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
  Diagnostic tests

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

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 & FAMILIAL NMJ DISORDERS 2
Congenital MG syndromes: General
  Clinical features
  Molecular localization
  AChRs: Kinetic abnormalities
  Inheritance
    All Recessive except Slow AChR Channels

Postsynaptic NMJ defects: AChR disorders
  AChR subunits: α, β, δ, e
  Kinetic changes in AChR function
    Numbers of AChRs at NMJs: Varied
      Reduced AChR #
        Slow AChR channels: Increased Response to ACh
              Delayed channel closure: AChR mutations
              Repeated channel reopening: AChR mutations
        Fast AChR channels: Reduced Response to ACh
              Mode-switching kinetics: AChR e subunit
              Gating abnormality: AChR α or e subunit
              Low ACh affinity: AChR δ or e subunit
              Reduced expression & fast channel: AChR δ
              Arthrogryposis: AChR δ subunit
        Also see: e 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: e 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
  ALG14: 1p21
  Limb-girdle MG + Tubular aggregates
    CMSTA2: DPAGT1; 11q23
    CMSTA3: ALG2; 9q22
  LRP4: 11p11
  MuSK: 9q31
  Plectin deficiency: Plectin; 8q24
  Rapsyn: 11p11
  Weakness, Episodic apnea & Bulbar Δ: SCN4A; 17q35
  Lethal congenital myopathy: Contactin-1; 12q11
  Arthrogryposis
    Intellectual Disability: ZC4H2; Xq11
    LCCS6: ZBTB42; 14q32

Presynaptic defects
  Arthrogryposis, Distal 5D: ECEL1; 2q37
  Congenital MG
    Episodic apnea (Infantile): ChAT; 10q11
    Lambert-Eaton
      LEMS-like
      SYT2
    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
  Limb-Girdle MG + Tubular Aggregates
    CMSTA1: GFPT1; 2p13
  MG syndrome: PREPL; 2p21

MG or Fatigue: Other hereditary
  Congenital MG
    Facial malformations: Rapsyn; 11p11
    Congenital + Acquired MG
    Other
  Familial immune
  RyR1
  TPM3
  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

Antibodies
Clinical features
Electrophysiology
Epidemiology
Neoplasms
Subgroups
Treatment

Also see
  Congenital LEMS syndrome

LEMS: Increment after exercise


From M Al-Lozi


CONGENITAL MYASTHENIC SYNDROMES

Acetylcholine receptors (AChRs)
  Kinetic abnormalities
  Mutations
Clinical features
Differential diagnosis


CONGENITAL MG SYNDROMES: Clinical features
CONGENITAL & FAMILIAL NMJ DISORDERS2: Molecular differential diagnosis

General: Syndromes differentiated by anatomic location of mutated protein


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


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

Paucity of Synaptic Vesicles and Reduced Quantal Release: Congenital

Acetylcholinesterase
Acetylcholinesterase
A12, Asymmetric
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
  Acetylcholine receptor α subunit ; Chromosome 2q31.1; Dominant
  Acetylcholine receptor β subunit ; Chromosome 17p13.1; Dominant
  Acetylcholine receptor δ subunit ; Chromosome 2q37.1; Dominant
  Acetylcholine receptor ε subunit ; Chromosome 17p13.2; Dominant or Recessive

AChR Deficiency and Short Channel Open Time: Altered Mode-switching Kinetics
  e subunit of AChR; Recessive

Abnormal ACh-AChR Interaction: Low-affinity, fast-channel syndrome
  AChR e subunit; 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: Congenital7
  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

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

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

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

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

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 ; Chromosome 2q31.1; Recessive
  Acetylcholine receptor β subunit ; Chromosome 17p13.1; Recessive
  Acetylcholine receptor δ subunit ; Chromosome 2q37.1; Recessive
  Acetylcholine receptor e subunit ; Chromosome 17p13.2; Recessive
  Rapsyn ; Chromosome 11p11.2; Recessive



Congenital MG syndrome resembling LEMS
LEMS ± Nonprogressive Motor Neuropathy 40
Synaptotagmin 2 (SYT2) Chromosome 1q32.1; Dominant
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

MUTATIONS OF AChR SUBUNITS

Acetylcholine & Acetylcholine Receptors
AChR subunit disorders: α, β, δ, e, γ
Diagrams
  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 (CHRNG)


Also see

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

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10/22/2014