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Table 2 Nomenclature proposals for individual CMS disease entities and mapping to pre-existing classifications

From: A nomenclature and classification for the congenital myasthenic syndromes: preparing for FAIR data in the genomic era

Gene involved Proposed descriptive name OMIM phenotype number and name Treatment options [4, 11] Existing Orphanet name (group level) Names in literature (group level) Names in literature (entity level)
AGRN Congenital myasthenic syndrome due to agrin deficiency caused by pathogenic variants in AGRN 615120: Myasthenic syndrome, congenital, 8; CMS8
Alternative/former titles:
Myasthenic syndrome, congenital, with pre- and postsynaptic defects; CMSPPD
Myasthenic syndrome, congenital, due to agrin deficiency
Salbutamol or ephedrine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes AND ORPHA:98914 Presynaptic congenital myasthenic syndromes • Defects in endplate development and maintenance • Agrin deficiency
ALG14 Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in ALG14 616227: Myasthenic syndrome, congenital, 15; CMS15
Alternative/former titles:
Myasthenic syndrome, congenital, without tubular aggregates; CMSWTA
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine ORPHA:353327 Congenital myasthenic syndromes with glycosylation defect • Limb-girdle-myasthenia with glycosylation deficiency
• CMS due to abnormal glycosylation
• Congenital defects of glycosylation
• Defects in protein glycosylation
• ALG14 myasthenia
ALG2 Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in ALG2 616228: Myasthenic syndrome, congenital, 14; CMS14
Alternative/former titles:
Myasthenic syndrome, congenital, with tubular aggregates 3; CMSTA3
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine ORPHA:353327 Congenital myasthenic syndromes with glycosylation defect • Limb-girdle-myasthenia with glycosylation deficiency
• CMS due to abnormal glycosylation
• Congenital defects of glycosylation
• Defects in protein glycosylation
• ALG2 myasthenia
CHAT Congenital myasthenic syndrome due to endplate choline acetyltransferase deficiency caused by pathogenic variants in CHAT 254210: Myasthenic syndrome, congenital, 6, presynaptic; CMS6
Alternative/former titles:
Myasthenic syndrome, presynaptic, congenital, associated with episodic apnea; CMSEA
Congenital myasthenic syndrome type Ia2, CMS1a2, CMS Ia2,
Myasthenia, familial infantile, FIM,
Myasthenia gravis, familial infantile, 2, FIMG2,
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine ORPHA:98914 Presynaptic congenital myasthenic syndromes • CMS with episodic apnea
• Synthesis and Recycling of Acetylcholine
• Endplate choline acetyltransferase deficiency
• CMS with episodic apnea
CHRNA1 Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNA1 601462: Myasthenic syndrome, congenital, 1a, slow-channel; CMS1a
Alternative/former titles:
Myasthenic syndrome, congenital, type IIA, CMS2a, CMS 2a
Fluoxetine or quinidine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Slow-channel syndrome, SCS
• Kinetic abnormalities of the AChR
 
CHRNA1 Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNA1 608930: Myasthenic syndrome, congenital, 1b, fast-channel; CMS1b
Myasthenic syndrome, congenital, 1b, fast-channel; CMS1b
Pyridostigmine as first line; may benefit from addition of salbutamol / ephedrine or 3,4-diaminopyridine. Avoid β2-adrenergic agonists (fluoxetine / quinidine) ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Fast-channel syndrome, FCS
• Kinetic abnormalities of the AChR
 
CHRNA1 Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNA1 N/A Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine N/A • Primary AChR deficiency  
CHRNB1 Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNB1 616313: Myasthenic syndrome, congenital, 2a, slow-channel; CMS2a Fluoxetine or quinidine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Slow-channel syndrome, SCS
• Kinetic abnormalities of the AChR
 
CHRNB1 Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNB1 N/A Pyridostigmine as first line; may benefit from addition of salbutamol / ephedrine or 3,4-diaminopyridine. Avoid β2-adrenergic agonists (fluoxetine / quinidine) N/A • Fast-channel syndrome, FCS
• Kinetic abnormalities of the AChR
 
CHRNB1 Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNB1 616314: Myasthenic syndrome, congenital, 2c, associated with acetylcholine receptor deficiency; CMS2c Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Primary AChR deficiency  
CHRND Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRND 616321: Myasthenic syndrome, congenital, 3a, slow-channel; CMS3a Fluoxetine or quinidine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Slow-channel syndrome, SCS
• Kinetic abnormalities of the AChR
 
CHRND Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRND 616322: Myasthenic syndrome, congenital, 3b, fast-channel; CMS3b Pyridostigmine as first line; may benefit from addition of salbutamol / ephedrine or 3,4-diaminopyridine. Avoid β2-adrenergic agonists (fluoxetine / quinidine) ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Fast-channel syndrome, FCS
• Kinetic abnormalities of the AChR
 
CHRND Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRND 616323: Myasthenic syndrome, congenital, 3c, associated with acetylcholine receptor deficiency; CMS3c Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Primary AChR deficiency  
CHRND Congenital myasthenic syndrome due to defects in acetylcholine receptor clustering caused by pathogenic variants in CHRND N/A Pyridostigmine N/A   
CHRNE Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNE 605809: Myasthenic syndrome, congenital, 4a, slow-channel; CMS4a
Alternative/former titles:
Congenital myasthenic syndrome type Ia1, CMS1a1, CMS Ia1
Fluoxetine or quinidine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Slow-channel syndrome, SCS
• Kinetic abnormalities of the AChR
 
CHRNE Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNE 616324: Myasthenic syndrome, congenital, 4b, fast-channel; CMS4b Pyridostigmine as first line; may benefit from addition of salbutamol / ephedrine or 3,4-diaminopyridine. Avoid β2-adrenergic agonists (fluoxetine / quinidine) ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Fast-channel syndrome, FCS
• Kinetic abnormalities of the AChR
 
CHRNE Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNE 608931: Myasthenic syndrome, congenital, 4c, associated with acetylcholine receptor deficiency; CMS4c
Alternative/former titles:
Myasthenic syndrome, congenital, type ID; CMS1D, CMS ID, Myasthenia, familial infantile, 1, FIM1,
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Primary AChR deficiency  
CHRNE Congenital myasthenic syndrome with kinetic defect due to reduced ion channel conductance caused by pathogenic variants in CHRNE N/A Pyridostigmine N/A • Kinetic abnormalities of the AChR
• Reduced ion channel conductance
 
COL13A1 Congenital myasthenic syndrome due to collagen 13 defects caused by pathogenic variants in COL13A1 616720: Myasthenic syndrome, congenital, 19; CMS19 Salbutamol / ephedrine as first line; may benefit from addition of 3,4-diaminopyridine. Pyridostigmine likely ineffective. ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Synaptic and basal-lamina associated syndromes
• Synaptic space
 
COLQ Congenital myasthenic syndrome due to endplate acetylcholinesterase deficiency caused by pathogenic variants in COLQ 603034: Myasthenic syndrome, congenital, 5; CMS5
Alternative/former titles:
Endplate acetylcholinesterase deficiency; EAD
Engel congenital myasthenic syndrome
Myasthenic syndrome, congenital, Engel type
Congenital myasthenic syndrome type IC, CMS1c, CMS IC
Salbutamol or ephedrine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98915 Synaptic congenital myasthenic syndromes • Synaptic and basal-lamina associated syndromes
• Synaptic space
• Endplate AChE deficiency
• Endplate acetylcholinesterase deficiency
DOK7 Congenital myasthenic syndrome due to defects in docking protein 7 caused by pathogenic variants in DOK7 254300: Myasthenic syndrome, congenital, 10; CMS10
Alternative/former titles:
Myasthenia, limb-girdle, familial, LGM,
Congenital myasthenic syndrome type Ib, CMS1b, CMS Ib, Myasthenic myopathy
Salbutamol or ephedrine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Defects within the AChR-clustering pathway
• Defects in endplate development and maintenance
• DOK7-associated limb-girdle-myasthenia
• DOK7 CMS
• Dok-7 myasthenia
DPAGT1 Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in DPAGT1 614750: Myasthenic syndrome, congenital, 13; CMS13
Alternative/former titles:
Myasthenic syndrome, congenital, with tubular aggregates 2; CMSta2
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine N/A • Limb-girdle-myasthenia with glycosylation deficiency
• CMS due to abnormal glycosylation
• Congenital defects of glycosylation
• Defects in protein glycosylation
• DPAGT1 myasthenia
GFPT1 Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in GFPT1 610542: Myasthenic syndrome, congenital, 12; CMS12
Alternative/former titles:
Myasthenic syndrome, congenital, with tubular aggregates 1; CMSTA1
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine N/A • Limb-girdle-myasthenia with glycosylation deficiency
• CMS due to abnormal glycosylation
• Congenital defects of glycosylation
• Defects in protein glycosylation
• GFPT1 myasthenia
GMPPB Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in GMPPB N/A
(615352 is for the LGMD phenotype minus the myasthenic features)
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine N/A • Limb-girdle-myasthenia with glycosylation deficiency
• CMS due to abnormal glycosylation
• Congenital defects of glycosylation
• Defects in protein glycosylation
• GMPPB myasthenia
LAMB2 Congenital myasthenic syndrome due to laminin beta 2 deficiency caused by pathogenic variants in LAMB2 N/A Salbutamol or ephedrine ORPHA:98915 Synaptic congenital myasthenic syndromes • Synaptic basal lamina-associated syndromes • Laminin beta2 deficiency
LRP4 Congenital myasthenic syndrome due to defects in low-density lipoprotein receptor-related protein 4 caused by pathogenic variants in LRP4 616304: Myasthenic syndrome, congenital, 17; CMS17 Salbutamol or ephedrine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Defects within the AChR-clustering pathway
• Defects in endplate development and maintenance
• LRP4 myasthenia
MUSK Congenital myasthenic syndrome due to defects in MuSK caused by pathogenic variants in MUSK 616,325: Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency; CMS9 Salbutamol or ephedrine as first line; avoid pyridostigmine / acetylcholinesterase inhibitors ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Defects within the AChR-clustering pathway
• Defects in endplate development and maintenance
• Congenital MuSK myasthenia
• MuSK deficiency
MYO9A Congenital myasthenic syndrome due to a defect in Myosin 9A caused by pathogenic variants in MYO9A N/A Pyridostigmine ORPHA:98914 Presynaptic congenital myasthenic syndromes • Axonal transport
• Presynaptic
• Myosin 9a deficiency
PLEC1 Congenital myasthenic syndrome due to plectin deficiency caused by pathogenic variants in PLEC1 N/A Pyridostigmine N/A • Other myasthenic syndromes • Plectin deficiency
PREPL Congenital myasthenic syndrome caused by pathogenic variants in PREPL that predict reduced filling of synaptic vesicles with ACh 616224: Myasthenic syndrome, congenital, 22; CMS22
Alternative/former titles:
PREPL deficiency
Pyridostigmine N/A • Limb-girdle-myasthenia with glycosylation deficiency
• Synthesis and Recycling of Acetylcholine
• Other myasthenic syndromes
• PREPL deletion syndrome
• PREPL deficiency
RAPSN Congenital myasthenic syndrome due to endplate rapsyn deficiency caused by pathogenic variants in RAPSN 616326: Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency; CMS11
Alternative/former titles:
Myasthenic syndrome, congenital, Ie, CMS1e, CMS Ie
Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine or salbutamol / ephedrine ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Defects within the AChR-clustering pathway
• Defects in endplate development and maintenance
• Endplate rapsyn deficiency
• Rapsyn deficiency
• Rapsyn CMS
SCN4A Congenital myasthenic syndrome due to a sodium channel 1.4 defect caused by pathogenic variants in SCN4A 614198: Myasthenic syndrome, congenital, 16; CMS16
Alternative/former titles:
Myasthenic syndrome, congenital, acetazolamide-responsive
Pyridostigmine as first line; acetazolamide may be helpful for periodic paralysis ORPHA:98913 Postsynaptic congenital myasthenic syndromes • Other myasthenic syndromes • Na channel myasthenia
• Sodium channel myasthenia
SLC18A3 Congenital myasthenic syndrome due to a vesicular acetylcholine transporter defect caused by pathogenic variants in SLC18A3 617239: Myasthenic syndrome, congenital, 21, presynaptic; CMS21 Pyridostigmine ORPHA:98914 Presynaptic congenital myasthenic syndromes • Synthesis and recycling of acetylcholine • Vesicular ACh transporter deficiency
SLC25A1 Congenital myasthenic syndrome due to a mitochondrial citrate carrier defect caused by pathogenic variants in SLC25A1 N/A Pyridostigmine as first line; may benefit from addition of 3,4-diaminopyridine ORPHA:98914 Presynaptic congenital myasthenic syndromes • Other syndromes • Mitochondrial citrate carrier deficiency
SLC5A7 Congenital myasthenic syndrome due to a choline transporter defect caused by pathogenic variants in SLC5A7 617143: Myasthenic syndrome, congenital, 20, presynaptic; CMS20 Pyridostigmine as first line; may benefit from addition of salbutamol / ephedrine ORPHA:98914 Presynaptic congenital myasthenic syndromes • Synthesis and recycling of acetylcholine • High-affinity presynaptic choline transporter
SNAP25B Congenital myasthenic syndrome due to a synaptosomal-associated protein 25 defect caused by pathogenic variants in SNAP25B 616330: Myasthenic syndrome, congenital, 18; CMS18
Alternative/former titles:
Myasthenic syndrome, congenital, 18, with intellectual disability and ataxia
3,4-diaminopyridine N/A • Synaptic vesicles exocytosis
• Presynaptic
• SNAP25-associated CMS
• SNAP25B CMS
• SNAP25B deficiency
SYT2 Congenital myasthenic syndrome due to a synaptotagmin defect caused by a pathogenic variant in SYT2 616040: Myasthenic syndrome, congenital, 7, presynaptic; CMS7
Alternative/former titles:
Myasthenic syndrome, presynaptic, congenital, with or without motor neuropathy; MYSPC
3,4-diaminopyridine ORPHA:98914 Presynaptic congenital myasthenic syndromes • Synaptic vesicles exocytosis
• Presynaptic
• SYT2 CMS
• Synaptotagmin 2 myasthenia
UNC13A Congenital myasthenic syndrome due to a mammalian uncoordinated-13 protein defect caused by a pathogenic variant in UNC13A N/A 3,4-diaminopyridine as first line; may benefit from addition of pyridostigmine N/A • Synaptic vesicles exocytosis
• Presynaptic
• Munc13–1 myasthenia
VAMP1 Congenital myasthenic syndrome due to a vesicle associated membrane protein 1 defect caused by a pathogenic variant in VAMP1 N/A Pyridostigmine N/A • Synaptic vesicles exocytosis
• Presynaptic
• Synaptobrevin-1 myasthenia