS syndrome

LEMS: Increment after exercise From M Al-Lozi

• Epidemiology¹⁷
  • Prevalence: 1 in 100,000
  • Sex ratio: Males slightly more common than Female
• Clinical features
  • Onset
    • Age
      • Range = 7 to 80 years
      • Onset younger: No associated neoplasm
      • Childhood: 5%
    • Weakness (82%), especially legs
    • Usually precedes cancer: > 80%
  • Weakness
    • Proximal > Distal
    • Legs (98%) & Arms (82%)
    • Neck (30%)
    • Respiratory (15%): Rarely severe
    • Bulbar: Dysphagia (22% to 56%); Dysarthria (Up to 80%)
    • Improves with: Brief sustained exercise
    • May worsen with: Sustained exercise; Heat or Fever
    • Fatigability (33%)
  • Extraocular muscles
    • Not involved at presentation
    • Rarely involved on examination
    • Occasional ptosis (30% to 50%)
    • Symptomatic diplopia in ~ 40%: Transient
  • Muscle pain: Occasional
  • Sensory neuropathy: Distal; Symmetric
  • Autonomic neuropathy
    • Association stronger with cancer than with LEMS
    • Dryness: Mouth > Eyes
    • Impotence: Males
    • Blurred vision
    • Other (10% to 50%): Bladder; Obstipation; Hypohidrosis
  • Tendon reflexes
    • At rest: Diminished or absent (90%)
    • Reappear after: Brief maximal voluntary contraction; Repeated tendon percussion
  • Associated neurologic syndromes
    • CNS
      • Ataxia (5% to 10%)
      • Encephalopathy
      • More common in paraneoplastic LEMS
      • Anti-Hu syndromes
    • Weight loss (24%)
    • "Viral" prodrome (34%)
  • Exacerbation of LEMS by drugs: Occasional
    • Neuromuscular junction blocking agents (for surgery)
    • Antibiotics: Aminoglycoside; Fluoroquinolone
    • Magnesium
    • Ca⁺⁺-channel blockers
    • IV contrast agents: Iodinated
  • Differences from Myasthenia Gravis¹²
    • LEMS never begins with ocular weakness
    • LEMS usually has weakness in Legs > Arms
• LEMS Subgroups⁵
  • LEMS without neoplasm (SCLC)
    • Epidemiology
      • Male (50%) = Female (50%)
      • Median age: 49.5 years
    • Weakness: More confined to proximal legs
    • Autonomic: Dry mouth
    • Slow progression with normal life expectancy
    • Immunosuppression (Corticosteroids + ..)
      • Improvement in most
      • Continued immunosuppression needed in most
    • Better prognosis with better clinical score at onset
    • No correlation with: Anti-P/Q-VGCC antibody titers; Size of increment on RNS
    • Lymphoma may be detected on follow-up (6%)
    • Associated immunologic disorders
      • Frequency: 27%
      • Common types: Myasthenia gravis; Pernicious anemia; Thyroid;
          Systemic lupus erythematosus; Celiac disease; Vitiligo; Diabetes
    • HLA association: DR3-B8
  • LEMS with neoplasm
    • Epidemiology
      • Male (70%) > Female (30%)
      • Median age: 58 years
      • Positive smoking history
      • Frequency in small cell lung cancer patients: 0.4% to 4%
    • Clinical
      • Progression: More rapid²²
      • Weakness
        • Onset: Proximal legs
        • Common progression: To arms & distal legs
        • Respiratory failure more common
        • Dysarthria
      • Weight loss: More common
      • Autonomic: Dry mouth; Impotence
      • Shortened life expectancy: Probably related to neoplasm
      • CNS: Ataxia more common (9%)
    • Laboratory
      • Associated immunologic disorders: 6%
      • ESR: High
    • Associated neoplasm
      • Especially small cell lung cancer
      • May be less malignant: Long survival more common²³
  • LEMS without anti-(VGCC) antibodies¹³
    • Frequency: 15% of LEMS patients
    • Clinical features: Similar to antibody positive group
    • Less associated small cell lung cancer: 12% vs 60% with antibodies
    • Survival when SCLC present: Shorter that antibody-positive patients
    • Serum IgG reduces quantal content of end plate potentials
• Pathophysiology: Presynaptic disorder
  • Reduced numbers of P/Q Ca⁺⁺ channels on presynaptic terminals
  • Ultrastructure: Active zone particles on presynaptic terminals reduced
  • Physiology
    • Reduced K⁺ stimulated Ca⁺⁺ flux into presynaptic terminals ®
    • Reduced Ca⁺⁺ dependent quantal ACh release
• Serum Antibodies
  • IgG vs Voltage Gated Calcium Channels (VGCC)
    • Frequency in LEMS
      • Overall: 85%
      • Cancer + LEMS: 98%
      • No cancer: 80%
    • More common with decrement at slow stimulation rates
    • False positives: Hypergammaglobulinemia; Chronic liver disorders; Infections
    • Normal population: < 3%
    • Target antigens
      • P/Q-type Ca⁺⁺ channel (85%): α_1A subunit; Especially domains II & IV
      • N-type Ca⁺⁺ channel (35%): ? α_1B subunit
  • Other associated serum antibodies
    • Glutamic acid decarboxylase (24%)
    • Thyroid (21%)
    • Parietal cell (14%)
      
    • Hu (3%)
    • Muscle nicotinic AChR (10%)
    • Synaptotagmin (20%)
    • M1 muscarinic AChRs
    • SOX1 antibodies ²⁷
      • Present
        • LEMS patients with associated Small cell lung neoplasm (64%)
        • IgG vs Voltage Gated Calcium Channels (50%)
      • Not present: LEMS patients without SCLC (0%)
      • Cerebellar staining pattern: Nuclei of Bergmann glia (AGNA)
      • Other associations
        • Hu Ab (32%)
        • Small cell lung cancer only (22%);
        • Voltage-gated K⁺ channel Ab
• Electrophysiology
  • Repetitive nerve stimulation
    • Increment
      • After rapid (50 Hz) RNS, or
      • Sustained muscle contraction
      • Prolonged by cooling
      • Muscles with most increment after 10 sec maximal voluntary contracture
      • Most specific for LEMS
        • > 60% to 100% in several muscles
        • > 400% in one muscle
        • Muscles: Abductor digiti minimi; Abductor policis brevis; Anconeus
    • Decrement on slow (5 Hz) RNS: Especially in small hand muscles
  • Small CMAP amplitude
  • Microphysiology
    • Ca⁺⁺ channel blockade: P most common; Q often; N minority of cases
    • Reduced quantal acetylcholine release from presynaptic nerve terminal
• Tumor
  • Clinical: See LEMS subgroups
  • Frequency of association with neoplasm
    • Overall: 50% to 60%
    • With risk factors: Up to 100%
  • Risk factors: Smoking; Increasing Age (> 50 years)
  • Associated neoplasms
    • Small Cell Lung Cancer
      • Most frequent associated neoplasm
      • Clincial LEMS: 3% to 5% of patients with SCLC
      • Serum IgG binding to VGCC: 10%; 8% to P-type calcium channel
      • Almost all SCLC with LEMS have smoking history
    • Lymphoproliferative: Reticulum-cell sarcoma; T-cell leukemia; Lymphoma; Castleman's disease
    • Other possible associations: Non-small cell lung; Prostate; Thymoma; Merkel cell carcinoma
  • Timing of neoplasm association
    • Usual (80% to 90%): LEMS onset 0.5 to 5 years before neoplasm detected
    • Neoplasm only found in follow-up
      • Frequency: 10%
      • Most commonly: < 1 year; Range 1 to 41 months
  • Work-up: Chest CT or MRI
    • If no neoplasm found at initial evaluation: 3 months, then q 1 year x 5 years later
    • Chest X-ray: Not sensitive
    • FDG-PET: May identify additional cases
• Treatment: Often Beneficial
  • Pharmacologic
    • 3,4 Diaminopyridine: 20 mg tid
    • Compassionate use from Jacobus (Phone: 609-921-7447; Fax: 609-799-1176)
    • ± Pyridostigmine
  • Immunosuppression
    • Anti-T-cell drugs
      • Prednisone
      • Cyclosporine A
    • Plasma Exchange
    • IV Ig
  • Treatment of neoplasm
• Also see: Congenital MG syndrome resembling LEMS
• Experimental model
  • Immunization with extracellular region (S5-S6 linker) of domain III of P/Q Ca⁺⁺ channel¹

CONGENITAL MYASTHENIC SYNDROMES

• Clinical
  • Onset: Often infancy or childhood
  • Later with: Some Slow-channel syndrome & Familial limb-Girdle myasthenia
  • Weakness
    • Ocular; Bulbar; Respiratory; Generalized
    • Wrist & finger extensors: Older patients with Endplate AChE deficiency & Slow-channel syndrome
    • Milder ocular involvement: Endplate AChE deficiency & Slow-channel syndrome
    • Delayed pupil light reflexes: Endplate AChE deficiency
    • Tendon reflexes reduced: Endplate AChE deficiency; Slow-channel syndrome (Severe); Lambert-Eaton CMG
  • Fatigue & Fluctuation of signs: Especially with MG + episodic apnea
  • Episodic apnea in childhood
    • MG + episodic apnea
    • Fast-channel syndromes
    • Rapsyn mutations
    • AChR δ subunit mutation (E381K)
  • Arthrogryposis
    • Recurrent congenital MG: Maternal antibodies vs fetal AChRs
    • Multiple pterygium syndrome (Escobar): AChR γ-subunit mutations
  • Progression
    • Usual: Slow or none in adolescence or adulthood
    • More progression: Slow channel syndrome; Acetylcholinesterase deficiency
• Antibodies vs AChRs: Absent
• Tensilon test: Often positive
  • Negative: Endplate AChE deficiency
• Electrophysiology
  • Decrement on Repetitive nerve stimulation
    • Common at 2Hz stimulation
    • Absent with CMG with episodic apnea when asymptomatic
  • Repetitive CMAP to single stimulus
    • Endplate AChE deficiency
    • Slow-channel syndrome
    • Patients taking high doses of AChE inhibitors
  • Decrement on RNS not corrected by edrophonium: Endplate AChE deficiency
• Morphology
  • NMJ
    • No IgG or complement at NMJs
    • Small endplate regions, Multiple: Slow-channel syndrome; AChR deficiency syndromes
    • Absent AChE staining: Endplate AChE deficiency
    • Reduced numbers of junctional folds in post-synaptic membrane
    • Molecular evaluation of NMJs: AChE, AChR, Agrin, B₂-laminin, Utrophin, Rapsyn
  • Muscle: Type I muscle fiber predominance; Type II muscle fiber atrophy
• Treatment
  • Anti-AChE medications: Not effective in AChE deficiency
  • 3,4-Diaminopyridine: Most effective in Fast-channel syndromes
  • Quinidine: Mainly effective in Slow-channel syndromes

• Presynaptic
  • Defects in evoked release of acetylcholine (ACh) quanta or ACh resynthesis (ChAT mutations)
  • Frequency: 8%
• Synaptic basal lamina
  • Defects caused by mutations in
    • Collagen tail of AChE: Frequency 16%
    • Laminin β2
• Postsynaptic
  • Most caused by mutations in subunits of AChRs
  • Other: Syndromes caused by plectin or rapsyn mutations
  • Frequency: 76%

• Congenital MG with episodic apnea (Familial infantile)
• Paucity of synaptic vesicles & Reduced quantal release
• Reduced quantal release¹⁶
• Congenital Lambert-Eaton-like
• Episodic ataxia 2

• Acetylcholinesterase (AChE) deficiency
• Laminin β2 (LAMB2) deficiency

• Kinetic abnormalities in AChR function
  • Reduced Numbers of AChRs at NMJs
    • Increased Response to ACh: Slow AChR channel syndromes
      • Delayed channel closure*
      • Repeated channel reopenings*
    • Reduced Response to ACh
      • Fast-channel syndrome: Mode-switching kinetics abnormality*
        
      • Fast channel syndrome: Gating abnormality*
    • Also see: e subunit disorders
  • Normal numbers of AChRs at NMJs
    • Reduced Response to ACh
      • Fast-channel syndrome: Low ACh-affinity of AChR*
      • Fast-channel syndrome: Reduced Probability of channel opening*
        
      • High conductance & Fast closure of AChRs
  • Increased Numbers of AChRs at NMJs
    • Slow AChR channel syndrome: βL262M*
• No kinetic abnormalities in AChR function
  • Reduced Numbers of AChRs at NMJs*
    • AChR mutations
      • Usually e subunit
      • Rare: α, β, δ subunit

• Rapsyn mutations: Cause reduced number of AChRs at NMJs
• Plectin deficiency

• Benign congenital MG & Facial malformations
• Congenital MG: Other
• Familial immune
• Limb-girdle MG: Familial

• Slow channel syndromes
  • Inheritance: Dominant; Occasionally recessive
  • Mutations: AChR subunits
  • Channel physiology: Opened for prolonged time
    • Endplate currents: Slow decay
    • Channel opening events: Prolonged
    • Open states: Stabilized
    • Closed states: Destabilized
    • Mechanisms of abnormality
      • AChR Affinity for ACh: Increased
      • AChR channel opening rate (β): Increased
      • AChR channel closing rate (α): Decreased
  • Clinical & Pathology: Slow channel syndromes
• Fast channel syndromes
    l Acetylcholine receptor α subunit ; Chromosome 2q24-q32; Recessive
    l Acetylcholine receptor δ subunit ; Chromosome 2q33-q34; Recessive
    l Acetylcholine receptor e subunit ; Chromosome 17p13-p12; Recessive
  
  
  • Inheritance: Recessive
  • Mutation effects: Loss of function
  • Consequences of fast channel mutation unmasked by null mutation in other allele
  • Channel physiology
    • Endplate currents: Rapid decay
    • Channel opening events: Brief
    • Open states: Destabilized
    • Closed states: Stabilized
    • Mechanisms of abnormality
      • Decreased affinity of AChR for ACh
      • Increased affinity of AChR for ACh with short open times (δ)
      • Decreased AChR channel opening rate (β)
      • Increased AChR channel closing rate (α)
      • Mode switching kinetics of AChR abnormal
  • Specific channel abnormalities: Brief, or reduced, channel activation due to several mechanisms
    • Decreased affinity for ACh
      • eP121L mutation
        • Mutation effect: Reduced affinity for ACh in AChR open state
        • Location
          • Extracellular domain of e subunit
          • Near ACh ligand binding site formed by α & e subunits
        • Physiology: Slowed channel opening
        • Clinical phenotype: Moderately severe MG
      • eD175N mutation
        • Mutation effect: Reduced affinity for ACh in AChR closed state; Impaired gating efficiency
        • Location: Near ACh ligand binding site formed by α & e subunits
      • δE59K mutation
        • Mutation effect: Reduced affinity of AChR for ACh
        • Location: Near ACh ligand binding site formed by α & δ subunits
        • Clinical phenotype: Multiple congenital joint contractures; Neonatal respiratory distress
    • Abnormal channel gating mechanism
      • eN182Y mutation
        • Mutation effect: Increases ACh affinity for the resting closed state
        • Clinical phenotype: Moderately severe MG
      • αV285I mutation
        • Location: M3 transmembrane domain of α subunit
        • Mutation effect: Impaired gating efficiency
        • Clinical phenotype: Mild MG
      • eR311W mutation
      • αA411P mutation
        • Heterogeneous gating kinetics
        • Location: Amphipathic helix of the long cytoplasmic loop
        • Clinical phenotype: Mild to moderate MG
    • Abnormal mode-switching kinetics: e1254ins18 mutation in cytoplasmic loop of e subunit
    • Reduced probability of channel opening after ACh binding
      • αV132L mutation¹⁵
        • Impaired ACh binding to AChRs in the resting closed state
        • Decreasing binding affinity for the second binding step 30-fold
        • Gating efficiency impaired only 2-fold: Similar mutation in δAChR subunit impairs gating
        • Location: Cys-loop domain of α subunit
        • Clinical phenotype: Most severe fast channel MG syndrome
          • Generalized weakness
          • Respiratory failure
    • Fast channel syndrome with arthrogryposis: δ subunit
    • Reduced expression of AChRs with fast channel properties
  • Commonly develop life threatening episodes of apnea in childhood
  • Clinical correlations
    • Mild disease: Abnormal gating efficiency
    • Moderate severity: Unstable channel kinetics
    • Severe disease: Abnormal ACh affinity ± Impaired gating efficiency
  • Pathology
    • May be Normal
    • Reduced numbers of AChRs at NMJs
    • Multiple small endplate regions
  • Treatment
    • 3,4-diaminopyridine
    • Best response when normal numbers of AChRs at NMJs

• Nosology: Other nammes
  • Defect in ACh resynthesis or packaging
  • Familial Infantile Myasthenia
• Gene mutations
  • Often missense
  • Occasionally 1 mutation is frame shifting
  • Most patients compound heterozygotes
  • Turkish families with homozygous I336T¹⁸
• ChAT protein
  • ChAT protein : Normal features
    • Location: Presynaptic nerve terminals
    • Function: Facilitates transfer of acetate to choline; Produces acetylcholine
    • External link: Williams
  • Mutation effects on ChAT protein
    • Kinetic disorders
      • Cause loss of function of ChAT
      • Often produce altered affinity of ChAT for AcCoA
    • Protein expression: Often reduced, but not absent
• Clinical features: Variable
  • Onset
    • Birth, or Early childhood
    • Hypotonia
    • Weakness: Bulbar & Respiratory
    • Gradual improvement
  • Weakness: Episodic rapid exacerbations
    • Onset: Infancy or Childhood
    • Ptosis: Fluctuating
    • Crises
      • Signs: Respiratory failure; Episodic sudden apnea; Weakness; Bulbar dysfunction
      • Precipitated by: Fever; Exertion; Excitement
      • Gradual improvement: Respiratory impairment may persist for weeks
    • Partial or complete recovery after each episode
    • Between episodes
      • Normal, or
      • Moderate myasthenic symptoms: Ptosis; Fatigability
  • Course
    • Improvement with age: Fewer exacerbations
    • Occasional sudden death
  • Tendon reflexes: Normal
  • Other
    • Muscle: No myopathy; Normal muscle bulk
    • Autonomic: Normal
    • CNS: Normal
  • Treatment
    • AChE inhibitors: Prophylactic pyridostigmine
    • ? 3,4 diaminopyridine
    • Availability of emergency ventilatory apparatus (Bag)
    • Apnea monitor
    • Avoid: Aminoglycoside antibiotics; Quinidine
• Electrophysiology¹⁰
  • Decrement with repetitive nerve stimulation
    • Variably present
      • Often not present in normal strength, rested muscles
      • More common during attacks
      • On 2 to 3 Hz RNS: Only in weak muscles
      • Decrement increased after
        • Exercise
        • 10 Hz stimulation of several minutes
      • Slow recovery of CMAP to normal amplitude after RNS finished
    • Corrected by
      • Rest: Improves slowly over > 2 minutes
      • Edrophonium
  • Single stimulus evokes single CMAP
  • CMAP amplitude: Normal at rest; Reduced with 10 Hz RNS for 5 minutes
  • MEPPs
    • Normal in resting muscle
    • Decreased Amplitude after 10 Hz RNS for 5 min: Persists for 10 to 15 minutes
  • End-plate potential (EPP): Quantal size Reduced; Quantal content normal
• Pathology: Presynaptic disorder
  • Probable mechanism: Reduced acetylcholine resynthesis or repackaging in presynaptic terminal
  • Synaptic vesicles
    • Rested muscle: Small synaptic vesicles
    • Stimulation: Increase or no change in size
  • Post-synaptic: Normal number of AChRs; Normal post-synaptic morphology

• Epidemiology: 1 patient reported
• Clinical features
  • Onset: Birth
  • Weakness
    • Bulbar & Limb
    • Ptosis & Face
    • Extraocular movements: Limited in some patients
  • Fatigability
  • Treatment: AChE inhibitors
• Electrophysiology
  • Repetitive nerve stimulation: Decrement
  • Endplate potential (EPP): Quantal content reduced to 20% of normal
  • CMAP amplitude: Normal
• Synaptic morphology
  • Presynaptic nerve terminal
    • Synaptic Vesicles: Reduced in number by 80%
    • Terminal size: Normal
  • Post-synaptic: Normal folds; Normal number of AChRs
• Possible defect: Reduced synthesis or axonal transport of vesicle precursors

Acetylcholinesterase A12, Asymmetric

Endplate Acetylcholinesterase (AChE) Deficiency

• 2nd most common mutated molecule in congenital MG
• Protein: ColQ
  • Collagen tail of asymmetric acetylcholinesterase
  • Proline-rich attachment domain (PRAD) of ColQ binds tetramer of AChE subunits
    • Produces asymmetric AChE: Concentrated at NMJ
  • ColQ tail anchors catalytic AChE subunits to the basal lamina
  • Tail formed by triple helix association of 3 collagen-like strands (ColQ)
• Clinical-Genetic correlations
  • >20 Different mutations described
  • Missense mutations (P59Q; D342E): Milder disease
  • Point mutations ® Stop codons: Severe disease
  • G240X mutation common in Palestinian Arabs
  • Functional effects of mutations differ
    • N-terminal (P59Q) or PRAD region (107del215)
      • Reduced Binding of ColQ to catalytic subunit of AChE
    • More distal mutations
      • Insertion of ColQ into basal lamina: Reduced
      • Formation of asymmetric forms of AChE: Reduced
• Clinical features
  • Onset
    • Birth to 2 years: Variable even with same mutations
    • Weakness: Generalized; Respiratory in some patients
  • Weakness
    • Slow motor milestones
    • Diffuse: Respiratory, Extraocular, Facial, Proximal trunk & Limb
    • Symmetric
    • Severely disabling: Most patients
  • Tendon reflexes: Reduced or Normal
  • Slow pupillary response to light: Some patients
  • Scoliosis: Older patients
  • Tensilon test: May make patient worse
  • Treatment
    • Ephedrine: 50 mg qid²⁴
    • No response to AChE inhibitors
  • Course: May be progressive, stable or improve
  • Variant: Partial AChE deficiency
    • Onset: ~ 6 years
    • Milder weakness
    • Disabling during 2nd decade
  • Variant
    • Mild symptoms in childhood
    • Worsening in 5th decade with severe respiratory insufficiency
    • Mutations
      • Splicing (IVS1-1GtoA): Affects exon encoding proline-rich attachment domain (PRAD)
      • R236X
• Electrophysiology
  • Decrement at 2 Hz RNS
    • In all muscles
    • Not corrected by edrophonium
    • Present in most patients: May develop during childhood
  • Repetitive CMAP response to single stimulus (80%)
    • Especially in well rested muscle
    • Present in all patients: May be absent during infancy
    • Repetitive CMAP is smaller amplitude & decrements faster than first CMAP
  • Microphysiology: Small EPP due to reduced number of immediately releasable quanta
  • No effect of AChE inhibitors on electrophysiological abnormalities
• Pathology: Endplate myopathy
  • AChE deficiency at neuromuscular junctions: Absent asymmetric forms
  • Small presynaptic motor nerve terminals
  • Simplified post-synaptic folds at some NMJs
  • Number of AChRs reduced
  • Schwann cell processes extend into the synaptic cleft

• Epidemiology: Single patient
• Genetics
  • Heterozygous mutations: 1478delG, 4804delC
  • Allelic with: Pierson syndrome (Congenital nephrosis & Ocular defects)
• LAMB2 protein
  • Laminins: Heterotrimeric glycoproteins containing &alpha, &beta & γ chains
  • Location: Basal lamina
  • NMJ laminins: Laminin-4, -9 & -11; All contain β2 chain
  • LAMB2 deficient mice: Defective neuromuscular synapses; Schwann cells intrude in synaptic cleft
• Clinical
  • Neonatal: Episodes of respiratory distress
  • Eyes
    • Pupils: Persistently constricted
    • Ptosis
    • EOM: Limited
    • Myopia: Impaired visual acuity
    • Fundus: Hypoplastic macula
  • Motor
    • Developoment: Delayed
    • Weakness: Proximal
  • Scoliosis
  • Treatments
    • Ephedrine
    • AChE inhibitor: Increased weakness
    • Renal transplant
• Laboratory
  • Nephrotic syndrome: Proteinuria
  • Repetitive nerve stimulation (3 Hz): Decrement
  • Endplate physiology
    • Reduced quantal content of end plate potentials (EPPs) evoked by nerve stimulation at 1 Hz
    • MEPP frequency & amplitudes: Reduced
  • Muscle biopsy
    • General morphology: Non-specific changes
      • Angular muscle fibers: Scattered
      • Type I muscle fiber predominance
    • LAMB2 staining: Absent
    • Neuromuscular junctions (NMJs)
      • Presynaptic
        • Axon terminals: Small size
        • Encasement of nerve endings by Schwann cells
        • Synaptic vesicles: Normal to reduced numbers
      • Primary synaptic cleft
        • Severe widening; Invasion by Schwann cell processes
        • Endplate acetylcholinesterase: Normal
      • Postsynaptic folds: Simplified
      • Endplate area: Reduced

• Genetics: Multiple mutations identified
  • Most in ion pore transmembrane domain (M2) of AChR subunits
    • Different functional effects
      • Slow AChR ion channel closure
      • Abnormal reopening of AChR
      • Enhanced agonist binding affinity of AChR
      • Increased AChR channel openings during ACh occupancy
      • Decreased desensitization of mutant AChR by ACh
    • Reduced number & density of AChRs at NMJs
    • Clinical correlations
      • Most severe with missense introduction of phenylalanine: εL269F ; αV249F
      • Generalized weakness may be present
    • Other mutations: αT254I; βL263M ; εT264P; βV266M ; δS268F
  • Other α subunit mutations
    • M1 transmembrane domain: αN217K
      • Clinical
        • Moderate weakness: Forearm & Face
        • Fatigability
      • Mutation effects
        • Slows rate of channel closing
        • Allows multiple reopenings per activation episode
      • Other M1 mutation: βV229F
    • Extracellular, near ACh binding site: αG153S
      • Decreased rate of dissociation of ACh from AChR
      • Repeated openings with normal open time
      • Mildest clinical syndrome
    • Extracellular: αV156M
      • ? Stabilizes open state
    • M2 domain: αV249F: Not facing channel lumen
      • Increased channel openings in absence of ACh
      • Increased ACh affinity for AChR in closed state
      • Prolonged or repeated opening in presence of ACh
      • Enhanced steady-state desensitization
      • Defects produce cationic overload & degeneration of junctional folds
      • Mutation in corresponding valine to phenylalanine in ε subunit (V259F): Causes slow-channel syndrome
    • Extracellular between M2 & M3: αS269I
      • ? Alters coupling between ACh binding & channel gating
  • βL262M mutation: More severe weakness
    • Near channel gate
    • Increased folding of postsynaptic membrane
    • Increased number of AChRs
  • δS268F mutation⁴
    • Widening of synaptic cleft
    • Accumulation of debris in synaptic cleft
    • Normal post-synaptic morphology
    • AChR #: Mildly reduced
  • εL78P mutation⁹
    • Recessive inheritance
    • Physiology: Prolonged AChR ion channel activations
    • Mutation location: Extracellular region of AChR molecule
    • Disease severity: Mild
  • εL221F mutation
    • Variable penetrance
    • Physiology: Prolonged AChR ion channel activations
    • Mutation location: M1 region of AChR molecule
  • εV259F mutation
    • Clinical: Late walking; Nasal speech; Ptosis; Proximal & face weakness
    • Electrophysiology: RNS decrement (on 2nd study); Abnormal jitter; No repetitive CMAP
    • Muscle pathology: Endplate myopathy; Tubulofilamentous inclusion bodies
    • Mutation in corresponding valine to phenylalanine in α subunit (V249F): Causes severe slow-channel syndrome
• Pathophysiology: General
  • Prolonged opening episodes of AChR channel
  • Activated by exposure to synaptic ACh & Serum choline
  • Cationic overload of junctional sarcoplasm: Causes endplate myopathy with loss of junctional AChR
  • Depolarization block: Due to summation of prolonged endplate potentials
  • Focal activation of caspases 3 & 9 at NMJs²⁰
• Clinical features
  • General: Variable phenotypes
    • Mild: Later onset
    • Severe: Infantile onset
  • Onset: Infant to 7th decade; Typical ~3 years
  • Cranial nerves
    • Often spared in milder cases
    • Ptosis
    • Ophthalmoplegia: More severe cases
    • Facial weakness: Especially eye closure
  • Weakness & Wasting
    • Cervical: Neck flexors
    • Scapular
    • Hand: Thumb abduction; Muscle wasting (Thenar eminence)
    • Forearm Extensors
    • Limbs: Upper > Lower
    • Respiratory: With disease progression; Failure to breathe after anesthetic
  • Fatigability
  • Spinal deformities: With disease progression
  • Progression: Slow; More with earlier onset
• Electrophysiology
  • Repetitive nerve stimulation (75%): Decrement in weak muscles
  • Repetitive CMAP response to single stimulus: Exacerbated by edrophonium
  • Jitter: abnormal
  • Postsynaptic recordings
    • Disorders due to: Slow closure of AChR ion channel
    • Miniature endplate currents: Prolonged & Biexponentially decay
      • Staircase summation
      • Depolarization block during subtetanic stimulation
    • Single channel recordings
      • Dual population of AChR channels: Normal & Prolonged opening episodes
      • Mutant chanels open even in absence of ACh
• Pathology
  • Type I muscle fiber predominance
  • Endplate myopathy
    • Autophagic vacuoles: Regions neighboring NMJ
    • Junctional folds: Severe damage; Similar to Dok-7 mutations
    • Apoptosis: Nuclei at NMJs
    • Reduced nerve terminal area
  • Some patients with
    • Tubular aggregates
    • Tubulofilamentous inclusions
• Treatment
  • Quinidine Sulfate (60%)
    • Dose: 200 mg 3 or 4 times per day; po
    • Serum concentrations 0.7-2.4 μg/ml
    • Mechanism of action: Blocker of open channel AChRs
    • Clinical response: Gradual improvement
  • Fluoxetine (100%): 80 to 120 mg/day
  • AChE inhibitors: No long term response; 50% with some initial response
• Also see: Acquired slow channel syndrome

• Mutations: Heterozygous
  • eC128S
    • Prevents formation of conserved disulfide group in extracellular domain
    • Arrests subunit assembly before formation of AChR pentamers
  • e1254ins18
    • Reduces AChR expression
    • Mutation adds new modes of gating to normal high efficiency
    • Effects of mutation on channel function
      • Slow opening of channels
      • Rapid closing of channels
• Clinical features
  • Onset < 2 years
  • May be More common in males
  • Weakness: Extraocular, Facial & Generalized
  • Course: Benign; Weakness persists into adulthood
  • Treatment: AChE Inhibitors; 3,4 Diaminopyridine
• Electrophysiology
  • Decrement in facial muscles
  • No exhaustion phenomenon
  • Short open time of AChR channel
• Muscle
  • Postsynaptic reduction in number of of AChRs
  • Elongated neuromuscular junctions
  • Simplified post synaptic folds
  • Compensatory increase in expression of γ AChR subunit
• AChR function: Heterozygous eC128S & e1254ins18
  • Some channels with short open times
  • Other channels with long open times: Probably AChRs containing γ, instead of e subunit
  • Mode switching kinetics
    • 2 new AChR modes, both with inefficient gate
    • In both modes channel opens more slowly and closes more rapidly than normal
    • Electrically silent during synaptic response to ACh

• AChR changes
  • Mutations
    • e subunit : P121L; G-8R (Signal peptide); S143L (Glycosylation site); D175N
  • eP121L mutation: Normal number of AChRs at NMJs
  • Reduced affinity of AChR for ACh: In open channel and desensitized states
  • Affinity is mainly reduced in open & desensitized states of AChR
  • Decreased rate, number & time of AChR channel openings
• Microphysiology (Patch clamp)
  • Infrequent (Reduced) AChR openings during ACh occupancy
  • Effects of mutation on channel function
    • Brief AChR activation
    • Resistance to desensitization
• Clinical features
  • Congenital
  • Weakness: Generalized
  • Postsynaptic defect in AChR
  • Decrement on RNS
  • NMJ anatomy: Normal
  • Treatment
    • 3,4-diaminopyridine
    • ? AChE inhibitors (Mestinon)
• NMJ morphology: Normal

• Mutations: Heterozygous
  • α subunit
    • αV285I (M3 domain): Abnormal gating properties
    • αF233V: Low expressor; Null mutation
  • e subunit
    • eR311W: Abnormal gating properties; Slow channel opening speeds agonist dissociation
    • e553del7: Low expressor; Null mutation
• Neuromuscular junction
  • Reduced Number of AChRs at NMJ
  • Some endplate regions have sparse or shallow junctional folds
  • Miniature endplate currents: Brief channel activation episodes
  • Channel properties
    • Slow opening
    • Fast closure
    • Reduced affinity for ACh: 2.5x
  • M3 domain of AChR subunits: Regulates rates of channel opening & closing in volume-dependent manner
• Clinical
  • Onset: Birth; Extraocular muscle paresis
  • Fatigability: Since early childhood
  • Weakness: Face; Neck flexor; Trunk; Limbs
  • Treatment: 3,4 Diaminopyridine + Mestinon

• Mutations: Heterozygous α subunit
  • αV132L (Cys-loop (β-hairpin) domain)
  • α381delC: Low expressor; Null mutation
• Neuromuscular junction
  • Normal number of AChRs at NMJ
  • Endplate ultrastructure normal
  • Miniature endplate currents
    • Brief channel activation episodes
    • Small amplitude
  • AChR properties
    • Opening probability after interaction with ACh reduced
    • Low affinity for ACh
    • Increased resistance to desensitization
  • Cys-loop of AChR subunits: Highly conserved domain
• Clinical
  • Onset: Birth
  • Fatigability: Since early childhood
  • Weakness: Diffuse; Respirator dependent
  • Repetitive nerve stimulation: 25% to 50% decrement
  • Treatment: Partial response to Mestinon

• Weakness: Ocular, Neck and patchy Limb
• Postsynaptic defect in AChR channel kinetics
• Decrement in hand muscles post-exercise
• Little response to AChE inhibitors

• Mutations: Heterozygous δ subunit
  • δ756ins2: Null mutation
  • δE59K
    • Short channel activations: Predict fast decay of endplate currents
    • Dysfunction of fetal & adult AChRs
• Clinical features
  • Reduced fetal movements
  • Birth: Joint contractures, Hand IP joints
  • Weakness
    • Onset: Congenital
    • Cranial nerve: Poor feeding; Ophthalmoplegia; Dysphagia
    • Respiratory failure
    • Distribution: Arms & Legs; Proximal & Distal
  • Fatigue
• Laboratory
  • Tensilon test: Positive
  • SFEMG: Abnormal, increased jitter
• Treatment: Anti-AChE medications
• Other Arthrogryposis syndromes with familial MG
  • Recurrent congenital MG: Maternal antibodies vs fetal AChRs
  • Multiple pterygium syndrome (Escobar): AChR γ-subunit mutations
  • Rapsyn mutations

• Genetics: Compound heterozygosity
  • β1276DelEQE
    • Located in long cytoplasmic loop between transmembrane domains M3 & M4
    • Disrupts interaction between β &δ subunits
    • Impairs AChR assembly
    • Reduces incorporation of AChRs into surface membrane: More AChRs remain in cytoplasm
  • Exon 8 deletion: Abolishes expression of pentameric AChR
• Clinical
  • Onset: Birth
  • Weakness: Severe; Respiratory failure; Poor feeding
  • Repetitive nerve stimulation: Decrement
  • Treatment: Partial response to acetylcholinesterase (AChE) inhibitors
  • Course
    • Static weakness
    • Survival at least through childhood with support of vital functions
• Neuromuscular junction pathology
  • More small endplate regions
  • Endplate regions distributed over 3x increase in muscle fiber surface
  • NMJ ultrastructure
    • Structure: Normal presynaptic & post synaptic
    • Size: Small presynaptic terminals; Small postsynaptic area
  • AChR #: Reduced to 7% of normal
• NMJ physiology
  • AChR channels: 89% normal; 11% with features of fetal AChRs (containing γ subunits)
  • Quantal release by impulse: Normal
  • Miniature endplate potentials (MEPPs): Reduced amplitude
  • AChR opening time: Normal MEPCs

• Mutation: P250Q missense in transmembrane domain 1; Homozygous
• Epidemiology: Saudi Arabian patients
• Clinical
  • Onset
    • Severe weakness at birth
    • Respiratory insufficiency or failure
    • Hypotonia
  • General: Small habitus; Large ears; Micrognathia; High-arched palate
  • Weakness
    • Ophthalmoplegia: Nearly complete
    • Ptosis: Moderate
    • Facial diplegia
    • Bulbar: Markedly weak lingual & masticatory muscles
    • Neck flexion: Very weak
    • Limb muscles: Moderate weakness
  • Improvement with age
• Laboratory
  • Channel disorders
    • Reduced numbers of AChRs at NMJs
      • 16% to 34% of normal
      • Impaired δ/α subunit association during early AChR assembly
    • Fast channel effects: Changes in gating & ACh binding
      • Hindered opening of the doubly occupied closed receptor (A2R)
      • Rapid dissociation of acetylcholine from A2R
      • Fast decaying, low-amplitude endplate currents
      • Abnormally brief channel opening events
      • NOTE: Similar mutations in e-AChR subunit have slow channel effects
    • Presynaptic: Number of quanta released by nerve impulse
      • Low-normal range
      • Differs from high normal range in α, β & e mutations
  • Pathology
    • Multiple large endplate regions on each muscle fiber
    • Some reduction of 2° postsynaptic folds
    • Type II muscle fiber atrophy: Mild
  • Repetitive nerve stimulation: Decrement
  • Treatment: Partial improvement with combined pyridostigmine & 3,4-diaminopyridine
• Other: AChR Delta subunit mutation syndromes

• Nosology: Also see Congenital MG with Facial Malformations
• Mutations in rapsyn: ~45 identified
  • Locations
    • Common mutations
      • N88K: Present in many patients of Western European ethnic origin
      • E-box of RAPSN promoter (-38A to G)
        • Homozygosity in Near-Eastern Jews
        • Marked facial malformations
        • Mild course
    • Tetratricopeptide repeats (TPRs) of rapsyn: Subserve self association; L14P, N88K, 553ins5
    • E-box: Regulate transcriptional activities; -38A to G & -27C to G
    • Other: R164C; L283P
  • Type: Missense & Insertion
  • Action
    • Diminished co-clustering of AChR with rapsyn
    • Normal rapsyn self-association
  • Also cause: Escobar syndrome
• Rapsyn protein
  • 43-kDa postsynaptic protein
  • Function: Clustering of AChRs at the NMJ
    • Rapsyn-dependent clustering may be independent of nerve
    • Effector of neural agrin
    • Nerve-derived agrin acts through MuSK to promote apposition of nerve terminals to AChR clusters
  • Structure
    • Tetratricopeptide repeats (TPRs): Subserve self association; 7 repeats
    • Coiled-coil domain: Binds to AChR
    • RING-H2 domain: Associates with β-dystroglycan; Links rapsyn to subsynaptic cytoskeleton
• Clinical
  • Onset
    • Age: Birth or Infancy
    • Weakness: Ptosis; Respiratory; Bulbar
  • Severity
    • Mild to Severe
    • May vary with same mutation
  • MG at birth: Early onset group
    • May have same mutations as later onset group
    • Prenatal: Reduced fetal movements
    • Motor
      • Hypotonia
      • Weak suck & Cry
      • Delayed motor milestones
    • Ptosis
    • Joint & Skeletal
      • Arthrogryposis: Most patients
      • Palate: High arched
      • Spine: Scoliosis or Lordosis
    • Episodic crises
      • Often with respiratory failure
      • Precipitated by: Infection, fever or no obvious event
    • Less ophthalmoplegia than AChR ε-subunit mutations
  • Childhood:
    • Early: Respiratory failure
    • Improvement with age
    • Walk in 2nd year
    • Reduced contractures
    • Less severe long term disability than AChR ε-subunit mutations with early onset
  • Late childhood & Adult: Late onset group
    • Onset: 13 to 48 years
    • Eyes: Ptosis without ophthalmoparesis
    • Weakness
      • Mild to moderate
      • Diffuse or Proximal
      • Masticatory muscles
      • Face strength may be normal
      • Normal early motor milestones
    • Fatigue
    • Tendon reflexes: Present
    • Mouth (-38A to G mutations): Mandibular prognathism; Malocclusion; High-arched palate; Crowded teeth
  • Course
    • Often benign with anti-AChE treatment
    • Occasional exacerbations: Temporary
    • Rare patient: Death in Childhood
• Laboratory
  • Pathology
    • Type 1 muscle fiber preponderance
    • Decreased staining at NMJs for
      • Rapsyn
      • AChRs: 8% to 48% of control; Less severe reduction than with AChR mutations
    • Normal AChE
    • Postsynaptic morphology
      • NMJ extended over increased length of muscle fiber
      • Increased number of end plate regions
      • Simplified post synaptic membrane: Reduced postsynaptic area & secondary clefts
  • Repetitive nerve stimulation
    • Decrement
      • 50% to 80% of patients
      • Normal: More frequent in
        • Congenital onset patients
        • Muscles with normal strength
      • Abnormal: Most later onset patients
    • Other
      • Decrement after exercise or subtetanic potentiation (10 Hz)
      • SFEMG abnormality: Most patients
  • Post synaptic physiology
    

    From M. Sadeh Congenital MG with Facial Malformations

    • MEPPs: Small
    • AChR function: Normal
    • ACh release: Normal
• Treatment: Combined
  • Anti-AChE medications: Incomplete benefit
  • 3,4 Diaminopyridine: May add to benefit from anti-AChE treatment
• Animal models
  • Zebrafish, Danio rerio
  • Mouse rapsyn knockout
    • Absence of initiation of postsynaptic differentiation

• Nosology: See Congenital MG with rapsyn mutations
• Genetics: -38A to G mutations
• Epidemiology: Inbred Iraqi & Iranian Jews
• Clinical
  • Extraocular
    • Ptosis
    • No ophthalmoplegia
  • Cranial nerves
    • Facial weakness
    • Dysarthria
    • Weak mastication
  • Face
    • Mandibular prognathism
    • Palate: High arched
    • Face: Elongated
  • Treatment: AChE inhibitors
  • Course: Stable & Benign
• Electrophysiology
  • Repetitive nerve stimulation
    • Decrement: Some patients
  • Single fiber EMG: Abnormal jitter

• Epidemiology: Single family
• Genetics: Heteroallelic MuSK mutations
  • Frameshift mutation: c.220insC
  • Missense: V790M
• MuSK protein functions
  • Tyrosine kinase receptor
  • Role in aggregation of molecules in postsynaptic NMJ membrane
    • AChRs
    • ErbB family receptor tyrosine kinases
  • Presynaptic differentiation: Absence leads to aberrant innervation
  • Mutated MuSK protein: Increased degradation rate
• Clinical
  • Onset: Neonatal
  • Motor
    • Respiratory involvement: Episodes during 1st year
    • Bulbar involvement: During childhood
    • Ocular
      • Ptosis
      • Upgaze limitation
    • Weakness
      • Arms > Legs
      • Proximal > Distal
      • Neck extensors
    • Fatigue
  • Course
    • Improvement during childhood
    • Exacerbation during pregnancy
  • Treatment
    • 3,4-diaminopyridine: 50 mg per day
    • No benefit: Acetylcholinesterase inhibitors
• Laboratory
• Pathology
  • Nerve terminals
    • Aberrant branching
    • No 200 kD neurofilament subunits
  • Several AChR patches on surface of single fibers
• Molecular
  • Acetylcholine receptors
    • ε-subunit: Reduced expression at NMJs
    • γ-subunit: Upregulated
  • MuSK: Reduced at NMJs; Increased in perijunctional regions
• Family history: Sibling with congenital MG
  • Neonatal hypotonia
  • Respiratory failure
  • Vocal cord paralysis
  • Death 1.5 years
• Other: Myasthenia gravis with serum IgG binding to MuSK
  • MuSK DNA polymorphisms: Reported in patient suffering from MuSK-seropositive autoimmune myasthenia gravis

• Epidemiology: 1 Swiss family, 2 patients
• Mutation: Homozygous; Gly1709Arg
• Agrin protein
  • Mutant protein: Destabilizes NMJs; Normal binding to α-dystroglycan
• Clinical
  • Onset
    • Age: Early childhood
    • Difficulty running
  • Weakness
    • Severity: Mild
    • Distribution: Face; Limbs
    • Eyes: Ptosis; Normal EOM & Pupils
    • Exacerbations: Menstrual periods; Pregnancy
    • Overall course: Non-progressive
  • No scoliosis or contractures
  • Treatment
    • Ephedrine (50 md/day x 3 days, then 2 mg/kg qAM)
    • Anti AChE drugs: No benefit
    • 3,4-diaminopyridine: Small benefit
• Laboratory
  • RNS
    • 3 Hz: Decrement (10% to 29%)
    • 30Hz: No potentiation
  • EMG: Early recruitment
  • NCV: Single stimuli produce single, normal amplitude CMAPs
  • Pathology: Disorganized NMJs
    • Nerve-terminals: Diameter decrease; Neurofilament destructuring
    • Synaptic gutters: Fragmented

• SCN4A gene mutation
  • Missense: V1442E
  • Associated mutation: Probable polymorphism: S246L
• SCN4A, α-subunit: Other disorders
  • Hyperkalemic periodic paralysis
  • Hypokalemic periodic paralysis
  • Paramyotonia congenita
  • Myotonia Fluctuans
  • Myotonia Permanens
  • Acetzolamide-responsive myotonia
  • Malignant hyperthermia
• Epidemiology
  • One patient described: No family history
• Onset
  • Infancy
  • Episodic respiratory failure
• Clinical
  • Episodic attacks
    • Sudden onset
    • Length: 3 to 30 mintues
    • Weakness: Respiratory failure; Bulbar dysfunction
  • Weakness
    • General: Face; Trunk; Limb
    • Ocular: Ptosis: Limited eye movements
  • Fatigue: Rapid over minutes
  • Skeletal
    • High-arched palate
    • Adduction deformity: Knees; ankles
    • Lumbar lordosis: Increased
  • CNS
    • Mental retardation: ? Related to apneic episodes
• Laboratory
  • Normokalemia
  • CMAP decrement: Up to 85%
    • 10-Hz stimulation for 5 min
    • 50-Hz stimulation for 2 sec
    • 2-Hz stimulation
      • No decrement in rested muscle
      • 50% decrement after 10-Hz conditioning stimuli for 1 min
  • Muscle pathology
    • Type 1 muscle fiber smallness
    • NMJs: Normal presynaptic terminals & Postsynaptic folds
  • MRI: Mild cerebral atrophy
• Micro-electrophysiology
  • AChRs at NMJs: Normal number & function
  • Muscle fiber membrane potential: Normal
  • MEPP amplitude and quantal content of the EPP: Normal
  • Failure of action potential stimulation by normal EPP
    • Depolarization of membrane to -40mV: Fails to trigger action potentials
  • Na channels
    • Normal density
    • Trapping of mutant channels in fast-inactivated state

Lethal Congenital Myopathy

• Nosology: Compton-North congenital myopathy
• Epidemiology: Egyptian family
• Mutation
  • Frameshift
  • Homozygous
  • c.871dupT
• Contactin-1 protein
  • Glycosyl phosphatidylinositol (GPI)-anchored
  • Neural adhesion molecule
    • Immunoglobulin superfamily
  • Ligand: NOTCH1
  • Muscle: Localized to NMJs in normals; Sarcolemmal membrane in dystroglycanopathies
  • Role in neurite growth & establishment and stabilization of synaptic connections
• Clinical
  • Pregnancy: Polyhydramnios; Growth retardation
  • Birth age: 28 to 35 weeks
  • Motor: No spontaneous movements or Intubation needed
  • Muscle mass: Reduced
  • Skeletal
    • Multiple contractures (Arthrogryposis)
    • Simian creases
    • Arachnodactyly with overlapping fingers
    • Camptodactyly
  • Death: Days to Months
• Laboratory
  • CK: Normal
  • Muscle pathology
    • Fiber size: Mild variation
    • Fiber architecture: Internal clear regions
    • Endomysial connective tissue: Normal or Mildly increased
    • Staining: Absent Integrin α7, β2-syntrophin, α-dystrobrevin

• Familial Limb-Girdle Myasthenia ¹¹
    l Dok-7 (C4ORF25) ; Chromosome 4p16.2; Recessive²⁵
  
  • Other Familial Limb-Girdle Myasthenia Syndromes
      l LG-MG with tubular aggregates ; Recessive
      l Sporadic
  • Epidemiology: Dok-7 MG
    • European, South & North American & Indian families
  • Dok-7 mutations
    • Type: Usually frameshift; Occasional missense
    • Location: Common in exon 7, Also exons 2, 3, 4, 5
    • Some mutations are complex: Identifiable only in cloned complementary DNA
    • 19 unrelated families
    • Common in different ethnic origins: European or Indian
  • Dok-7 protein
    • Location: Post-synaptic
    • Required for neuromuscular synaptogenesis & maintenance of NMJs
    • Induces: Activation of MuSK & Clustering of AChRs
    • AChR β-subunit phosphorylation
  • Clinical features
    • Onset age
      • Dok-7
        • Age
          • Common: Birth to 2nd year
          • Range: Birth to 3rd decade
          • Occasional: Decreased fetal movements
        • Hypotonia; Falling; Gait disorder; Weakness
      • Other Familial syndromes: Childhood or Adolescence; Normal at birth
      • Acquired LG myasthenia: Onset 14 to 42 years
    • Weakness
      • Proximal
        • Arms & Legs
        • Trunk & Neck
        • Symmetric
        • Difficulty walking: Waddling gait
      • Respiratory: Common with Dok-7 mutations
      • Face: Weak; Ptosis, may be asymmetric
      • Extra-ocular muscles: Normal
      • Fatiguable: Worse after exercise & emotional events
      • Severity: Variable
        • Mild: Static weakness
        • Severe: Progressive generalized
      • Course
        • Progressive: Especially in severe patients
        • Intermittent exacerbations: Duration days to weeks
    • Other muscle features
      • Muscle wasting
      • Discomfort: Cramps; Pain
    • Skeletal
      • Scoliosis
      • No joint contractures
    • Occasional systemic features
      • Contractures
      • Cardiac repolarization defect
    • Treatment
      • Ephedrine
      • ? AChE inhibitors
        • May benefit or worsen some patients with limb-girdle MG syndromes
        • Dok-7 mutations
          • No long-term benefit
          • May have positive tensilon test
        • No Dok-7 mutations
          • More response to anti-AChE medications
  • Laboratory
    • Serum CK: Normal to Mildly high; 160 to 320
    • Electrophysiology
      • RNS: Decrement
      • SF-EMG: Often increased jitter
      • Muscle fiber irritability: Some patients
    • Muscle pathology
      • Internal nuclei
      • Neuromuscular junctions
        • Small size: Some
        • Post-synaptic folds: Reduced
        • Single or Multiple
        • EM
          • Destruction & remodeling of EPs
          • Degeneration of post-synaptic folds
          • Similar to: Slow channel syndromes
        • Dok-7 protein
          • Dok-7 mutations: Normal or reduced amounts at NMJs
          • May be reduced with AChR mutations
        • AChR function: Normal
        • Presynaptic function: Normal
      • Tubular aggregates: Not present with Dok-7 mutations
  
  
• Familial immune MG
    l Autosomal recessive
  • Epidemiology
    • + Family history in 3% to 5% of MG
    • Most commonly same generation: Sibs or cousins
  • Onset
    • Earlier than nonfamilial autoimmune MG
    • Age 2 to 20 years: Similar clinical features to non-familial adult patients
  • ? More commonly have no anti-AChR antibodies
  • Rule out: Transient neonatal MG; Recurrent congenital arthrogryposis
  
    l Also see
  • Myasthenia gravis with thymus hyperplasia
  • Acquired MG: Genetic Associations
  
  
• Reduction in number of AChRs at NMJs and Paucity of Secondary Synaptic Clefts
  
  
• Presynaptic defects in ACh synthesis, mobilization or storage

• Most common type of congenital MG syndrome
• AChR mutations
  • Often recessive
  • Subunits: Usually e mutations; Occasional α, β, or rarely δ, mutations
  • May be compound heterozygous or homozygous
  • Types
    • Premature termination of translation: Frame shifting; Splice site; Stop codon
    • Missense in signal peptide region (eG-8R)
    • Missense in amino acids needed for assembly of pentameric AChR: eS143L; eC128S; eR147L
    • Missense affecting both AchR expression & kinetics
    • Point mutations in promoter region of subunit gene
  • e subunit nonsense mutations
    • e1101insT
      • Reduced AChR expression
      • Normal channel function
    • e1293insG
      • No channel function
    • Other frameshifting mutations
    • Many patients are heteroallelic
    • Expression of γ AChR (immature) at NMJs: ? Compensatory
• Rapsyn mutations
• Morphology
  • Endplate regions: Increased Number; Distributed over larger surface area of muscle fiber
  • Most junctions: Integrity of post-synaptic membrane folds is preserved
  • Occasional junctions: Endplate regions are simplified & small
  • AChR on junctional folds: Patchy distribution; Reduced Density
• Physiology
  • Reduced amplitiude of miniature endplate potentials & currents
  • High quantal release by nerve impulse: frequent
  • Fetal AChRs at NMJ containing γ instead of adult e AChR subunits
• Clinical features: Variable
  • Severe form
  • Onset: Birth
  • Weakness
    • Diffuse: Ocular; Bulbar; Respiratory; Limbs; Trunk
    • Delayed motor milestones
    • Respiratory insufficiency: Frequent
  • Muscle bulk: Reduced
  • Tendon reflexes: Normal or Reduced
  • Skeletal
    • Facial deformities: Prognathism; Malocclusion
    • Scoliosis
  • Intermediate form
    • Onset: Early childhood
    • Ocular paresis & Ptosis: Onset 1st year
    • Weakness: Diffuse; Moderate disability
    • Fatigue
  • Mild form
  • Normal motor milestones
  • Mild ptosis common
  • Ophthalmoplegia: Partial
  • Motor: Clumsy; Poor running
  • Sensitivity to neuromuscular blocking agents
• Treatment
  • AChE inhibitors
  • 3,4-Diaminopyridine: 1 mg/kg/day in doses q 3 to 5 hours

• Epidemiology: 2 patients reported
• Genetics: Normal CACNA1A gene
• Clinical
  • Onset: Birth
  • Motor development: Delayed; Hypotonia
  • Weakness: Bulbar & limb
  • Mental retardation
• Electrophysiology: Repetitive nerve stimulation
  • Small initial CMAP
  • Rapid stimulation: Increment up to 5-fold
  • Slow stimulation: Decrement
• Neuromuscular junctions
  • AChRs: Normal number
  • MEPPS: Normal amplitude
  • EPP: Small quantal content; Increased after 40 Hz RNS
• 3,4 Diaminopyridine treatment
  • Improves electrophysiologic defects
  • Little clinical benefit

• Onset: Infancy to 5 years
• Clinical
  • Myasthenic symptoms
    • Weakness
    • Extraocular muscles: Normal
  • Cerebellar: Trunk & limb ataxia; Nystagmus
• Electrophysiology
  • Decremental response on 2-Hz stimulation: Not improved by stimulation at higher frequencies
  • Normal first-evoked CMAP
  • Marked decrease in number of quanta released by 1-Hz stimulation
• Treatment: Some patients improve with combined treatment with pyridostigmine & 3,4-DAP

• Epidemiology +
  • Single patient: HLA type DR3-B8-A1
  • Sibling with congenital MG but no acquired disease: Thymectomy performed at 3 years
• Congential MG
  • AChR mutations
    • e-subunit
    • Heteroallelic
    • Truncating: Y15X; 70insG
  • Onset: Birth; Ptosis
  • Slow motor development
  • Weakness
    • Severity: Moderate
    • Distribution: Limb, Ocular & Bulbar
    • Progression: None
  • Laboratory
    • Anti-AChR antibodies: None
    • SF-EMG: Mild jitter
  • Treatment: Anti-AChE agents (Pyridostigmine)
• Acquired MG
  • Onset age: 34 years; After pregnancy
  • Weakness
    • Severe
    • Increasing over 1 year
    • Respiratory failure
  • Laboratory
    • Anti-AChR antibodies: Present; Bind to adult & fetal AChRs
    • SF-EMG: Increased jitter
    • NMJ pathology
      • Reduced number of AChRs
      • Multiple endplate regions on individual muscle fibers
  • Treatment: Immunosuppression

MUTATIONS OF AChR SUBUNITS

• Disorders
  • Slow AChR channel syndromes: Dominant
  • Low-affinity, fast AChR channel syndrome: Recessive
  • Fast channel, gating MG syndrome: Recessive
  • Multiple pterygium syndrome: Recessive

• Disorders
  • Slow channel syndromes: Dominant
  • Congenital myasthenia gravis: Severe; Recessive

• Most common cause of congenital MG syndromes
• Inheritance
  • Recessive: Congenital MG syndromes with
    • AChR Deficiency, Kinetic δ, Low affinity for ACh
    • Slow channel syndrome
  • Dominant: Slow channel syndrome
• Genetics
  • Most patients compound heterozygotes
  • Each patient with one null & one missense mutation
  • AChR dysfunction & phenotype correlates with missense mutation
  • Majority of AChR mutations in congenital MG identified in e subunit.
  • e subunit: Only AChR subunit with null mutations in congenital MG
  • North Africa: 1293insG founder mutation
• AChR changes
  • Abnormal channel open times: Also see Slow channel syndromes
  • Abnormal ACh-AChR interaction: Low-affinity, fast-channel syndrome
  • Reduced AChR expression
    • Postsynaptic reduction in number of AChRs at NMJs
  • Short AChR open time
• Compensation for e subunit loss: Allows some NMJ function & survival of patient
  • γ subunit may be upregulated
  • Mutations between M3 & M4 (e1267delG): Retention of intron 11 in some mRNA transcripts
    • Restores reading frame
    • Production of e subunit at reduced level
    • Partially rescues adult AChR function
• Clinical features
  • Onset: Congenital
  • Weakness: Variable severity
    • Generalized: Proximal & Distal
    • Face
    • Ptosis
    • Ophthalmoplegia
  • Fatigue
• Electrophysiology
  • Decrement on RNS
  • Slow channel syndrome also has repetitive CMAP response to single stimulus
• Pathology
  • Post-synaptic folding: Normal
  • Endplate morphology: Multiple small regions distributed over larger region of muscle fiber
• Variant syndromes
  • Congenital MG with acquired MG developing in 4th decade
  • Dominant families: See Slow channel syndrome
  • North Africa: 1293insG founder mutation²⁹
    • No fetal involvement
    • Moderate hypotonia & oculobulbar involvement
    • Disease course: Mild & Stable
    • Treatment: Good response to cholinesterase inhibitors

• Mutation types: Point mutations; Missense & Truncating
• Genetic correlations: Mutation actions
  • Fast channel syndromes
    • Reduced expression of AChRs with fast channel properties
      • δ subunit mutation (P250Q): Recessive
      • δ subunit mutation (L42P): Fast channel (Short open times); Increased affinity for ACh
      • General features: Reduced AChR expression; Fast channel syndromes
    • Fast channel syndrome with arthrogryposis: Recessive
  • Slow channel syndrome: δS268F; Dominant
  • Disruption of AChR clustering: E381K (Heterozygous with null mutation)²⁶
    • CHRND mutant protein: Reduced binding to rapsyn
    • Early onset: Feeding difficulties
    • Ptosis
    • Weakness: Moderate, General, Proximal > Distal
    • Recurrent episodes of respiratory insufficiency provoked by infections
    • Decrement on 3 Hz stimulation
    • Moderate response to anticholinesterase treatment
  • Nonsense mutations
    • Multiple pterygium syndrome: Lethal; Recessive

• Expressed in fetal, but not adult, muscle
• Disorder: Multiple pterygium syndrome (Escobar)

• Drug- induced myasthenic syndromes
• Patient information