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

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 MuSK-accessory specificity component ErbB Receptor
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



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 Presynaptic defects
Synaptic basal lamina defect
Postsynaptic defects

    AChR disorders
    Postsynaptic disorders: Other Other hereditary MG syndromes
* Mutations identified in AChR subunits



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


Congenital MG with episodic apnea
  l Choline acetyltransferase (ChAT) ; Chromosome 10q11.2; Recessive

Paucity of Synaptic Vesicles and Reduced Quantal Release: Congenital

Acetylcholinesterase
Acetylcholinesterase
A12, Asymmetric
Endplate Acetylcholinesterase (AChE) Deficiency
  l ColQ ; Chromosome 3p25; Recessive

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


Slow Acetylcholine Receptor (AChR) Channel Syndromes
  l Acetylcholine receptor α subunit ; Chromosome 2q24-q32; Dominant
  l Acetylcholine receptor β subunit ; Chromosome 17p13.1; Dominant
  l Acetylcholine receptor δ subunit ; Chromosome 2q33-q34; Dominant
  l Acetylcholine receptor ε subunit ; Chromosome 17p13-p12; 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; Autosomal 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-p11.1; Recessive

Congenital MG with facial malformations 8
  l Rapsyn ; Chromosome 11p11.2-p11.1; Recessive

Congenital MG, MuSK mutations: Reduced expression of AChRs21
  l MuSK ; Chromosome 9q31.3-q32; Recessive

Congenital MG, Agrin mutations31
  l Agrin (AGRN) ; Chromosome 1pter-p32; Recessive

Weakness + Episodic apnea & Bulbar dysfunction19
  l Sodium Channel - α subunit (SCN4A) ; Chromosome 17q35; ? Dominant


Lethal Congenital Myopathy 28
  l Contactin-1 (CNTN1) ; Chromosome 12q11-q12; Recessive


Other Familial MG syndromes


Reduction in number of AChRs at Neuromuscular Junctions
  l Acetylcholine receptor α subunit ; Chromosome 2q24-q32; Recessive
  l Acetylcholine receptor β subunit ; Chromosome 17p13.1; Recessive
  l Acetylcholine receptor δ subunit ; Chromosome 2q33-q34; Recessive
  l Acetylcholine receptor e subunit ; Chromosome 17p13-p12; Recessive
  l Rapsyn ; Chromosome 11p11.2-p11.1; 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 2q24-q32
Mutations of beta subunit of AChR (CHRNB1)
l Chromosome 17p12-p11 Mutations of epsilon subunit of AChR (CHRNE)
  l Chromosome 17p13-p12 Delta subunits of AChR (CHRND)
  l Chromosome 2q33-q34
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

References
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