Myasthenia Gravis &
Neuromuscular Junction (NMJ)

  Acetylcholine receptors (AChRs)
  AChR structure
  AChR subunit mutations: α; β; e; δ
  Neuromuscular junction (NMJ)
  Diagnostic tests

  Myasthenia gravis
    Autoimmune myasthenia gravis
    Childhood MG
    Drug-induced MG
    Neonatal MG
      AChR inactivation
    Anti-MuSK antibody positive
    Domestic animals
  Myasthenic syndrome (Lambert-Eaton)
  Snake venom toxins

Synaptic and Post-synaptic
molecules at the NMJ

AChR, epsilon subunit AChR, alpha subunit AChR, beta subunit AChR, delta subunit AChR, alpha subunit Rapsyn Rapsyn Perlecan Plectin Muscle, skeletal, receptor tyrosine kinase Ion Channel Acetylcholine binding site Acetylcholine binding site Acetylcholinesterase Acetylcholine receptors Neural agrin Lrp4 ErbB Receptor
Congenital MG syndromes: General
  Differential Diagnoses
    Molecular & Localization
  AChRs: Kinetic abnormalities
    Recessive: Most
Dominant: Slow AChR Channels
  Muscle pathology

Postsynaptic NMJ defects: AChR disorders
  AChR subunits: α, β, δ, ε
  Kinetic changes in AChR function
    Numbers of AChRs at NMJs: Varied
      Reduced AChR #
        Slow AChR channels: ↑ Response to ACh
              Delayed channel closure: AChR mutations
              Repeated channel reopening: AChR mutations
        Fast AChR channels: ↓ Response to ACh
              Mode-switching kinetics: AChR ε subunit
              Gating abnormality: AChR α or ε subunit
              Low ACh affinity: AChR δ or ε subunit
              Reduced expression & fast channel: AChR δ
              Arthrogryposis: AChR δ subunit
        Also see: ε subunit disorders
      Normal AChR #
            Fast-channel syndromes
              Low ACh-affinity of AChR; AChR ε subunit
              Reduced channel openings: AChR α subunit
            High conductance & Fast closure of AChRs
      Increased AChR #
            Slow AChR channels: AChR subunit β L262M
  No kinetic abnormalities in AChR function
      Reduced Numbers of AChRs at NMJs
        AChR mutations
          Usually: ε subunit: 17p13
          Rarely other subunits: α; 2q24, β; 17p12, δ; 2q33
  Arthrogryposis syndromes
      Multiple pterygium (Escobar): AChR γ-subunit
      Recurrent congenital MG: Immune
        Maternal antibodies vs fetal AChRs

Synaptic (NMJ) basal lamina defects
  Acetylcholinesterase deficiency: ColQ; 3p25
  Laminin β2 (LAMB2) deficiency: 3p21
Postsynaptic NMJ defects: Other
  LRP4: 11p11
  MuSK: 9q31
  Plectin deficiency: Plectin; 8q24
  Rapsyn: 11p11
  Weakness, Episodic apnea & Bulbar Δ: SCN4A; 17q35
  Lethal congenital myopathy: Contactin-1; 12q11
    Intellectual Disability: ZC4H2; Xq11
    LCCS6: ZBTB42; 14q32

Presynaptic defects
  Arthrogryposis, Distal 5D: ECEL1; 2q37
  Congenital MG
    Episodic apnea (Infantile): ChAT; 10q11
      SYT2: 1q32
    Myasthenia + CNS: SNAP25b; 20p12
    Reduced synaptic vesicles & quantal release
    Reduced quantal release
  Episodic ataxia 2: CACNA1A; 19p13

Presynaptic + Postsynaptic defects
  Agrin: 1p36
  Centronuclear myopathies: MTM1; DNM2
  Limb-Girdle MG
    Familial: Dok-7; 4p16
    Glycosylation disorders
      ALG14: 1p21
      Limb-Girdle MG + Tubular Aggregates
        CMSTA1: GFPT1; 2p13
        CMSTA2: DPAGT1; 11q23
        CMSTA3: ALG2; 9q22
  CMS19: Col13A1; 10q22
  MG syndrome: PREPL; 2p21

MG or Fatigue: Other hereditary
  Congenital MG
    Facial malformations: Rapsyn; 11p11
    Congenital + Acquired MG
  Familial immune
  Ophthalmoplegia with curare sensitivity

Myasthenia Gravis: Autoimmune

Posey & Spiller: The Eye and Nervous System, 1906
Fatigue (Ptosis) in a patient with MG

Repetitive nerve stimulation: Decrement

Myasthenic Syndrome (Lambert-Eaton; LEMS): Autoimmune

Clinical features

Also see
  Congenital LEMS syndrome

LEMS: Increment after exercise

From M Al-Lozi


Acetylcholine receptors (AChRs)
  Kinetic abnormalities
Differential diagnosis
  Clinical features
  Cell & Molecular

CONGENITAL & FAMILIAL NMJ DISORDERS 2: Molecular differential diagnosis

General: Syndromes differentiated by anatomic location of mutated protein

CONGENITAL MG SYNDROMES: General types of AChR Kinetic abnormalities & Other disease features

CMS6: Congenital MG with episodic apnea
  Choline acetyltransferase (ChAT) ; Chromosome 10q11.23; Recessive

Paucity of Synaptic Vesicles and Reduced Quantal Release: Congenital

A12, Asymmetric
CMS5: Endplate Acetylcholinesterase (AChE) Deficiency
  Collagenic tail of endplate acetylcholinesterase (ColQ) ; Chromosome 3p25.1; Recessive

Congenital Myasthenic Syndrome 30
  Laminin β2 (LAMB2) ; Chromosome 3p21.31; Recessive

Slow Acetylcholine Receptor (AChR) Channel Syndromes (SCCMS; CMS3)
  Acetylcholine receptor α subunit (CHRNA1) ; Chromosome 2q31.1; Dominant
  Acetylcholine receptor β subunit (CHRNB) ; Chromosome 17p13.1; Dominant
  Acetylcholine receptor δ subunit (CHRND) ; Chromosome 2q37.1; Dominant
  Acetylcholine receptor ε subunit (CHRNE) ; Chromosome 17p13.2; Dominant or Recessive

AChR Deficiency and Short Channel Open Time: Altered Mode-switching Kinetics
  Acetylcholine receptor ε subunit (CHRNE) ; Chromosome 17p13.2; Recessive

Abnormal ACh-AChR Interaction: Low-affinity, fast-channel syndrome
  Acetylcholine receptor ε subunit (CHRNE) ; Chromosome 17p13.2; Recessive

Abnormal ACh-AChR Interaction: Fast-channel syndrome due to Gating abnormality
  Autosomal Recessive

Fast-channel MG syndrome with Decreased probabiltiy of AChR channel opening 3
  Autosomal Recessive

High Conductance & Fast Closure of AChRs: Congenital

Fast-channel MG syndrome with Arthrogryposis multiplex congenita: Congenital 7
  Autosomal Recessive

Congenital MG, Beta subunit mutations: Reduced expression of AChRs & Severe weakness

Congenital MG, Delta subunit mutations with Reduced expression of AChRs and fast channel effects 6

CMS11: Congenital MG, Rapsyn mutations; Reduced expression of AChRs (CMS1E) 8
  Rapsyn ; Chromosome 11p11.2; Recessive

Congenital MG with facial malformations 8
  Rapsyn ; Chromosome 11p11.2; Recessive

CMS9: Congenital MG, MuSK mutations; Reduced expression of AChRs 21
  MuSK ; Chromosome 9q31.3; Recessive

CMS8: Congenital MG, Agrin mutations 31
  Agrin (AGRN) ; Chromosome 1p36.33; Recessive
CMS17: Congenital MG, LRP4 mutations 38
  Low density lipoprotein receptor-related protein 4 (LRP4) ; Chromosome 11p11.2; Recessive

CMS16: Weakness + Episodic apnea & Bulbar dysfunction 19
  Sodium Channel - α subunit (SCN4A) ; Chromosome 17q23.3; ? Dominant

Lethal Congenital Myopathy 28
  Contactin-1 (CNTN1) ; Chromosome 12q12; Recessive

Other Familial MG syndromes

Reduction in number of AChRs at Neuromuscular Junctions
  Acetylcholine receptor α subunit (CHRNA1) ; Chromosome 2q31.1; Recessive
  Acetylcholine receptor β subunit (CHRNB) ; Chromosome 17p13.1; Recessive
  Acetylcholine receptor δ subunit (CHRND) ; Chromosome 2q37.1; Recessive
  Acetylcholine receptor ε subunit (CHRNE) ; Chromosome 17p13.2; Recessive
  Receptor-associated protein of the synapse, 43-kD (RAPSN; Rapsyn) ; Chromosome 11p11.2; Recessive

Congenital MG syndrome resembling LEMS
CMS7: LEMS ± Nonprogressive Motor Neuropathy 40
  Synaptotagmin 2 (SYT2) Chromosome 1q32.1; Dominant
CMS18: Myasthenia, Cortical hyperexcitability, Ataxia & Intellectual disability 41
  Synaptosomal-associated protein, 25-kD (SNAP25) ; Chromosome 20p12.2; Dominant
CMS19: Congenital Myasthenic Syndrome 19 43
  Collagen, type XIII, alpha-1 (COL13A1) ; Chromosome 10q22.1; Recessive
Congenital MG with reduced quantal release by nerve terminals 16
Congenital MG with acquired MG developing in 4th decade 14
Ocular myopathy with curare sensitivity


Acetylcholine & Acetylcholine Receptors
AChR subunit disorders: α, β, δ, e, γ
  Neuromuscular junction
  Neuromuscular junction disorders
  Neuromuscular junction molecules

Also see: Myosin & related proteins

Mutations of alpha subunit of AChR (CHRNA1)
  Chromosome 2q31.1
Mutations of beta subunit of AChR (CHRNB1)
  Chromosome 17p13.1
Mutations of epsilon subunit of AChR (CHRNE)
  Chromosome 17p13.2
Delta subunits of AChR (CHRND)
  Chromosome 2q37.1
Gamma subunits of AChR
  Cholinergic receptor, nicotinic, gamma (γ) polypeptide (CHRNG) ; Chromosome 2q37.1; Recessive

Also see

Return to Myopathy & NMJ Index
Return to Acetylcholine & AChRs
Return to Syndrome Index
Return to Neuromuscular Home Page

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