Table 1. CMS treatment recommendations stratified by type, including key references and total number of primary reports evaluated.

Gene involved	Descriptive name	First-line treatment recommendation	Supplemental treatment recommendation 1	Supplemental treatment recommendation 2	Likely ineffective	Avoid treatment (may worsen)	Expert summary of the evidence	Key reference	Number of publications
AGRN	Congenital myasthenic syndrome due to agrin deficiency caused by pathogenic variants in AGRN	Salbutamol or ephedrine				Pyridostigmine	Small number of reported cases; exploratory treatment with β2-adrenergic receptor agonists	[56]	7
ALG14	Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in ALG14	Pyridostigmine	3,4-DAP				Small number of reported cases; exploratory treatment with an acetylcholinesterase inhibitor	[57]	2
ALG2	Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in ALG2	Pyridostigmine	3,4-DAP				Small number of reported cases; exploratory treatment with an acetylcholinesterase inhibitor	[57]	1
CHAT	Congenital myasthenic syndrome due to endplate choline acetyltransferase deficiency caused by pathogenic variants in CHAT	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Acetylcholinesterase inhibitors recommended including in oligosymptomatic patients to reduce EA	[58]	18
CHRNA1	Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNA1	Fluoxetine or quinidine				Pyridostigmine	Channel blocker recommended; avoid acetylcholinesterase inhibitors	[35,42]	8
CHRNA1	Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNA1	Pyridostigmine	Salbutamol or ephedrine	3,4-DAP		Fluoxetine or quinidine	Acetylcholinesterase inhibitors recommended; may require add-on second-line therapy	[59]	4
CHRNA1	Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNA1	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitor	[40]	3
CHRNB1	Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNB1	Fluoxetine or quinidine				Pyridostigmine	Channel blocker recommended; avoid acetylcholinesterase inhibitors	[35,42]	5
CHRNB1	Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNB1	Pyridostigmine	Salbutamol or ephedrine	3,4-DAP		Fluoxetine or quinidine	Acetylcholinesterase inhibitors recommended; may require add-on second-line therapy	[60]	1
CHRNB1	Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNB1	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitor	[36]	1
CHRND	Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRND	Fluoxetine or quinidine				Pyridostigmine	Channel blocker recommended; avoid acetylcholinesterase inhibitors	[35,42]	2
CHRND	Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRND	Pyridostigmine	Salbutamol or ephedrine	3,4-DAP		Fluoxetine or quinidine	Acetylcholinesterase inhibitors recommended; may require add-on second-line therapy	[59]	4
CHRND	Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRND	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitor	[12]	2
CHRND	Congenital myasthenic syndrome due to defects in acetylcholine receptor clustering caused by pathogenic variants in CHRND	Pyridostigmine					Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitor	[61]	1
CHRNE	Slow-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by a pathogenic variant in CHRNE	Fluoxetine or quinidine				Pyridostigmine	Channel blocker recommended; avoid acetylcholinesterase inhibitors	[35,42]	11
CHRNE	Fast-channel congenital myasthenic syndrome due to an acetylcholine receptor defect caused by pathogenic variants in CHRNE	Pyridostigmine	Salbutamol or ephedrine	3,4-DAP		Fluoxetine or quinidine	Acetylcholinesterase inhibitors recommended; may require add-on second-line therapy	[59]	6
CHRNE	Congenital myasthenic syndrome due to primary acetylcholine receptor deficiency caused by pathogenic variants in CHRNE	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Acetylcholinesterase inhibitors recommended; may require add-on second-line therapy	[34]	40
CHRNE	Congenital myasthenic syndrome with kinetic defect due to reduced ion channel conductance caused by pathogenic variants in CHRNE	Pyridostigmine					Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitor	[62]	1
COL13A1	Congenital myasthenic syndrome due to collagen 13 defects caused by pathogenic variants in COL13A1	3,4-DAP	Salbutamol or ephedrine		Pyridostigmine		Small number of reported cases; exploratory treatment with β2 adrenergic receptor agonists and 3,4-DAP	[63]	2
COLQ	Congenital myasthenic syndrome due to endplate acetylcholinesterase deficiency caused by pathogenic variants in COLQ	Salbutamol or ephedrine				Pyridostigmine	β2 adrenergic receptor agonists recommended; avoid acetylcholinesterase inhibitors	[31]	35
DOK7	Congenital myasthenic syndrome due to defects in docking protein 7 caused by pathogenic variants in DOK7	Salbutamol or ephedrine				Pyridostigmine	β2 adrenergic receptor agonists recommended; avoid acetylcholinesterase inhibitors	[27]	40
DPAGT1	Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in DPAGT1	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Acetylcholinesterase inhibitors recommended. May see additional benefit with addition of 3,4-DAP and salbutamol	[64]	7
GFPT1	Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in GFPT1	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Acetylcholinesterase inhibitors recommended. May see additional benefit with the addition of 3,4-DAP and salbutamol; no effect on dystrophy expected	[38]	10
GMPPB	Congenital myasthenic syndrome due to a defect of glycosylation caused by pathogenic variants in GMPPB	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine			Acetylcholinesterase inhibitors recommended. May see additional benefit with the addition of 3,4-DAP and salbutamol; no effect on dystrophy expected	[65]	6
LAMB2	Congenital myasthenic syndrome due to laminin β2 deficiency caused by pathogenic variants in LAMB2	Salbutamol or ephedrine					Small number of reported cases; exploratory treatment with β2 adrenergic receptor agonists	[66]	1
LRP4	Congenital myasthenic syndrome due to defects in low-density lipoprotein receptor-related protein 4 caused by pathogenic variants in LRP4	Salbutamol or ephedrine				Pyridostigmine	Small number of reported cases; exploratory treatment with β2 adrenergic receptor agonists	[67]	2
MUSK	Congenital myasthenic syndrome due to defects in MuSK caused by pathogenic variants in MUSK	Salbutamol or ephedrine				Pyridostigmine	Small number of reported cases; exploratory treatment with β2 adrenergic receptor agonists	[68]	11
MYO9A	Congenital myasthenic syndrome due to a defect in Myosin 9A caused by pathogenic variants in MYO9A	Pyridostigmine					Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitors	[69]	2
PLEC1	Congenital myasthenic syndrome due to plectin deficiency caused by pathogenic variants in PLEC1	Pyridostigmine					Small number of reported cases	[70]	2
PREPL	Congenital myasthenic syndrome due to pathogenic variants in PREPL that predict reduced filling of synaptic vesicles with ACh	Pyridostigmine					Small number of reported cases; acetylcholinesterase inhibitors possibly beneficial in infancy	[71]	2
RAPSN	Congenital myasthenic syndrome due to endplate rapsyn deficiency caused by pathogenic variants in RAPSN	Pyridostigmine	3,4-DAP	Salbutamol or ephedrine		Fluoxetine	Acetylcholinesterase inhibitors recommended. May see additional benefit with addition of 3,4-DAP and salbutamol	[72]	40
SCN4A	Congenital myasthenic syndrome due to a sodium channel 1.4 defect caused by pathogenic variants in SCN4A	Pyridostigmine	Acetazolamide				Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitors. Acetazolamide may be helpful for periodic paralysis	[73]	3
SLC18A3	Congenital myasthenic syndrome due to a vesicular acetylcholine transporter defect caused by pathogenic variants in SLC18A3	Pyridostigmine					Acetylcholinesterase inhibitors may be useful for respiratory crisis	[12]	2
SLC25A1	Congenital myasthenic syndrome due to a mitochondrial citrate carrier defect caused by pathogenic variants in SLC25A1	Pyridostigmine	3,4-DAP				Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitors	[74]	1
SLC5A7	Congenital myasthenic syndrome due to a choline transporter defect caused by pathogenic variants in SLC5A7	Pyridostigmine	Ephedrine				Acetylcholinesterase inhibitors recommended	[12]	4
SNAP25B	Congenital myasthenic syndrome due to a synaptosomal-associated protein 25 defect caused by pathogenic variants in SNAP25B	3,4-DAP					Small number of reported cases; exploratory treatment with 3,4-DAP	[75]	1
SYT2	Congenital myasthenic syndrome due to a synaptotagmin defect caused by a pathogenic variant in SYT2	3,4-DAP					Small number of reported cases; exploratory treatment with 3,4-DAP	[76]	1
UNC13A	Congenital myasthenic syndrome due to a mammalian unco-ordinated-13 protein defect caused by a pathogenic variant in UNC13A	3,4-DAP	Pyridostigmine				Small number of reported cases; exploratory treatment with 3,4-DAP	[77]	1
VAMP1	Congenital myasthenic syndrome due to a vesicle-associated membrane protein 1 defect caused by a pathogenic variant in VAMP1	Pyridostigmine					Small number of reported cases; exploratory treatment with acetylcholinesterase inhibitors	[78]	1