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

Presynaptic defects
  Arthrogryposis, Distal 5D: ECEL1; 2q37
  Congenital MG
    Episodic apnea (Infantile): ChAT; 10q11
    Lambert-Eaton-like
    Reduced synaptic vesicles & quantal release
    Reduced quantal release
  Episodic ataxia 2: CACNA1A; 19p13

Synaptic (NMJ) basal lamina defects
  Acetylcholinesterase deficiency: ColQ; 3p25
  Laminin β2 (LAMB2) deficiency: 3p21

Presynaptic + Postsynaptic defects
  Centronuclear myopathies
  Limb-Girdle MG
    Familial: Dok-7; 4p16
  Limb-Girdle MG + Tubular Aggregates
    CMSTA1: GFPT1; 2p13

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

Postsynaptic NMJ defects: Other
  Agrin: 1p36
  ALG14: 1p21
  Limb-girdle MG + Tubular aggregates
    CMSTA2: DPAGT1; 11q23
    CMSTA3: ALG2; 9q22
  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




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


Repetitive nerve stimulation: Decrement

Myasthenia Gravis: Autoimmune



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
  l Choline acetyltransferase (ChAT) ; Chromosome 10q11.23; Recessive

Paucity of Synaptic Vesicles and Reduced Quantal Release: Congenital

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

Congenital Myasthenic Syndrome30
  l Laminin β2 (LAMB2) ; Chromosome 3p21.31; Recessive


Slow Acetylcholine Receptor (AChR) Channel Syndromes
  l Acetylcholine receptor α subunit ; Chromosome 2q31.1; Dominant
  l Acetylcholine receptor β subunit ; Chromosome 17p13.1; Dominant
  l Acetylcholine receptor δ subunit ; Chromosome 2q37.1; Dominant
  l Acetylcholine receptor ε subunit ; Chromosome 17p13.2; Dominant or Recessive

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

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

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

Fast-channel MG syndrome with Decreased probabiltiy of AChR channel opening3
  l Autosomal Recessive

High Conductance & Fast Closure of AChRs: Congenital

Fast-channel MG syndrome with Arthrogryposis multiplex congenita: Congenital7
  l 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 effects6

Congenital MG, Rapsyn mutations: Reduced expression of AChRs8
  l Rapsyn ; Chromosome 11p11.2; Recessive

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

Congenital MG, MuSK mutations: Reduced expression of AChRs21
  l MuSK ; Chromosome 9q31.3; Recessive

Congenital MG, Agrin mutations31
  l Agrin (AGRN) ; Chromosome 1p36.33; Recessive

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


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


Other Familial MG syndromes
  • Familial Limb-Girdle Myasthenia with Tubular Aggregates (CMSTA) 37
      l ALG2 ; Chromosome 9q22.33; Recessive

  • Familial Myasthenic Syndrome 37
      l ALG14 ; Chromosome 1p21.3; Recessive

  • Familial immune MG
      l Autosomal recessive
      l Also see
  • Reduction in number of AChRs at NMJs and Paucity of Secondary Synaptic Clefts

  • Presynaptic defects in ACh synthesis, mobilization or storage


    Reduction in number of AChRs at Neuromuscular Junctions
      l Acetylcholine receptor α subunit ; Chromosome 2q31.1; Recessive
      l Acetylcholine receptor β subunit ; Chromosome 17p13.1; Recessive
      l Acetylcholine receptor δ subunit ; Chromosome 2q37.1; Recessive
      l Acetylcholine receptor e subunit ; Chromosome 17p13.2; Recessive
      l Rapsyn ; Chromosome 11p11.2; Recessive



    Congenital MG syndrome resembling LEMS
    Congenital MG with reduced quantal release by nerve terminals16
    Congenital MG with acquired MG developing in 4th decade14

    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)
    l Chromosome 2q31.1
    Mutations of beta subunit of AChR (CHRNB1)
    l Chromosome 17p13.1 Mutations of epsilon subunit of AChR (CHRNE)
      l Chromosome 17p13.2 Delta subunits of AChR (CHRND)
      l 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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