Congenital MG syndromes (CMS)
General
Differential Diagnoses
Clinical
Molecular & Localization
AChRs: Kinetic abnormalities
Inheritance
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
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Postsynaptic NMJ defects: Other
LRP4: 11p11
MACF1: 1p34
MuSK: 9q31
Plectin deficiency: Plectin; 8q24
Rapsyn: 11p11
Digenic with AK9
Weakness, Apnea & Bulbar Δ: SCN4A; 17q35
Lethal congenital myopathy: Contactin-1; 12q11
Arthrogryposis
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
Lambert-Eaton
LEMS-like
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
MTM1
DNM2
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
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