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