Table 1 CMS treatment recommendations stratified by type, including key references and total number of primary reports evaluated
Gene involvedDescriptive nameFirst-line treatment recommendationSupplemental treatment recommendation 1Supplemental treatment recommendation 2Likely ineffectiveAvoid treatment (may worsen)Expert summary of the evidenceKey referenceNumber of publications
AGRNCongenital myasthenic syndrome due to agrin deficiency caused by pathogenic variants in AGRNSalbutamol or ephedrinePyridostigmineSmall number of reported cases; exploratory treatment with β2-adrenergic receptor agonists[56]7
ALG14Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in ALG14Pyridostigmine3,4-DAPSmall number of reported cases; exploratory treatment with an acetylcholinesterase inhibitor[57]2
ALG2Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in ALG2Pyridostigmine3,4-DAPSmall number of reported cases; exploratory treatment with an acetylcholinesterase inhibitor[57]1
CHATCongenital myasthenic syndrome due to endplate choline acetyltransferase deficiency caused by pathogenic variants in CHATPyridostigmine3,4-DAPSalbutamol or ephedrineAcetylcholinesterase inhibitors recommended including in oligosymptomatic patients to reduce EA[58]18
CHRNA1Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNA1Fluoxetine or quinidinePyridostigmineChannel blocker recommended; avoid acetylcholinesterase inhibitors[35,42]8
CHRNA1Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNA1PyridostigmineSalbutamol or ephedrine3,4-DAPFluoxetine or quinidineAcetylcholinesterase inhibitors recommended; may require add-on second-line therapy[59]4
CHRNA1Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNA1Pyridostigmine3,4-DAPSalbutamol or ephedrineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitor[40]3
CHRNB1Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNB1Fluoxetine or quinidinePyridostigmineChannel blocker recommended; avoid acetylcholinesterase inhibitors[35,42]5
CHRNB1Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNB1PyridostigmineSalbutamol or ephedrine3,4-DAPFluoxetine or quinidineAcetylcholinesterase inhibitors recommended; may require add-on second-line therapy[60]1
CHRNB1Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNB1Pyridostigmine3,4-DAPSalbutamol or ephedrineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitor[36]1
CHRNDSlow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNDFluoxetine or quinidinePyridostigmineChannel blocker recommended; avoid acetylcholinesterase inhibitors[35,42]2
CHRNDFast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNDPyridostigmineSalbutamol or ephedrine3,4-DAPFluoxetine or quinidineAcetylcholinesterase inhibitors recommended; may require add-on second-line therapy[59]4
CHRNDCongenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNDPyridostigmine3,4-DAPSalbutamol or ephedrineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitor[12]2
CHRNDCongenital myasthenic syndrome due to defects in acetylcholine receptor clustering caused by pathogenic variants in CHRNDPyridostigmineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitor[61]1
CHRNESlow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNEFluoxetine or quinidinePyridostigmineChannel blocker recommended; avoid acetylcholinesterase inhibitors[35,42]11
CHRNEFast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNEPyridostigmineSalbutamol or ephedrine3,4-DAPFluoxetine or quinidineAcetylcholinesterase inhibitors recommended; may require add-on second-line therapy[59]6
CHRNECongenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNEPyridostigmine3,4-DAPSalbutamol or ephedrineAcetylcholinesterase inhibitors recommended; may require add-on second-line therapy[34]40
CHRNECongenital myasthenic syndrome with kinetic defect due to reduced ion channel conductance caused by pathogenic variants in CHRNEPyridostigmineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitor[62]1
COL13A1Congenital myasthenic syndrome due to collagen 13 defects caused by pathogenic variants in COL13A13,4-DAPSalbutamol or ephedrinePyridostigmineSmall number of reported cases; exploratory treatment with β2 adrenergic receptor agonists and 3,4-DAP[63]2
COLQCongenital myasthenic syndrome due to endplate acetylcholinesterase deficiency caused by pathogenic variants in COLQSalbutamol or ephedrinePyridostigmineβ2 adrenergic receptor agonists recommended; avoid acetylcholinesterase inhibitors[31]35
DOK7Congenital myasthenic syndrome due to defects in docking protein 7 caused by pathogenic variants in DOK7Salbutamol or ephedrinePyridostigmineβ2 adrenergic receptor agonists recommended; avoid acetylcholinesterase inhibitors[27]40
DPAGT1Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in DPAGT1Pyridostigmine3,4-DAPSalbutamol or ephedrineAcetylcholinesterase inhibitors recommended. May see additional benefit with addition of 3,4-DAP and salbutamol[64]7
GFPT1Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in GFPT1Pyridostigmine3,4-DAPSalbutamol or ephedrineAcetylcholinesterase inhibitors recommended. May see additional benefit with the addition of 3,4-DAP and salbutamol; no effect on dystrophy expected[38]10
GMPPBCongenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in GMPPBPyridostigmine3,4-DAPSalbutamol or ephedrineAcetylcholinesterase inhibitors recommended. May see additional benefit with the addition of 3,4-DAP and salbutamol; no effect on dystrophy expected[65]6
LAMB2Congenital myasthenic syndrome due to laminin β2 deficiency caused by pathogenic variants in LAMB2Salbutamol or ephedrineSmall number of reported cases; exploratory treatment with β2 adrenergic receptor agonists[66]1
LRP4Congenital myasthenic syndrome due to defects in low-density lipoprotein receptor-related protein 4 caused by pathogenic variants in LRP4Salbutamol or ephedrinePyridostigmineSmall number of reported cases; exploratory treatment with β2 adrenergic receptor agonists[67]2
MUSKCongenital myasthenic syndrome due to defects in MuSK caused by pathogenic variants in MUSKSalbutamol or ephedrinePyridostigmineSmall number of reported cases; exploratory treatment with β2 adrenergic receptor agonists[68]11
MYO9ACongenital myasthenic syndrome due to a defect in Myosin 9A caused by pathogenic variants in MYO9APyridostigmineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitors[69]2
PLEC1Congenital myasthenic syndrome due to plectin deficiency caused by pathogenic variants in PLEC1PyridostigmineSmall number of reported cases[70]2
PREPLCongenital myasthenic syndrome due to pathogenic variants in PREPL that predict reduced filling of synaptic vesicles with AChPyridostigmineSmall number of reported cases; acetylcholinesterase inhibitors possibly beneficial in infancy[71]2
RAPSNCongenital myasthenic syndrome due to endplate rapsyn deficiency caused by pathogenic variants in RAPSNPyridostigmine3,4-DAPSalbutamol or ephedrineFluoxetineAcetylcholinesterase inhibitors recommended. May see additional benefit with addition of 3,4-DAP and salbutamol[72]40
SCN4ACongenital myasthenic syndrome due to a sodium channel 1.4 defect caused by pathogenic variants in SCN4APyridostigmineAcetazolamideSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitors. Acetazolamide may be helpful for periodic paralysis[73]3
SLC18A3Congenital myasthenic syndrome due to a vesicular acetylcholine transporter defect caused by pathogenic variants in SLC18A3PyridostigmineAcetylcholinesterase inhibitors may be useful for respiratory crisis[12]2
SLC25A1Congenital myasthenic syndrome due to a mitochondrial citrate carrier defect caused by pathogenic variants in SLC25A1Pyridostigmine3,4-DAPSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitors[74]1
SLC5A7Congenital myasthenic syndrome due to a choline transporter defect caused by pathogenic variants in SLC5A7PyridostigmineEphedrineAcetylcholinesterase inhibitors recommended[12]4
SNAP25BCongenital myasthenic syndrome due to a synaptosomal-associated protein 25 defect caused by pathogenic variants in SNAP25B3,4-DAPSmall number of reported cases; exploratory treatment with 3,4-DAP[75]1
SYT2Congenital myasthenic syndrome due to a synaptotagmin defect caused by a pathogenic variant in SYT23,4-DAPSmall number of reported cases; exploratory treatment with 3,4-DAP[76]1
UNC13ACongenital myasthenic syndrome due to a mammalian unco-ordinated-13 protein defect caused by a pathogenic variant in UNC13A3,4-DAPPyridostigmineSmall number of reported cases; exploratory treatment with 3,4-DAP[77]1
VAMP1Congenital myasthenic syndrome due to a vesicle-associated membrane protein 1 defect caused by a pathogenic variant in VAMP1PyridostigmineSmall number of reported cases; exploratory treatment with acetylcholinesterase inhibitors[78]1