Myasthenia Gravis &
Neuromuscular Junction (NMJ)

  Acetylcholine receptors (AChRs)
    Subunit mutations: α; β; ε; δ
  Neuromuscular junction (NMJ)
    Illustrations: A; B
  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

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 (CMS)
  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, γ
  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 α, δ or ε subunit
              Reduced # & Fast channel: AChR β;δ
              Arthrogryposis: AChR δ subunit
        Cl- channel conversion: AChR α
        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; RAPSN; TPM2
      Recurrent congenital MG: Immune
        Maternal antibodies vs fetal AChRs

Synaptic (NMJ) basal lamina defects
  Acetylcholinesterase deficiency: ColQ; 3p25
  Laminin β2 (LAMB2) deficiency: 3p21
  Laminin α5 (LAMA5) deficiency: 20q13
Postsynaptic NMJ defects: Other
  Desmin: 2q35
  DNM2: 19p13
  LRP4: 11p11
  MACF1: 1p34
  MTM1: Xq28
  MuSK: 9q31
  Plectin deficiency: Plectin; 8q24
  Rapsyn: 11p11
    Digenic with AK9
  Weakness, Apnea & Bulbar Δ: SCN4A; 17q35
  Lethal congenital myopathy: Contactin-1; 12q11
    Arthrogryposis: UNC50; 2q11
    Intellectual Disability: ZC4H2; Xq11
    LCCS6: ZBTB42; 14q32

Presynaptic defects
  Arthrogryposis, Distal 5D: ECEL1; 2q37
  Congenital Myasthenic Gravis (MG)
    Episodic apnea (Infantile)
      ChAT; 10q11
      SLC5A7 (CHT); 2q12
      SLC18A3; 10q11
      SYT2: 1q32
    MG + CNS
      Munc13-1: 19p13
      RPH3A: 12q24
      SNAP25: 20p12
    SLC25A1: 22q11
    VAMP1: 12p13
    Reduced synaptic vesicles & quantal release
    Reduced quantal release
  Episodic ataxia 2: CACNA1A; 19p13

Presynaptic + Postsynaptic defects
  Agrin: 1p36
  Centronuclear myopathies
  Limb-Girdle MG
    Familial: Dok-7; 4p16
    Glycosylation disorders
      ALG14: 1p21
      GMPPB: 3p21
      Limb-Girdle MG + Tubular Aggregates
        CMSTA1: GFPT1; 2p13
        CMSTA2: DPAGT1; 11q23
        CMSTA3: ALG2; 9q22
  Col13A1: 10q22
  MYO9A: 15q23
  PREPL: 2p21
  CHD8: 14q11
    1A; 1B: CHRNA1; 2q31
    2A; 2C: CHRNB1; 17p13
    3A, 3B; 3C: CHRND; 2q33
    4A, 4B; 4C: CHRNE; 17p13
      A = Slow AChRs; Dom
      B = Fast AChRs; Rec
      C = Reduced AChR #s; Rec
  5: COLQ; 3p25
  6: ChAT; 10q
  7A; 7B: SYT2; 1q32
  8: AGRN; 1p
  9: MUSK; 9q31
  10: DOK7; 4p
  11: RAPSN; 11p11
  12: GFPT1; 2p14
  13: DPAGT1; 11q23
  14: ALG2; 9q22
  15: ALG14; 1p21
  16: SCN4A; 17q35
  17: LRP4; 11p12
  18: SNAP25; 20p12
  19: COL13A1; 10q22
  20: SLC5A7 (CHT); 2q12
  21: SLC18A3; 10q11
  22: PREPL; 2p21
  23: SLC25A1; 22q11
  24: MYO9A; 15q23
  25: VAMP1; 12p13

MG, RNS Decrement or Fatigue
  Congenital MG
    Face malform: Rapsyn; 11p11
    Congenital + Acquired MG
    CNM1: DNM2; 12q21
    CNM2: BIN1; 2q14
    CNMX: MTM1; Xq28
    DES: 2q35
    LGMD D1: DNAJB6; 7q36
    PURA: 5q31
    TEFM: 17q11
  Familial Immune
  Ophthalmoplegia + Curare sens
  Pitt-Hopkins: TCF4
  TOR1AP1: 1q25

Myasthenia Gravis: Autoimmune

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

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

Episodic Apnea

CMS6: Congenital MG with Episodic apnea
  Choline acetyltransferase (ChAT) ; Chromosome 10q11.23; Recessive
CMS21: Congenital MG with Episodic apnea 46
  Solute carrier family 18 (Vesicular acetylcholine), Member 3 (SLC18A3; VAChT) ; Chromosome 10q11.23; Recessive

Paucity of Synaptic Vesicles and Reduced Quantal Release: Congenital
CMS5: Endplate Acetylcholinesterase (AChE) Deficiency
  Collagenic Tail of Endplate Ecetylcholinesterase (ColQ) ; Chromosome 3p25.1; Recessive

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

Congenital Myasthenic Syndrome 48
  Laminin α5 (LAMA5) ; Chromosome 20q13.33; Recessive

Slow Acetylcholine Receptor (AChR) Channel Syndromes (SCCMS; CMS3) 57
  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
AChR conversion into Chloride conductance at Positive potentials 50
  Acetylcholine receptor α subunit (CHRNA1) ; Chromosome 2q31.1; Dominant

Abnormal ACh-AChR Interaction: Low-affinity, Fast-channel syndrome
  Acetylcholine receptor ε subunit (CHRNE) ; Chromosome 17p13.2; Recessive
  Acetylcholine receptor α subunit (CHRNA1) ; Chromosome 2q31.1; Dominant

CMS1B: Abnormal ACh-AChR Interaction; Fast-channel syndrome due to Gating abnormality
  AChR, α-subunit (CHRNA1) ; Chromosome 2q31.1; Recessive
CMS1B: Fast-channel MG syndrome with Decreased probability of AChR channel opening 3
  AChR, α-subunit (CHRNA1) ; Chromosome 2q31.1; Recessive

High Conductance & Fast Closure of AChRs: Congenital
CMS2B: Congenital MG, Beta subunit mutation; Fast Channel syndrome + Reduced AChR expression 52
  AChR, β-subunit (CHRNB1) ; Chromosome 17p13.1; Recessive
CMS2C: Congenital MG, Beta subunit mutations; Reduced expression of AChRs & Severe weakness
  AChR, β-subunit (CHRNB1) ; Chromosome 17p13.1; Recessive
CMS3B: Congenital MG, Delta subunit mutations; Fast-channel MG syndrome + Arthrogryposis multiplex congenita 7
  AChR, δ-subunit (CHRND1) ; Chromosome 2q37.1; Recessive
CMS3B: Congenital MG, Delta subunit mutations; Reduced expression of AChRs & Fast channel effects 6
  AChR, δ-subunit (CHRND1) ; Chromosome 2q37.1; Recessive
CMS8: Congenital MG, Agrin mutations 31
  Agrin (AGRN) ; Chromosome 1p36.33; Recessive
CMS9: Congenital MG, MuSK mutations; Reduced expression of AChRs 21
  MuSK ; Chromosome 9q31.3; Recessive
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
Congenital Limb-Girdle MG with Digenic RAPSN & AK9 mutations 47
  Rapsyn (RAPSN) ; Chromosome 11p11.2; Recessive
  Adenylate kinase 9 (AK9) ; Chromosome 6q21; Recessive

CMS15: Familial Myasthenic Syndrome (CMSWTA) 37
  Alg14 UDP-N-Acetylglucosaminyltransferase subunit (ALG14) ; Chromosome 1p21.3; Recessive

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

CMS17: Congenital MG, LRP4 mutations 38
  Low density lipoprotein receptor-related protein 4 (LRP4) ; Chromosome 11p11.2; Recessive
CMS22: Familial Myasthenic Syndrome 39
  Prolyl endopeptidase-like (PREPL) ; Chromosome 2p21; Recessive

CMS: Familial Myasthenic Syndrome 51
  Chromodomain helicase DNA-binding protein 8/Duplin (CHD8) ; Chromosome 14q11.2; Dominant, de novo
CMYO12: Lethal Congenital Myopathy 28
  Contactin-1 (CNTN1) ; Chromosome 12q12; Recessive

Familial Limb-Girdle MG syndromes
Familial MG Syndromes: Other

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
CMS7A: LEMS ± Nonprogressive Motor Neuropathy 40
  Synaptotagmin 2 (SYT2) Chromosome 1q32.1; Dominant, de novo, or Recessive
CMS18: Myasthenia, Cortical hyperexcitability, Ataxia & Intellectual disability 41
  Synaptosomal-associated protein, 25-kD (SNAP25) ; Chromosome 20p12.2; Dominant or de novo
CMS19: Congenital Myasthenic Syndrome 19 43
  Collagen, type XIII, alpha-1 (COL13A1) ; Chromosome 10q22.1; Recessive
CMS24: Congenital Myasthenic Syndrome 24, Presynaptic 44
  Myosin IXA (MYO9A) ; Chromosome 15q23; Recessive
CMS: Congenital Myasthenic Syndrome with Microcephaly & Cortical hyperexcitability 45
  Munc13-1 (UNC13A) ; Chromosome 19p13.11; Recessive
CMS: Congenital Myasthenic Syndrome with Altered Synaptic Vesicle Homeostasis 49
  Rhabphilin 3A (RPH3A) ; Chromosome 12q24.13; 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, ε, γ
  Neuromuscular junction
  Neuromuscular junction disorders
  Neuromuscular junction molecules

Also see: Myosin & related proteins

α-subunit of AChR (CHRNA1): Mutations
  Chromosome 2q31.1
β-subunit of (CHRNB1)
  Chromosome 17p13.1
ε-subunit of AChR (CHRNE)
  Chromosome 17p13.2
Delta subunits of AChR (CHRND)
  Cholinergic receptor, nicotinic, delta (δ) polypeptide (CHRND) ; Chromosome 2q37.1
Gamma subunit 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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