Congenital Myasthenic Syndrome

Mendelian MONDO:0018940 Pathograph 39 Show in embeddings browser Neuromuscular Disease

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of inherited disorders of neuromuscular junction (NMJ) transmission, caused by germline pathogenic variants in genes expressed at the motor endplate. At least 35 CMS-associated genes have been reported. Despite the diversity of the upstream molecular lesion, all subtypes converge on a single shared terminal mechanism — a reduced safety factor of neuromuscular transmission — that produces the uniform clinical phenotype of fatigable muscle weakness affecting ocular, bulbar, facial, axial, respiratory, and limb muscles. CMS is distinguished from autoimmune myasthenia gravis by its genetic (rather than antibody-mediated) etiology, typical onset in infancy or childhood, and the absence of anti-AChR / anti-MuSK autoantibodies. Diagnosis requires demonstration of a decremental compound muscle action potential response on low-frequency repetitive nerve stimulation (RNS) and/or abnormal single-fiber EMG jitter, with confirmatory genetic testing. This is the umbrella entry for the CMS family; subtypes are organized by the NMJ location of the defective protein — presynaptic, synaptic (basal-lamina), postsynaptic, and an N-glycosylation group — because therapeutic response is largely predictable from this mechanistic class (a drug helpful in one subtype may be ineffective or harmful in another). The prenatal-lethal CHRNA1 fetal akinesia disorder is curated separately as the severe end of the AChR spectrum, and CHAT-related CMS with episodic apnea (congenital myasthenic syndrome 6) is curated separately as Congenital_Myasthenic_Syndrome_6.

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Subtypes

nmj compartment

Presynaptic CMS MONDO:0700466 MONDO:0009689

MONDO MONDO:0009689

Defects in acetylcholine (ACh) synthesis, vesicular packaging, or release at the motor nerve terminal. CHAT (choline acetyltransferase) is the commonest presynaptic gene; other genes include SLC5A7, SLC18A3, SNAP25, SYT2, VAMP1, and UNC13A. Presynaptic CMS comprise roughly 5-10% of all CMS and frequently present prenatally/neonatally with a severe phenotype that can include arthrogryposis, developmental delay, and episodic/sudden apneic crises (classically CHAT-CMS, "CMS with episodic apnea").

CMS20
CMS21
CMS22
CMS23
CMS24
CMS25

Show evidence (2 references)

PMID:37212067 SUPPORT Human Clinical

"They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft."

Defines the presynaptic CMS mechanistic group by the affected step of ACh handling.

PMID:37212067 SUPPORT Human Clinical

"Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis."

Establishes the severe prenatal/neonatal presentation typical of presynaptic CMS.

Synaptic (Basal-Lamina) CMS

Defects in proteins of the synaptic basal lamina. The prototype is COLQ-CMS: COLQ encodes the collagen-like tail subunit that anchors acetylcholinesterase (AChE) in the synaptic cleft, so biallelic loss produces endplate AChE deficiency with prolonged ACh action. Other synaptic-cleft genes include LAMB2, LAMA5, and COL13A1. Synaptic CMS characteristically does NOT respond to (and may worsen with) cholinesterase inhibitors, but responds to ephedrine and salbutamol.

CMS5
CMS19

Show evidence (1 reference)

PMID:38475910 SUPPORT Human Clinical

"Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency."

Defines COLQ-CMS as the synaptic basal-lamina subtype with endplate AChE deficiency.

Postsynaptic CMS MONDO:0020344

Defects of the postsynaptic membrane — by far the largest group. Includes primary AChR deficiency and AChR kinetic abnormalities (slow-channel and fast-channel syndromes) from variants in the AChR subunit genes (CHRNE, CHRNA1, CHRNB1, CHRND, CHRNG), and defects of endplate development / maintenance and AChR clustering (RAPSN, DOK7, MUSK, AGRN, LRP4). CHRNE low-expressor variants and DOK7 are among the most common CMS genotypes overall. Slow-channel CMS (SCCMS) is the principal autosomal dominant form.

CMS1A
CMS1B
CMS2A
CMS2C
CMS3A
CMS3B
CMS3C
CMS4
CMS8
CMS9
CMS10
CMS11
CMS17

Show evidence (1 reference)

PMID:38696726 SUPPORT Human Clinical

"CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%)."

Quantifies the dominant postsynaptic genotypes (CHRNE, DOK7, RAPSN) in a 235-patient adult cohort.

Glycosylation-Related CMS

Defects in the N-linked protein glycosylation pathway (GFPT1, DPAGT1, ALG2, ALG14, GMPPB) that impair glycosylation of multiple NMJ glycoproteins, including the AChR, producing a "combination" endplate defect. These typically present as a limb-girdle CMS, often with tubular aggregates on muscle biopsy and elevated creatine kinase, and respond to cholinesterase inhibitors. Glycosylation genes are an increasingly recognized cause, accounting for over 20% of cases in some cohorts.

CMS12
CMS13

Show evidence (1 reference)

PMID:37721175 SUPPORT Human Clinical

"postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%)."

Quantifies the relative frequency of the four mechanistic subtype groups in a 156-patient Indian cohort.

gene defined

CHRNA1-related congenital myasthenic syndrome (CMS1A) MONDO:0011088

CHRNA1 hgnc:1955 Autosomal dominant inheritance

Slow-channel CMS (SCCMS) caused by a heterozygous missense variant in CHRNA1, the AChR alpha-1 subunit. Slow-channel variants abnormally prolong the AChR channel opening time, so the resting membrane potential depolarizes, AChRs desensitize, and excessive calcium influx produces an endplate myopathy. Cholinesterase inhibitors are mostly ineffective, whereas quinidine and fluoxetine ameliorate the slow-channel phenotype.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNA1 to CMS1A within the SCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRNA1-related congenital myasthenic syndrome (CMS1B) MONDO:0012156

CHRNA1 hgnc:1955 Autosomal recessive inheritance

Fast-channel CMS (FCCMS) caused by biallelic CHRNA1 variants that abnormally shorten the AChR channel opening time, kinetically the mirror image of the slow-channel form in the same gene. Cholinesterase inhibitors are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNA1 to CMS1B within the FCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRNB1-related congenital myasthenic syndrome (CMS2A) MONDO:0014581

CHRNB1 hgnc:1961 Autosomal dominant inheritance

Slow-channel CMS caused by a heterozygous missense variant in CHRNB1, the AChR beta-1 subunit, sharing the prolonged-channel-opening mechanism and the quinidine and fluoxetine response of the other slow-channel subtypes.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNB1 to CMS2A within the SCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRNB1-related congenital myasthenic syndrome (CMS2C) MONDO:0014582

CHRNB1 hgnc:1961 Autosomal recessive inheritance

Endplate AChR deficiency caused by biallelic CHRNB1 variants that reduce the number of AChRs at the endplate rather than altering their gating, giving a low-amplitude miniature endplate potential and current. Cholinesterase inhibitors, ephedrine, salbutamol and amifampridine are all generally effective for endplate AChR deficiency. No fast-channel CHRNB1 subtype has been reported, and a synonym-inclusive MONDO search returns no CMS2B term.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNB1 to CMS2C within the Endplate AChR deficiency pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRND-related congenital myasthenic syndrome (CMS3A) MONDO:0014583

CHRND hgnc:1965 Autosomal dominant inheritance

Slow-channel CMS caused by a heterozygous missense variant in CHRND, the AChR delta subunit, producing prolonged synaptic currents and early-onset progressive weakness.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRND to CMS3A within the SCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRND-related congenital myasthenic syndrome (CMS3B) MONDO:0014584

CHRND hgnc:1965 Autosomal recessive inheritance

Fast-channel CMS caused by biallelic CHRND variants that abbreviate the endplate current so that it decays before the muscle fibre reaches depolarization threshold. Cholinesterase inhibitors are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRND to CMS3B within the FCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRND-related congenital myasthenic syndrome (CMS3C) MONDO:0014585

CHRND hgnc:1965 Autosomal recessive inheritance

Endplate AChR deficiency caused by biallelic CHRND variants that reduce endplate AChR number. Separating this from the fast-channel CHRND subtype requires microelectrode or single-channel recordings, whose unavailability is likely to account for the rarity of fast-channel CMS.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRND to CMS3C within the Endplate AChR deficiency pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

CHRNE-related congenital myasthenic syndrome (CMS4) MONDO:1040021

CHRNE hgnc:1966 Autosomal dominant inheritance Autosomal recessive inheritance

The CHRNE-defined branch of CMS, and the MONDO grouping term above CMS4A (slow-channel), CMS4B (fast-channel) and CMS4C (endplate AChR deficiency). CHRNE encodes the AChR epsilon subunit, which replaces the embryonic gamma subunit after birth; a biallelic lack of the epsilon subunit can be compensated for by the gamma subunit and is not fatal. CHRNE is the most commonly affected CMS gene in several cohorts. Apart from one dominantly inherited hemiallelic missense variant causing slow-channel disease, the effects of CHRNE missense variants cannot be differentiated without expression studies.

Show evidence (3 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNE to CMS4A within the SCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNE to CMS4B within the FCCMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

Table 1 of this review assigns CHRNE to CMS4C within the Endplate AChR deficiency pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

COLQ-related congenital myasthenic syndrome (CMS5) MONDO:0011281

COLQ hgnc:2226 Autosomal recessive inheritance

Endplate acetylcholinesterase deficiency caused by biallelic COLQ variants. ColQ is the triple-helical collagenic tail that anchors the asymmetric forms of acetylcholinesterase at the neuromuscular junction, so its loss leaves acetylcholine in the cleft for a prolonged period and a single nerve stimulus elicits a repetitive CMAP. Cholinesterase inhibitors are contraindicated because of severe adverse effects including respiratory arrest in some patients; ephedrine and salbutamol are effective in some patients.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Endplate AChE deficiency | COLQ | CMS5"

Table 1 of this review assigns COLQ to CMS5 within the Endplate AChE deficiency pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

AGRN-related congenital myasthenic syndrome (CMS8) MONDO:0014052

AGRN hgnc:329 Autosomal recessive inheritance

CMS caused by defective AChR clustering, from biallelic variants in AGRN. Agrin is released from the nerve terminal and binds LRP4 at the motor endplate, which induces MuSK phosphorylation and drives AChR clustering. Cholinesterase inhibitors are ineffective or only mildly effective; ephedrine and salbutamol are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective AChR clustering | AGRN | CMS8"

Table 1 of this review assigns AGRN to CMS8 within the CMS caused by defective AChR clustering pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

MUSK-related congenital myasthenic syndrome (CMS9) MONDO:0014587

MUSK hgnc:7525 Autosomal recessive inheritance

CMS caused by defective AChR clustering, from biallelic variants in MUSK. Agrin-bound LRP4 induces MuSK phosphorylation, and phosphorylated MuSK in turn phosphorylates the AChR beta-1 subunit, which binds rapsyn to form endplate AChR clusters. Cholinesterase inhibitors are effective in some patients and worsen weakness in others, while amifampridine and salbutamol are mildly or markedly effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective AChR clustering | MUSK | CMS9"

Table 1 of this review assigns MUSK to CMS9 within the CMS caused by defective AChR clustering pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

DOK7-related congenital myasthenic syndrome (CMS10) MONDO:0009690

DOK7 hgnc:26594 Autosomal recessive inheritance

CMS caused by defective AChR clustering, from biallelic variants in DOK7, the cytoplasmic adaptor that enhances MuSK phosphorylation. DOK7 is one of the genes in which pathogenic CMS variants are frequently observed, and it presents as a limb-girdle myasthenia with proximal and truncal weakness and frequent scoliosis. Cholinesterase inhibitors are generally ineffective and sometimes worsen symptoms, whereas ephedrine and salbutamol are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective AChR clustering | DOK7 | CMS10"

Table 1 of this review assigns DOK7 to CMS10 within the CMS caused by defective AChR clustering pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

RAPSN-related congenital myasthenic syndrome (CMS11) MONDO:0014588

RAPSN hgnc:9863 Autosomal recessive inheritance

Endplate AChR deficiency caused by biallelic variants in RAPSN, the submembranous scaffold that binds the phosphorylated AChR beta-1 subunit to form endplate AChR clusters. Onset is typically neonatal with fluctuating lid ptosis, bulbar signs, neck muscle weakness and mild limb weakness, with episodic worsening in adults. Cholinesterase inhibitors, ephedrine, salbutamol and amifampridine are all generally effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Endplate AChR deficiency | RAPSN | CMS11"

Table 1 of this review assigns RAPSN to CMS11 within the Endplate AChR deficiency pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

GFPT1-related congenital myasthenic syndrome (CMS12) MONDO:0012518

GFPT1 hgnc:4241 Autosomal recessive inheritance

Glycosylation-deficient CMS caused by biallelic variants in GFPT1, which controls the rate-limiting step of the hexosamine pathway feeding N-linked glycosylation. Muscle biopsy shows tubular aggregates and serum creatine kinase is raised to about three times the upper limit of normal. Cholinesterase inhibitors and salbutamol are effective.

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"~3 times in tubular aggregates in GFPT1-CMS and DOK7-CMS"

Sources the creatine kinase elevation quoted in this row's description.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Glycosylation-deficient CMS | GFPT1 | CMS12"

Table 1 of this review assigns GFPT1 to CMS12 within the Glycosylation-deficient CMS pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

DPAGT1-related congenital myasthenic syndrome (CMS13) MONDO:0013883

DPAGT1 hgnc:2995 Autosomal recessive inheritance

Glycosylation-deficient CMS caused by biallelic variants in DPAGT1, which catalyses the first committed step of N-linked glycosylation. Muscle biopsy shows tubular aggregates or rimmed vacuoles. This is the limb-girdle myasthenic disease allelic to the systemic DPAGT1 congenital disorder of glycosylation, which has its own MONDO term and its own KB entry.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Glycosylation-deficient CMS | DPAGT1 | CMS13"

Table 1 of this review assigns DPAGT1 to CMS13 within the Glycosylation-deficient CMS pathomechanistic group, the assignment quoted here being the review's own gene-to-subtype-number mapping.

LRP4-related congenital myasthenic syndrome (CMS17) MONDO:0014578

LRP4 hgnc:6696 Autosomal recessive inheritance

CMS caused by defective AChR clustering, from biallelic variants in LRP4, the agrin co-receptor: two LRP4 molecules bind two MuSK molecules to form a heterotetrameric receptor complex, and agrin binding to LRP4 induces MuSK phosphorylation. Cholinesterase inhibitors worsen symptoms in LRP4-CMS.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective AChR clustering | LRP4 | CMS17 | 1 | AR | decrement"

Table 1 of this review assigns LRP4 to CMS17 within the CMS caused by defective AChR clustering pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

COL13A1-related congenital myasthenic syndrome (CMS19) MONDO:0014745

COL13A1 hgnc:2190 Autosomal recessive inheritance

CMS caused by biallelic variants in COL13A1, a single-pass transmembrane collagen enriched at the neuromuscular junction that is essential for the maturation and maintenance of endplate AChRs. All reported patients developed respiratory distress and weak sucking at birth, with facial, bulbar, respiratory and truncal weakness while the limb muscles are relatively spared. Cholinesterase inhibitors are ineffective, whereas salbutamol and amifampridine are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Synaptic CMS | COL13A1 | CMS19 | 41 | AR | decrement"

Table 1 of this review assigns COL13A1 to CMS19 within the Synaptic CMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

SLC5A7-related congenital myasthenic syndrome (CMS20) MONDO:0014939

SLC5A7 hgnc:14025 Autosomal recessive inheritance

CMS caused by defective recycling of acetylcholine, from biallelic loss-of-function variants in SLC5A7, the high-affinity choline transporter that takes choline up into the nerve terminal. Hemiallelic frameshifting variants of the same gene instead cause autosomal dominant distal hereditary motor neuropathy type VIIA, and why comparable reductions in transporter activity give two different phenotypes remains unknown. The presentation is neonatal-onset episodic apnea with hypotonia, weakness and weak crying. Cholinesterase inhibitors are effective and ephedrine adds benefit, whereas amifampridine is ineffective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective recycling of ACh | SLC5A7 | CMS20 | 12 | AR | decrement at rest or only after isometric muscle contraction"

Table 1 of this review assigns SLC5A7 to CMS20 within the CMS caused by defective recycling of ACh pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

SLC18A3-related congenital myasthenic syndrome (CMS21) MONDO:0014983

SLC18A3 hgnc:10936 Autosomal recessive inheritance

CMS caused by defective recycling of acetylcholine, from biallelic variants in SLC18A3, the vesicular acetylcholine transporter that loads newly synthesized acetylcholine into synaptic vesicles. SLC18A3 lies within the first intron of CHAT, a nested arrangement conserved as far back as C. elegans. Patients show severe weakness at birth with hypotonia, arthrogryposis and respiratory distress, and a decremental CMAP may appear only after isometric contraction. Cholinesterase inhibitors, ephedrine and amifampridine are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective recycling of ACh | SLC18A3 | CMS21 | 7 | AR | decrement at rest or only after isometric muscle contraction"

Table 1 of this review assigns SLC18A3 to CMS21 within the CMS caused by defective recycling of ACh pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

PREPL-related congenital myasthenic syndrome (CMS22) MONDO:0044299

PREPL hgnc:30228 Autosomal recessive inheritance

CMS caused by defective recycling of acetylcholine, from loss-of-function variants in PREPL, a serine peptidase whose physiological substrate is unknown. PREPL loss does not cause endplate AChR deficiency; it inhibits refilling of acetylcholine into synaptic vesicles, reduces the number of releasable quanta and lowers the probability of vesicular release. PREPL and SLC3A1 are encoded on opposite strands and overlap at their 3-prime ends, so a deletion spanning both gives hypotonia-cystinuria syndrome. Ten reported patients, including those with the contiguous deletion, were initially diagnosed as Prader-Willi syndrome. Cholinesterase inhibitors are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective recycling of ACh | PREPL | CMS22 | 18 | AR | decrement"

Table 1 of this review assigns PREPL to CMS22 within the CMS caused by defective recycling of ACh pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

SLC25A1-related congenital myasthenic syndrome (CMS23) MONDO:0032596

SLC25A1 hgnc:10979 Autosomal recessive inheritance

CMS caused by defective nerve terminal formation, from biallelic variants in SLC25A1, a mitochondrial inner-membrane transporter whose variants also cause combined D-2- and L-2-hydroxyglutaric aciduria. Knockdown in zebrafish disturbs axonal elongation of spinal motor neurons and compromises neuromuscular junction formation, so the myasthenia is predicted to arise presynaptically. Limb myasthenia and palpebral ptosis are the shared clinical features. Cholinesterase inhibitors and amifampridine are generally ineffective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective nerve terminal formation | SLC25A1 | CMS23 | 19 | AR | decrement"

Table 1 of this review assigns SLC25A1 to CMS23 within the CMS caused by defective nerve terminal formation pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

MYO9A-related congenital myasthenic syndrome (CMS24) MONDO:0032597

MYO9A hgnc:7608 Autosomal recessive inheritance

CMS caused by defective nerve terminal formation, from biallelic loss-of-function variants in MYO9A, an unconventional myosin carrying a Rho GTPase-activating domain that regulates intracellular transport in peripheral nerve. Knockdown of the two zebrafish orthologues shortens and abnormally branches spinal motor axons and impairs neuromuscular transmission. Reported patients had reduced fetal movement, neonatal ptosis, later swallowing difficulty, episodic apnea and developmental delay. Cholinesterase inhibitors are effective.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMS caused by defective nerve terminal formation | MYO9A | CMS24 | 3 | AR | decrement"

Table 1 of this review assigns MYO9A to CMS24 within the CMS caused by defective nerve terminal formation pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

VAMP1-related congenital myasthenic syndrome (CMS25) MONDO:0032675

VAMP1 hgnc:12642 Autosomal recessive inheritance

Lambert-Eaton-like CMS caused by biallelic loss-of-function variants in VAMP1, which encodes synaptobrevin-1, the vesicle SNARE. Because the lesion is in vesicle fusion itself, low-frequency repetitive nerve stimulation produces a decrement while high-frequency stimulation produces an increment, as in Lambert-Eaton myasthenic syndrome. Cholinesterase inhibitors are effective; amifampridine has not been given and its effect is unknown.

Show evidence (1 reference)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"LEMS-like CMS | VAMP1 | CMS25 | 9 | AR | decrement"

Table 1 of this review assigns VAMP1 to CMS25 within the LEMS-like CMS pathomechanistic group, with the inheritance pattern and the low-frequency repetitive-nerve-stimulation finding quoted here.

◈

Mechanistic Hypotheses

Canonical NMJ Transmission Failure Model

canonical_nmj_transmission_failure_model CANONICAL

Congenital myasthenic syndromes are caused by germline pathogenic variants in genes encoding proteins of the neuromuscular junction. Regardless of whether the primary lesion is presynaptic (impaired ACh synthesis, packaging, or release), synaptic (basal-lamina / endplate AChE anchoring), postsynaptic (AChR deficiency or abnormal channel kinetics, or impaired AChR clustering), or in the N-glycosylation pathway, the converging consequence is a reduced safety factor of neuromuscular transmission — the endplate potential fails to reliably reach the threshold needed to trigger a muscle fiber action potential, especially during sustained or repetitive activity. This manifests electrophysiologically as a decremental CMAP response on low-frequency repetitive nerve stimulation and increased jitter/blocking on single-fiber EMG, and clinically as fatigable muscle weakness. The mechanistic subtype predicts the pharmacological response: cholinesterase inhibitors help most groups but are contraindicated in some (e.g. COLQ / endplate AChE deficiency and slow-channel CMS), whereas salbutamol/ephedrine are broadly beneficial.

⚙

Pathophysiology

Impaired Neuromuscular Junction Transmission

The shared terminal mechanism of all CMS subtypes. A defect in any component of the motor endplate — presynaptic ACh handling, synaptic AChE anchoring, postsynaptic AChR density/kinetics, AChR clustering, or NMJ glycoprotein glycosylation — reduces the safety factor of cholinergic synaptic transmission. The endplate potential generated by ACh release becomes insufficient to consistently trigger a postsynaptic muscle fiber action potential, and this insufficiency worsens with repetitive activity, producing fatigable weakness.

Skeletal muscle fiber (postsynaptic motor endplate) CL:0008002 Motor neuron (presynaptic terminal) CL:0000100

Cholinergic synaptic transmission at the NMJ GO:0007271 ↓ DECREASED Neuromuscular synaptic transmission GO:0007274 ↓ DECREASED

Downstream

Neck Muscle Weakness Orphanet records neck muscle weakness as a very frequent phenotype in congenital myasthenic syndrome.

Dysphagia Orphanet records dysphagia as a very frequent bulbar phenotype in congenital myasthenic syndrome.

Poor Suck Orphanet records poor suck as a very frequent early feeding phenotype in congenital myasthenic syndrome.

Feeding Difficulties Orphanet records feeding difficulties as a very frequent phenotype in congenital myasthenic syndrome.

Ataxia Orphanet records ataxia as a frequent neurologic phenotype in congenital myasthenic syndrome.

Gait Disturbance Orphanet records gait disturbance as a frequent neurologic phenotype in congenital myasthenic syndrome.

Central Sleep Apnea Orphanet records central sleep apnea as a frequent respiratory phenotype in congenital myasthenic syndrome.

Choking Episodes Orphanet records choking episodes as a frequent feeding/respiratory phenotype in congenital myasthenic syndrome.

Arthrogryposis Multiplex Congenita Orphanet records arthrogryposis multiplex congenita as a frequent musculoskeletal phenotype in congenital myasthenic syndrome.

Show evidence (2 references)

PMID:36835142 SUPPORT Human Clinical

"Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ)."

Establishes impaired NMJ transmission as the unifying pathomechanism across all CMS genes.

PMID:37239850 SUPPORT Human Clinical

"While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission."

Confirms that disrupted NMJ transmission is the common terminal mechanism despite phenotypic diversity.

Presynaptic Acetylcholine Handling Defect

The acetylcholine-handling arm of presynaptic CMS: the lesion lies in the supply of transmitter rather than in the release machinery. Choline acetyltransferase (CHAT) synthesizes ACh, the high-affinity choline transporter (SLC5A7) recovers choline into the terminal, the vesicular ACh transporter (SLC18A3) loads it into synaptic vesicles, and PREPL is required for those vesicles to be refilled. A defect at any of these steps lowers the quantal content of ACh release and so the endplate potential. In this group a decrement on low-frequency stimulation is elicited at rest in some patients, but only after exercise or high-frequency stimulation in the others. The downstream fusion step is modeled separately in Defective SNARE-Mediated Synaptic Vesicle Fusion, and terminal development in Defective Motor Nerve Terminal Formation.

Motor neuron presynaptic terminal CL:0000100

CHAT hgnc:1912 SLC5A7 hgnc:14025 SLC18A3 hgnc:10936 PREPL hgnc:30228

Acetylcholine biosynthetic process GO:0008292 ↓ DECREASED

Downstream

Impaired Neuromuscular Junction Transmission Defective acetylcholine synthesis, packaging, or release at the nerve terminal reduces the safety margin of neuromuscular transmission.

Show evidence (1 reference)

PMID:37212067 SUPPORT Human Clinical

"They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft."

Defines the presynaptic ACh-handling defect at the nerve terminal.

Endplate Acetylcholinesterase Deficiency

In synaptic (basal-lamina) CMS, loss of COLQ removes the collagen tail that anchors acetylcholinesterase in the synaptic cleft. The resulting endplate AChE deficiency prolongs ACh dwell time, causing cationic overload and depolarization block / endplate myopathy. Because residual AChE activity is already absent, cholinesterase inhibitors provide no benefit and may be harmful.

Skeletal muscle fiber endplate CL:0008002

COLQ hgnc:2226

Downstream

Impaired Neuromuscular Junction Transmission Loss of endplate acetylcholinesterase prolongs ACh dwell time, causing cationic overload and depolarization block that impairs transmission.

Show evidence (2 references)

PMID:38475910 SUPPORT Human Clinical

Establishes endplate AChE deficiency as the synaptic CMS mechanism caused by COLQ loss.

PMID:38475910 SUPPORT Human Clinical

"There was no benefit from esterase inhibitor treatment, while treatment with ephedrine and salbutamol was objectively efficient in all cases."

Confirms the mechanistically predicted lack of AChE-inhibitor benefit in endplate AChE deficiency.

Postsynaptic AChR Deficiency, Kinetic Defect, and Impaired Clustering

The largest mechanistic group. Variants in AChR subunit genes (CHRNE, CHRNA1, CHRNB1, CHRND) reduce endplate AChR density (primary AChR deficiency) or alter channel gating kinetics — prolonged openings in slow-channel CMS (cationic overload, endplate degeneration) or abbreviated openings in fast-channel CMS (reduced response to ACh). Variants in the agrin-LRP4-MuSK-DOK7-rapsyn signaling axis (AGRN, LRP4, MUSK, DOK7, RAPSN) impair AChR clustering and endplate development/maintenance.

Skeletal muscle fiber postsynaptic membrane CL:0008002

CHRNA1 hgnc:1955 CHRNB1 hgnc:1961 CHRND hgnc:1965 CHRNE hgnc:1966 RAPSN hgnc:9863 DOK7 hgnc:26594 MUSK hgnc:7525 AGRN hgnc:329 LRP4 hgnc:6696

Skeletal muscle acetylcholine-gated channel clustering GO:0071340 ↓ DECREASED Neuromuscular junction development GO:0007528 ⚠ ABNORMAL

Downstream

Impaired Neuromuscular Junction Transmission Reduced postsynaptic AChR density, altered channel gating, or impaired AChR clustering diminishes the endplate response to acetylcholine.

Show evidence (1 reference)

PMID:38696726 SUPPORT Human Clinical

"CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%)."

Identifies the dominant postsynaptic AChR-subunit and clustering-pathway genotypes.

NMJ Glycoprotein Glycosylation Defect

In glycosylation-related CMS, variants in the N-linked glycosylation pathway (GFPT1, DPAGT1, ALG2, ALG14, GMPPB) reduce glycosylation of multiple NMJ glycoproteins including the AChR, producing a combined endplate defect with a characteristic limb-girdle distribution and frequently tubular aggregates on muscle biopsy.

Skeletal muscle fiber CL:0008002

GFPT1 hgnc:4241 DPAGT1 hgnc:2995 GMPPB hgnc:22932

Protein N-linked glycosylation GO:0006487 ↓ DECREASED

Downstream

Impaired Neuromuscular Junction Transmission Hypoglycosylation of NMJ glycoproteins (including the AChR) produces a combined endplate defect that impairs neuromuscular transmission.

Show evidence (1 reference)

PMID:37721175 SUPPORT Human Clinical

"underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects"

Establishes the N-glycosylation pathway genes as a mechanistic cause of NMJ dysfunction.

Defective SNARE-Mediated Synaptic Vesicle Fusion

Calcium entering the motor nerve terminal through the P/Q-type calcium channel binds the two C2B domains of synaptotagmin-2 and triggers assembly of the SNARE complex - SNAP25, syntaxin and the vesicle SNARE synaptobrevin-1 (VAMP1) - which fuses acetylcholine-laden synaptic vesicles with the presynaptic membrane. Variants in SYT2 or VAMP1 break that calcium-to-fusion coupling, so fewer quanta are released per nerve impulse. The result is a Lambert-Eaton-like electrophysiology, with a decrement on low-frequency repetitive nerve stimulation and an increment at high frequency, which is why amifampridine, which enhances calcium entry into the nerve terminal, is effective in this group. This node is distinct from the upstream acetylcholine synthesis and vesicle-loading defects: here the vesicles are filled, but they do not fuse on cue.

Motor neuron presynaptic terminal CL:0000100

SYT2 hgnc:11510 VAMP1 hgnc:12642

Acetylcholine secretion at the nerve terminal GO:0014055 ↓ DECREASED Calcium-ion regulated exocytosis of synaptic vesicles GO:0017156 ↓ DECREASED

Downstream

Impaired Neuromuscular Junction Transmission Defective calcium-triggered fusion of acetylcholine-laden vesicles reduces the quantal content of each nerve impulse, lowering the endplate potential and the safety factor of neuromuscular transmission.

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Other

"The calcium ions bind to two C2B domains of synaptotagmin 2 (SYT2), and activate the SNARE complex to fuse synaptic vesicles containing ACh to the presynaptic membrane"

States the calcium-to-SNARE-to-fusion step this node models.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"SYT2-CMS, SNAP25-CMS, VAMP1-CMS, UNC13A-CMS, RPH3A-CMS, and LAMA5-CMS are characterized by defects in the SNARE complex, and phenotypically similar to Lambert-Eaton myasthenic syndrome (LEMS)"

Groups the SNARE-defect CMS genes and gives the Lambert-Eaton-like phenotype this node predicts.

Defective Motor Nerve Terminal Formation

A distinct presynaptic lesion in which the nerve terminal itself is built wrongly, rather than the acetylcholine cycle or the fusion machinery failing within an otherwise normal terminal. MYO9A, an unconventional myosin with a Rho GTPase-activating domain, regulates intracellular transport in peripheral nerve; SLC25A1 is a mitochondrial inner-membrane transporter. Knockdown of either in zebrafish disturbs the elongation and branching of spinal motor axons and compromises neuromuscular junction formation, so the myasthenia in CMS23 and CMS24 is attributed to defective nerve terminal development. Cholinesterase inhibitors are effective in MYO9A-CMS, whereas both cholinesterase inhibitors and amifampridine are generally ineffective in SLC25A1-CMS.

Motor neuron presynaptic terminal CL:0000100

SLC25A1 hgnc:10979 MYO9A hgnc:7608

Presynapse assembly at the motor endplate GO:0099054 ⚠ ABNORMAL Neuromuscular junction development GO:0007528 ⚠ ABNORMAL

Downstream

Impaired Neuromuscular Junction Transmission A malformed motor nerve terminal cannot establish or sustain a normal endplate, reducing the safety factor of neuromuscular transmission.

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Model Organism

"Knockdown of two orthologs, myo9aa/ab, in zebrafish causes shortening and abnormal branching of spinal motor neurons, and defective NMJ signal transmission"

Links MYO9A loss to abnormal motor axon morphology and failed neuromuscular transmission.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Model Organism

"Knockdown of Slc25a1 in zebrafish causes aberration in the axonal elongation of spinal motor neurons and compromise the formation of the NMJ"

Links SLC25A1 loss to the same defect in motor axon elongation and NMJ formation.

Endplate Collagen XIII Deficiency

Collagen XIII is a single-pass transmembrane collagen enriched at the neuromuscular junction that is required for the maturation and maintenance of endplate acetylcholine receptors. Biallelic COL13A1 variants reduce AChR clustering, and Col13a1-deficient mice form the junction abnormally. The mechanism therefore sits in the synaptic compartment alongside the COLQ lesion but is not an acetylcholinesterase-anchoring defect, which is why the two synaptic subtypes differ in their drug response: cholinesterase inhibitors are contraindicated in COLQ-CMS and merely ineffective in COL13A1-CMS, while salbutamol is reported to help in both.

Skeletal muscle fiber endplate CL:0008002

COL13A1 hgnc:2190

Skeletal muscle acetylcholine-gated channel clustering GO:0071340 ↓ DECREASED

Downstream

Impaired Neuromuscular Junction Transmission Loss of collagen XIII leaves endplate acetylcholine receptors immature and poorly maintained, reducing the endplate response to acetylcholine and the safety factor of neuromuscular transmission.

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS In Vitro

"Introduction of the pathogenic variants into C2C12 myotubes reduced AChR clustering"

Shows the reported COL13A1 variants impair AChR clustering in a myotube model.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Model Organism

"Col13a1-deficient mice show abnormal formation of the NMJ"

Mouse knockout reproduces abnormal neuromuscular junction formation.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 3

Dysphagia VERY_FREQUENT HP:0002015

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0002015 | Dysphagia | Very frequent (99-80%)"

Orphanet records dysphagia as very frequent in CMS.

Poor Suck VERY_FREQUENT HP:0002033

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0002033 | Poor suck | Very frequent (99-80%)"

Orphanet records poor suck as very frequent in CMS.

Feeding Difficulties VERY_FREQUENT HP:0011968

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0011968 | Feeding difficulties | Very frequent (99-80%)"

Orphanet records feeding difficulties as very frequent in CMS.

Eye 2

Ptosis HP:0000508

Show evidence (1 reference)

PMID:38475910 SUPPORT Human Clinical

"Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy."

Ptosis is a common presenting ocular sign in CMS.

Ophthalmoparesis HP:0000597

Show evidence (1 reference)

PMID:38475910 SUPPORT Human Clinical

"Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy."

Ophthalmoparesis is a common ocular manifestation of CMS.

Head and Neck 1

Bifacial Weakness Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:38907197 SUPPORT Human Clinical

"ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2"

Bifacial weakness was observed in a DOK7-CMS case series.

Limbs 1

Limb-Girdle Muscle Weakness HP:0003325

Show evidence (1 reference)

PMID:38907197 SUPPORT Human Clinical

"Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3"

Limb-girdle weakness was the most common manifestation in a DOK7-CMS series (6/7 patients).

Musculoskeletal 8

Fatigable Muscle Weakness Fatigable weakness HP:0003473

Show evidence (1 reference)

PMID:30808424 SUPPORT Human Clinical

"these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay."

Establishes fatigable/fluctuating weakness across muscle groups as the core CMS phenotype.

Increased Muscle Fatigability Increased muscle fatiguability HP:0003750

Show evidence (1 reference)

PMID:30808424 SUPPORT Human Clinical

"these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay."

Documents abnormal fatigability as a defining CMS feature.

Respiratory Insufficiency Respiratory insufficiency due to muscle weakness HP:0002747

Show evidence (1 reference)

PMID:38696726 SUPPORT Human Clinical

"At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation"

Quantifies respiratory insufficiency requiring ventilation in the most severely affected subtypes.

Bulbar Weakness Bulbar palsy HP:0001283

Show evidence (1 reference)

PMID:30808424 SUPPORT Human Clinical

"weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles"

Bulbar muscle weakness is part of the CMS clinical spectrum.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:30808424 SUPPORT Human Clinical

"weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay."

Hypotonia is a recognized CMS manifestation, particularly in infantile presentations.

Decremental RNS Response EMG: decremental response of compound muscle action potential to repetitive nerve stimulation HP:0003403

Show evidence (2 references)

PMID:38964204 SUPPORT Human Clinical

"RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement."

Documents a pathologic decremental RNS response in the majority of tested CMS patients.

PMID:36835142 SUPPORT Human Clinical

"Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS."

Establishes the decremental RNS response as the required diagnostic electrophysiology.

Neck Muscle Weakness VERY_FREQUENT HP:0000467

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0000467 | Neck muscle weakness | Very frequent (99-80%)"

Orphanet records neck muscle weakness as very frequent in CMS.

Arthrogryposis Multiplex Congenita FREQUENT HP:0002804

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0002804 | Arthrogryposis multiplex congenita | Frequent (79-30%)"

Orphanet records arthrogryposis multiplex congenita as frequent in CMS.

Nervous System 5

Motor Developmental Delay Motor delay HP:0001270

Show evidence (1 reference)

PMID:38475910 SUPPORT Human Clinical

"Delayed developmental motor milestones were detected in 13 patients (∼ 52%)"

Quantifies motor developmental delay in a genetically confirmed COLQ-CMS cohort.

Ataxia FREQUENT HP:0001251

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0001251 | Ataxia | Frequent (79-30%)"

Orphanet records ataxia as frequent in CMS.

Gait Disturbance FREQUENT HP:0001288

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0001288 | Gait disturbance | Frequent (79-30%)"

Orphanet records gait disturbance as frequent in CMS.

Central Sleep Apnea FREQUENT HP:0010536

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0010536 | Central sleep apnea | Frequent (79-30%)"

Orphanet records central sleep apnea as frequent in CMS.

Choking Episodes FREQUENT HP:0030842

Show evidence (1 reference)

ORPHA:590 SUPPORT Other

"HP:0030842 | Choking episodes | Frequent (79-30%)"

Orphanet records choking episodes as frequent in CMS.

Respiratory 1

Sudden Episodic Apnea HP:0002882

Temporal: RECURRENT

Show evidence (1 reference)

PMID:37212067 SUPPORT Human Clinical

"Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis."

Documents apneic crises as a feature of (presynaptic) CMS.

🧬

Genetic Associations

CHRNE (Causal)

Gene: CHRNE hgnc:1966

Show evidence (1 reference)

PMID:37721175 SUPPORT Human Clinical

"Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%)"

CHRNE was the single most common CMS gene in the Indian cohort.

DOK7 (Causal)

Gene: DOK7 hgnc:26594

Show evidence (2 references)

PMID:38696726 SUPPORT Human Clinical

"followed by variants in DOK7 (18.7%) and RAPSN (14%)"

DOK7 is the second most common CMS genotype in the French adult cohort.

PMID:38907197 SUPPORT Human Clinical

"c.1124_1127dupTGCC is the most common variant; three patients had this variant."

Identifies the recurrent DOK7 frameshift variant.

RAPSN (Causal)

Gene: RAPSN hgnc:9863

Show evidence (1 reference)

PMID:38696726 SUPPORT Human Clinical

"RAPSN patients, often severely affected in early childhood, subsequently improved."

Describes the characteristic RAPSN-CMS natural history.

COLQ (Causal)

Gene: COLQ hgnc:2226

Show evidence (1 reference)

PMID:38475910 SUPPORT Human Clinical

COLQ is the prototypical synaptic basal-lamina CMS gene.

CHAT (Causal)

Gene: CHAT hgnc:1912 gene page

Show evidence (1 reference)

PMID:37212067 SUPPORT Human Clinical

"They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling"

CHAT-mediated ACh synthesis defect underlies the commonest presynaptic CMS.

MUSK (Causal)

Gene: MUSK hgnc:7525

Show evidence (1 reference)

PMID:38696726 SUPPORT Human Clinical

"RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%)"

MUSK-CMS had one of the highest ICU-admission rates in the French cohort.

GFPT1 (Causal)

Gene: GFPT1 hgnc:4241

Show evidence (1 reference)

PMID:37721175 SUPPORT Human Clinical

"DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%)"

GFPT1 is a recurrent glycosylation-pathway CMS gene in the Indian cohort.

DPAGT1 (Causal)

Gene: DPAGT1 hgnc:2995 gene page

Show evidence (1 reference)

PMID:37721175 SUPPORT Human Clinical

"DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected."

Identifies a suspected DPAGT1 founder variant in this population.

CHRNA1 (Causal)

Gene: CHRNA1 hgnc:1955 gene page

CHRNB1 (Causal)

Gene: CHRNB1 hgnc:1961

CHRND (Causal)

Gene: CHRND hgnc:1965

AGRN (Causal)

Gene: AGRN hgnc:329 gene page

LRP4 (Causal)

Gene: LRP4 hgnc:6696 gene page

GMPPB (Causal)

Gene: GMPPB hgnc:22932 gene page

Show evidence (1 reference)

PMID:37721175 SUPPORT Human Clinical

"Myopathy and muscular dystrophy genes such as GMPPB and DES, presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum."

Documents the limb-girdle myopathic GMPPB-CMS presentation.

COL13A1 (Causal)

Gene: COL13A1 hgnc:2190

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS In Vitro

"Introduction of the pathogenic variants into C2C12 myotubes reduced AChR clustering"

Shows that the reported COL13A1 variants impair AChR clustering in a myotube model.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"All patients developed respiratory distress and weak sucking at birth"

Describes the uniform neonatal presentation of COL13A1-CMS.

SLC5A7 (Causal)

Gene: SLC5A7 hgnc:14025 gene page

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Other

"High affinity choline transporter (ChT, SLC5A7) expressed at the nerve terminal membrane uptakes choline to the nerve terminal"

States the presynaptic transport step that SLC5A7 carries out.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Later, recessive pathogenic variants of SLC5A7 were reported to cause CMS"

Establishes recessive SLC5A7 variants as a cause of CMS.

SLC18A3 (Causal)

Gene: SLC18A3 hgnc:10936

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Other

"Vesicular acetylcholine transporter (vAChT, SLC18A3) transports synthesized ACh to the synaptic vesicle"

States the vesicular loading step that SLC18A3 carries out.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Loss-of-function variants of SLC18A3 also cause CMS"

Establishes loss-of-function SLC18A3 variants as a cause of CMS.

PREPL (Causal)

Gene: PREPL hgnc:30228 gene page

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Other

"Loss-of-function variants of PREPL do not cause endplate AChR deficiency, but inhibit refilling of ACh to synaptic vesicles, reduce the number of releasable ACh quanta, and decrease the probability of vesicular release"

States the presynaptic mechanism of PREPL loss and excludes an AChR-deficiency mechanism.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Ten patients with PREPL-CMS including HCS were initially diagnosed as Prader-Willi syndrome"

Records the characteristic initial misdiagnosis in PREPL-CMS.

SLC25A1 (Causal)

Gene: SLC25A1 hgnc:10979

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Model Organism

"Knockdown of Slc25a1 in zebrafish causes aberration in the axonal elongation of spinal motor neurons and compromise the formation of the NMJ"

Zebrafish knockdown links SLC25A1 loss to defective motor axon and NMJ formation.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Other

"SLC25A1-CMS is thus predicted to be caused by presynaptic defects"

Assigns SLC25A1-CMS to the presynaptic compartment.

MYO9A (Causal)

Gene: MYO9A hgnc:7608

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Biallelic loss-of-function variants of MYO9A cause CMS"

Establishes biallelic MYO9A loss of function as a cause of CMS.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Model Organism

"Knockdown of two orthologs, myo9aa/ab, in zebrafish causes shortening and abnormal branching of spinal motor neurons, and defective NMJ signal transmission"

Zebrafish knockdown links MYO9A loss to abnormal motor axons and failed NMJ transmission.

VAMP1 (Causal)

Gene: VAMP1 hgnc:12642

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Biallelic loss-of-function variant of VAMP1 encoding another component of the SNARE complex, synaptobrevin1, cause a neonatal onset CMS"

Establishes biallelic VAMP1 loss of function as a cause of neonatal-onset CMS.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Model Organism

"Vamp1-deficient mice showed marked shrinkage of motor endplate and reduction in endplate potentials, which is electrophysiologically similar to LEMS"

Mouse knockout reproduces the Lambert-Eaton-like endplate physiology.

SYT2 (Causal)

Gene: SYT2 hgnc:11510 gene page

Show evidence (2 references)

PMID:36835142 SUPPORT REVIEW SYNTHESIS Other

"Synaptotagmin 2 (SYT2) senses Ca2+ ions entering into the nerve terminal through P/Q-type calcium channel and triggers the formation of the SNARE complex that releases ACh in synaptic vesicles to the synaptic space"

States the presynaptic calcium-sensing and SNARE-triggering step that SYT2 carries out.

PMID:36835142 SUPPORT REVIEW SYNTHESIS Human Clinical

"Hemiallelic pathogenic variants were identified in SYT2 in patients with CMS resembling LEMS"

Establishes SYT2 variants as a cause of Lambert-Eaton-like CMS.

💊

Medical Actions

Acetylcholinesterase Inhibitor Therapy

Action: acetylcholinesterase inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: pyridostigmine CHEBI:8665

Platform: Small molecule

Pyridostigmine and related cholinesterase inhibitors prolong ACh action at the endplate and benefit most CMS subtypes (e.g. AChR deficiency, RAPSN, glycosylation CMS). They are CONTRAINDICATED in endplate AChE deficiency (COLQ) and in slow-channel CMS, where they can worsen the cationic-overload endplate myopathy. Therapy selection is therefore genotype-guided.

Show evidence (1 reference)

PMID:36835142 SUPPORT Human Clinical

"cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS."

Establishes both the broad efficacy and the subtype-specific contraindication of cholinesterase inhibitors.

Beta-2 Adrenergic Agonist Therapy (Salbutamol)

Action: Pharmacotherapy NCIT:C15986

Agent: salbutamol CHEBI:2549

Platform: Small molecule

Salbutamol (albuterol) is broadly beneficial in CMS, including subtypes that do not respond to cholinesterase inhibitors (COLQ, DOK7). It is recommended as first-line therapy for DOK7-CMS.

Show evidence (2 references)

PMID:38907197 SUPPORT Human Clinical

"We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients."

Establishes salbutamol as first-line therapy for DOK7-CMS.

PMID:38475910 SUPPORT Human Clinical

"treatment with ephedrine and salbutamol was objectively efficient in all cases."

Documents objective salbutamol benefit in COLQ-CMS where AChE inhibitors fail.

Ephedrine Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: ephedrine CHEBI:15407

Platform: Small molecule

Ephedrine, a sympathomimetic, is effective in many CMS subtypes including endplate AChE deficiency (COLQ); historically used before salbutamol became a preferred alternative.

Show evidence (1 reference)

PMID:38475910 SUPPORT Human Clinical

"treatment with ephedrine and salbutamol was objectively efficient in all cases."

Documents objective ephedrine benefit in COLQ-CMS.

Amifampridine (3,4-Diaminopyridine) Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: amifampridine CHEBI:135948

Platform: Small molecule

Amifampridine (3,4-diaminopyridine) is a potassium-channel blocker that enhances presynaptic ACh release, beneficial in several CMS subtypes (notably presynaptic and fast-channel forms), but not effective in all.

Show evidence (1 reference)

PMID:36835142 SUPPORT Human Clinical

"ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS."

Establishes amifampridine as effective in most, but not all, CMS subtypes.

Noninvasive Ventilation

Action: noninvasive ventilation Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457

Platform: Device

Respiratory support, including noninvasive ventilation, is used for respiratory insufficiency and apneic crises; long-term ventilation is needed in the most severely affected subtypes (slow-channel CMS, DOK7).

Show evidence (1 reference)

PMID:38696726 SUPPORT Human Clinical

"At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation"

Documents the need for ventilatory support in severe CMS subtypes.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for affected individuals and families, given the mostly autosomal recessive inheritance (with autosomal dominant slow-channel CMS and some presynaptic forms). Molecular diagnosis is essential to guide genotype-specific therapy.

📊

Related Datasets

Neuromics / RD-Connect - congenital myasthenic syndrome ega:EGAS00001000693

This study contains omics datasets from the Neuromics project (www.rd-neuromics.eu) on rare neuromuscular and neurodegenerative disorders. Data includes BAM and VCF files from whole-exome sequencing and standardised phenotypic data mapped to the human phenotype ontology (HPO). In some cases proteomic, transcriptomic and metabolomic data may also be available. This study groups together datasets from individuals with a congenital myasthenic syndrome phenotype and also includes some unaffected family members. Search under the Neuromics name to find related studies for other neuromuscular and neurodegenerative disorders.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Congenital Myasthenic Syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

🔬

Clinical Trials

NCT06436742 PHASE_I RECRUITING

Phase 1b randomized, double-blind, placebo-controlled study of ARGX-119, an agonist antibody targeting MuSK, in adults with genetically confirmed DOK7-CMS; primary objective safety/tolerability, with exploratory efficacy including the 6-minute walk test.

Target Phenotypes: Limb-girdle muscle weakness HP:0003325

Show evidence (1 reference)

clinicaltrials:NCT06436742 SUPPORT

"ARGX-119"

Phase 1b trial of ARGX-119 in DOK7-CMS, an emerging targeted therapy for the postsynaptic clustering pathway.

{ }

Source YAML

click to show

name: Congenital Myasthenic Syndrome
creation_date: "2026-06-15T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Congenital Myasthenic Syndrome
  term:
    id: MONDO:0018940
    label: congenital myasthenic syndrome
parents:
- Neuromuscular Disease
description: >-
  Congenital myasthenic syndromes (CMS) are a clinically and genetically
  heterogeneous group of inherited disorders of neuromuscular junction (NMJ)
  transmission, caused by germline pathogenic variants in genes expressed at the
  motor endplate. At least 35 CMS-associated genes have been reported. Despite
  the diversity of the upstream molecular lesion, all subtypes converge on a
  single shared terminal mechanism — a reduced safety factor of neuromuscular
  transmission — that produces the uniform clinical phenotype of fatigable
  muscle weakness affecting ocular, bulbar, facial, axial, respiratory, and
  limb muscles. CMS is distinguished from autoimmune myasthenia gravis by its
  genetic (rather than antibody-mediated) etiology, typical onset in infancy or
  childhood, and the absence of anti-AChR / anti-MuSK autoantibodies.
  Diagnosis requires demonstration of a decremental compound muscle action
  potential response on low-frequency repetitive nerve stimulation (RNS) and/or
  abnormal single-fiber EMG jitter, with confirmatory genetic testing.
  This is the umbrella entry for the CMS family; subtypes are organized by the
  NMJ location of the defective protein — presynaptic, synaptic (basal-lamina),
  postsynaptic, and an N-glycosylation group — because therapeutic response is
  largely predictable from this mechanistic class (a drug helpful in one subtype
  may be ineffective or harmful in another). The prenatal-lethal CHRNA1 fetal
  akinesia disorder is curated separately as the severe end of the AChR
  spectrum, and CHAT-related CMS with episodic apnea (congenital myasthenic
  syndrome 6) is curated separately as Congenital_Myasthenic_Syndrome_6.
has_subtypes:
- name: Presynaptic
  display_name: Presynaptic CMS
  classification: nmj_compartment
  subtype_term:
    preferred_term: presynaptic congenital myasthenic syndrome
    term:
      id: MONDO:0700466
      label: presynaptic congenital myasthenic syndrome
  children:
  - CMS20
  - CMS21
  - CMS22
  - CMS23
  - CMS24
  - CMS25
  review_notes: >-
    Two further presynaptic gene-defined subtypes are curated as their own
    Disease entries rather than as children here, because each already carries
    its own pathophysiology nodes and phenotypes: CHAT-CMS (CMS6, MONDO:0009689) in
    kb/disorders/Congenital_Myasthenic_Syndrome_6.yaml, and SYT2-CMS (CMS7,
    MONDO:0014468, which covers both the dominant CMS7A and the recessive
    CMS7B forms) in kb/disorders/Congenital_Myasthenic_Syndrome_7.yaml.
    SNAP25-CMS (CMS18) is likewise not a child here: its MONDO term,
    MONDO:0014590, is the disease_term of
    kb/disorders/SNAP25_Encephalopathy.yaml, because OMIM has retitled
    OMIM:616330 as developmental and epileptic encephalopathy 117 while MONDO's
    label still lags. That entry's own notes record that its presynaptic
    myasthenic arm is deliberately under-curated there.
  description: >-
    Defects in acetylcholine (ACh) synthesis, vesicular packaging, or release at
    the motor nerve terminal. CHAT (choline acetyltransferase) is the commonest
    presynaptic gene; other genes include SLC5A7, SLC18A3, SNAP25, SYT2, VAMP1,
    and UNC13A. Presynaptic CMS comprise roughly 5-10% of all CMS and frequently
    present prenatally/neonatally with a severe phenotype that can include
    arthrogryposis, developmental delay, and episodic/sudden apneic crises
    (classically CHAT-CMS, "CMS with episodic apnea").
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0009689
        label: congenital myasthenic syndrome 6
      mapping_predicate: skos:narrowMatch
      mapping_source: MONDO
      mapping_justification: >-
        MONDO:0009689 (congenital myasthenic syndrome 6) is defined in MONDO
        as CMS caused specifically by CHAT mutations and is_a
        MONDO:0700466 (presynaptic congenital myasthenic syndrome); it is
        narrower than this Presynaptic subtype, which also covers SLC5A7-,
        SLC18A3-, SNAP25-, SYT2-, VAMP1-, and UNC13A-related presynaptic CMS.
        CHAT-CMS is modeled here as the commonest presynaptic gene, with a
        dedicated CHAT genetic entry below, and is curated in full as
        Congenital_Myasthenic_Syndrome_6.yaml.
  evidence:
  - reference: PMID:37212067
    reference_title: "Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft."
    explanation: Defines the presynaptic CMS mechanistic group by the affected step of ACh handling.
  - reference: PMID:37212067
    reference_title: "Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis."
    explanation: Establishes the severe prenatal/neonatal presentation typical of presynaptic CMS.
- name: Synaptic
  display_name: Synaptic (Basal-Lamina) CMS
  classification: nmj_compartment
  children:
  - CMS5
  - CMS19
  review_notes: >-
    Deliberately left without a subtype_term. MONDO's synaptic-CMS grouping
    class, MONDO:0020346 "synaptic congenital myasthenic syndrome", is
    obsolete. A synonym-inclusive MONDO search (runoak search "t~synaptic
    congenital myasthenic") surfaces that class and no other synaptic grouping
    class, and no synaptic grouping class appears among the 37 is_a
    descendants of MONDO:0018940 either, where the live presynaptic
    (MONDO:0700466) and postsynaptic (MONDO:0020344) classes both do. No live
    MONDO term therefore denotes this group. MONDO classifies CMS19
    (COL13A1) under both its presynaptic and its postsynaptic classes; it is
    placed here instead, following PMID:36835142, whose Table 1 files COL13A1
    with COLQ and LAMB2 as synaptic CMS.
  description: >-
    Defects in proteins of the synaptic basal lamina. The prototype is COLQ-CMS:
    COLQ encodes the collagen-like tail subunit that anchors acetylcholinesterase
    (AChE) in the synaptic cleft, so biallelic loss produces endplate AChE
    deficiency with prolonged ACh action. Other synaptic-cleft genes include
    LAMB2, LAMA5, and COL13A1. Synaptic CMS characteristically does NOT respond
    to (and may worsen with) cholinesterase inhibitors, but responds to ephedrine
    and salbutamol.
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency."
    explanation: Defines COLQ-CMS as the synaptic basal-lamina subtype with endplate AChE deficiency.
- name: Postsynaptic
  display_name: Postsynaptic CMS
  classification: nmj_compartment
  subtype_term:
    preferred_term: postsynaptic congenital myasthenic syndrome
    term:
      id: MONDO:0020344
      label: postsynaptic congenital myasthenic syndrome
  children:
  - CMS1A
  - CMS1B
  - CMS2A
  - CMS2C
  - CMS3A
  - CMS3B
  - CMS3C
  - CMS4
  - CMS8
  - CMS9
  - CMS10
  - CMS11
  - CMS17
  review_notes: >-
    SCN4A-CMS (CMS16, MONDO:0013620) is a further postsynaptic MONDO term, for
    a sarcolemmal sodium-channel rather than an AChR-pathway defect. Nothing in
    kb/ carries MONDO:0013620 or the string CMS16, so it is genuinely
    uncurated; SCN4A itself is bound in other entries, for other SCN4A
    diseases. MONDO also files CMS8 (AGRN) under its presynaptic
    class as well as here, which is defensible: agrin is released from the
    nerve terminal even though it acts on the postsynaptic LRP4-MuSK complex.
  description: >-
    Defects of the postsynaptic membrane — by far the largest group. Includes
    primary AChR deficiency and AChR kinetic abnormalities (slow-channel and
    fast-channel syndromes) from variants in the AChR subunit genes (CHRNE,
    CHRNA1, CHRNB1, CHRND, CHRNG), and defects of endplate development /
    maintenance and AChR clustering (RAPSN, DOK7, MUSK, AGRN, LRP4). CHRNE
    low-expressor variants and DOK7 are among the most common CMS genotypes
    overall. Slow-channel CMS (SCCMS) is the principal autosomal dominant form.
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%)."
    explanation: Quantifies the dominant postsynaptic genotypes (CHRNE, DOK7, RAPSN) in a 235-patient adult cohort.
- name: Glycosylation
  display_name: Glycosylation-Related CMS
  classification: nmj_compartment
  children:
  - CMS12
  - CMS13
  review_notes: >-
    Deliberately left without a subtype_term. MONDO's grouping class for this
    set, MONDO:0018144 "congenital myasthenic syndromes with glycosylation
    defect", is obsolete; a synonym-inclusive MONDO search ("t~glycosylation
    defect") returns it and the three member terms CMS12, CMS13 and CMS14, but
    no live grouping class. The other three glycosylation CMS genes are
    curated elsewhere rather than here: ALG2-CMS (CMS14, MONDO:0014543) is a
    has_subtypes row of
    kb/disorders/ALG2-Congenital_Disorder_of_Glycosylation.yaml, a lump/split
    call that entry's own notes argue explicitly; ALG14-CMS (CMS15,
    MONDO:0014542) has its own Disease entry at
    kb/disorders/Congenital_Myasthenic_Syndrome_15.yaml; and GMPPB-CMS has no
    numbered CMS designation and no term among the 37 is_a descendants of
    MONDO:0018940, so it is recorded only in genetic: and on this row.
    MONDO:0700084 "myopathy caused by variation in GMPPB" exists but is a
    myopathy class, not a congenital myasthenic syndrome one.
  description: >-
    Defects in the N-linked protein glycosylation pathway (GFPT1, DPAGT1, ALG2,
    ALG14, GMPPB) that impair glycosylation of multiple NMJ glycoproteins,
    including the AChR, producing a "combination" endplate defect. These
    typically present as a limb-girdle CMS, often with tubular aggregates on
    muscle biopsy and elevated creatine kinase, and respond to cholinesterase
    inhibitors. Glycosylation genes are an increasingly recognized cause,
    accounting for over 20% of cases in some cohorts.
  evidence:
  - reference: PMID:37721175
    reference_title: "Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postsynaptic defects were most common (62.4%), followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%)."
    explanation: Quantifies the relative frequency of the four mechanistic subtype groups in a 156-patient Indian cohort.
- name: CMS1A
  display_name: CHRNA1-related congenital myasthenic syndrome (CMS1A)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 1A
    term:
      id: MONDO:0011088
      label: congenital myasthenic syndrome 1A
  genes:
  - preferred_term: CHRNA1
    term:
      id: hgnc:1955
      label: CHRNA1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    Slow-channel CMS (SCCMS) caused by a heterozygous missense variant in
    CHRNA1, the AChR alpha-1 subunit. Slow-channel variants abnormally prolong
    the AChR channel opening time, so the resting membrane potential
    depolarizes, AChRs desensitize, and excessive calcium influx produces an
    endplate myopathy. Cholinesterase inhibitors are mostly ineffective,
    whereas quinidine and fluoxetine ameliorate the slow-channel phenotype.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "SCCMS | CHRNA1 | CMS1A | (14) | AD | decrement, repetitive CMAP"
    explanation: >-
      Table 1 of this review assigns CHRNA1 to CMS1A within the SCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
- name: CMS1B
  display_name: CHRNA1-related congenital myasthenic syndrome (CMS1B)
  classification: gene_defined
  subtype_term:
    preferred_term: myasthenic syndrome, congenital, 1B, fast-channel
    term:
      id: MONDO:0012156
      label: myasthenic syndrome, congenital, 1B, fast-channel
  genes:
  - preferred_term: CHRNA1
    term:
      id: hgnc:1955
      label: CHRNA1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Fast-channel CMS (FCCMS) caused by biallelic CHRNA1 variants that
    abnormally shorten the AChR channel opening time, kinetically the mirror
    image of the slow-channel form in the same gene. Cholinesterase inhibitors
    are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "FCCMS | CHRNA1 | CMS1B | (3) c | AR | decrement"
    explanation: >-
      Table 1 of this review assigns CHRNA1 to CMS1B within the FCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
- name: CMS2A
  display_name: CHRNB1-related congenital myasthenic syndrome (CMS2A)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 2A
    term:
      id: MONDO:0014581
      label: congenital myasthenic syndrome 2A
  genes:
  - preferred_term: CHRNB1
    term:
      id: hgnc:1961
      label: CHRNB1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    Slow-channel CMS caused by a heterozygous missense variant in CHRNB1, the
    AChR beta-1 subunit, sharing the prolonged-channel-opening mechanism and
    the quinidine and fluoxetine response of the other slow-channel subtypes.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "SCCMS | CHRNB1 | CMS2A | (5) | AD | decrement, repetitive CMAP"
    explanation: >-
      Table 1 of this review assigns CHRNB1 to CMS2A within the SCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
- name: CMS2C
  display_name: CHRNB1-related congenital myasthenic syndrome (CMS2C)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 2C
    term:
      id: MONDO:0014582
      label: congenital myasthenic syndrome 2C
  genes:
  - preferred_term: CHRNB1
    term:
      id: hgnc:1961
      label: CHRNB1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Endplate AChR deficiency caused by biallelic CHRNB1 variants that reduce
    the number of AChRs at the endplate rather than altering their gating,
    giving a low-amplitude miniature endplate potential and current.
    Cholinesterase inhibitors, ephedrine, salbutamol and amifampridine are all
    generally effective for endplate AChR deficiency. No fast-channel CHRNB1
    subtype has been reported, and a synonym-inclusive MONDO search returns no
    CMS2B term.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Endplate AChR deficiency | CHRNB1 | CMS2C | - b | AR | decrement"
    explanation: >-
      Table 1 of this review assigns CHRNB1 to CMS2C within the Endplate AChR
      deficiency pathomechanistic group, with the inheritance pattern and the
      low-frequency repetitive-nerve-stimulation finding quoted here.
- name: CMS3A
  display_name: CHRND-related congenital myasthenic syndrome (CMS3A)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 3A
    term:
      id: MONDO:0014583
      label: congenital myasthenic syndrome 3A
  genes:
  - preferred_term: CHRND
    term:
      id: hgnc:1965
      label: CHRND
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    Slow-channel CMS caused by a heterozygous missense variant in CHRND, the
    AChR delta subunit, producing prolonged synaptic currents and early-onset
    progressive weakness.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "SCCMS | CHRND | CMS3A | (4) | AD | decrement, repetitive CMAP"
    explanation: >-
      Table 1 of this review assigns CHRND to CMS3A within the SCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
- name: CMS3B
  display_name: CHRND-related congenital myasthenic syndrome (CMS3B)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 3B
    term:
      id: MONDO:0014584
      label: congenital myasthenic syndrome 3B
  genes:
  - preferred_term: CHRND
    term:
      id: hgnc:1965
      label: CHRND
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Fast-channel CMS caused by biallelic CHRND variants that abbreviate the
    endplate current so that it decays before the muscle fibre reaches
    depolarization threshold. Cholinesterase inhibitors are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "FCCMS | CHRND | CMS3B | (1) c | AR | decrement"
    explanation: >-
      Table 1 of this review assigns CHRND to CMS3B within the FCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
- name: CMS3C
  display_name: CHRND-related congenital myasthenic syndrome (CMS3C)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 3C
    term:
      id: MONDO:0014585
      label: congenital myasthenic syndrome 3C
  genes:
  - preferred_term: CHRND
    term:
      id: hgnc:1965
      label: CHRND
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Endplate AChR deficiency caused by biallelic CHRND variants that reduce
    endplate AChR number. Separating this from the fast-channel CHRND subtype
    requires microelectrode or single-channel recordings, whose unavailability
    is likely to account for the rarity of fast-channel CMS.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Endplate AChR deficiency | CHRND | CMS3C | - b | AR | decrement"
    explanation: >-
      Table 1 of this review assigns CHRND to CMS3C within the Endplate AChR
      deficiency pathomechanistic group, with the inheritance pattern and the
      low-frequency repetitive-nerve-stimulation finding quoted here.
- name: CMS4
  display_name: CHRNE-related congenital myasthenic syndrome (CMS4)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 4
    term:
      id: MONDO:1040021
      label: congenital myasthenic syndrome 4
  genes:
  - preferred_term: CHRNE
    term:
      id: hgnc:1966
      label: CHRNE
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    The CHRNE-defined branch of CMS, and the MONDO grouping term above CMS4A
    (slow-channel), CMS4B (fast-channel) and CMS4C (endplate AChR deficiency).
    CHRNE encodes the AChR epsilon subunit, which replaces the embryonic gamma
    subunit after birth; a biallelic lack of the epsilon subunit can be
    compensated for by the gamma subunit and is not fatal. CHRNE is the most
    commonly affected CMS gene in several cohorts. Apart from one dominantly
    inherited hemiallelic missense variant causing slow-channel disease, the
    effects of CHRNE missense variants cannot be differentiated without
    expression studies.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "SCCMS | CHRNE | CMS4A | (11) | AD/AR | decrement, repetitive CMAP"
    explanation: >-
      Table 1 of this review assigns CHRNE to CMS4A within the SCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "FCCMS | CHRNE | CMS4B | (6) c | AR | decrement"
    explanation: >-
      Table 1 of this review assigns CHRNE to CMS4B within the FCCMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Endplate AChR deficiency | CHRNE | CMS4C | - b | AR | decrement"
    explanation: >-
      Table 1 of this review assigns CHRNE to CMS4C within the Endplate AChR
      deficiency pathomechanistic group, with the inheritance pattern and the
      low-frequency repetitive-nerve-stimulation finding quoted here.
- name: CMS5
  display_name: COLQ-related congenital myasthenic syndrome (CMS5)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 5
    term:
      id: MONDO:0011281
      label: congenital myasthenic syndrome 5
  genes:
  - preferred_term: COLQ
    term:
      id: hgnc:2226
      label: COLQ
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Endplate acetylcholinesterase deficiency caused by biallelic COLQ
    variants. ColQ is the triple-helical collagenic tail that anchors the
    asymmetric forms of acetylcholinesterase at the neuromuscular junction, so
    its loss leaves acetylcholine in the cleft for a prolonged period and a
    single nerve stimulus elicits a repetitive CMAP. Cholinesterase inhibitors
    are contraindicated because of severe adverse effects including
    respiratory arrest in some patients; ephedrine and salbutamol are
    effective in some patients.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Endplate AChE deficiency | COLQ | CMS5"
    explanation: >-
      Table 1 of this review assigns COLQ to CMS5 within the Endplate AChE
      deficiency pathomechanistic group, the assignment quoted here being the
      review's own gene-to-subtype-number mapping.
- name: CMS8
  display_name: AGRN-related congenital myasthenic syndrome (CMS8)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 8
    term:
      id: MONDO:0014052
      label: congenital myasthenic syndrome 8
  genes:
  - preferred_term: AGRN
    term:
      id: hgnc:329
      label: AGRN
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective AChR clustering, from biallelic variants in AGRN.
    Agrin is released from the nerve terminal and binds LRP4 at the motor
    endplate, which induces MuSK phosphorylation and drives AChR clustering.
    Cholinesterase inhibitors are ineffective or only mildly effective;
    ephedrine and salbutamol are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective AChR clustering | AGRN | CMS8"
    explanation: >-
      Table 1 of this review assigns AGRN to CMS8 within the CMS caused by
      defective AChR clustering pathomechanistic group, the assignment quoted
      here being the review's own gene-to-subtype-number mapping.
- name: CMS9
  display_name: MUSK-related congenital myasthenic syndrome (CMS9)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 9
    term:
      id: MONDO:0014587
      label: congenital myasthenic syndrome 9
  genes:
  - preferred_term: MUSK
    term:
      id: hgnc:7525
      label: MUSK
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective AChR clustering, from biallelic variants in MUSK.
    Agrin-bound LRP4 induces MuSK phosphorylation, and phosphorylated MuSK in
    turn phosphorylates the AChR beta-1 subunit, which binds rapsyn to form
    endplate AChR clusters. Cholinesterase inhibitors are effective in some
    patients and worsen weakness in others, while amifampridine and salbutamol
    are mildly or markedly effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective AChR clustering | MUSK | CMS9"
    explanation: >-
      Table 1 of this review assigns MUSK to CMS9 within the CMS caused by
      defective AChR clustering pathomechanistic group, the assignment quoted
      here being the review's own gene-to-subtype-number mapping.
- name: CMS10
  display_name: DOK7-related congenital myasthenic syndrome (CMS10)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 10
    term:
      id: MONDO:0009690
      label: congenital myasthenic syndrome 10
  genes:
  - preferred_term: DOK7
    term:
      id: hgnc:26594
      label: DOK7
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective AChR clustering, from biallelic variants in DOK7,
    the cytoplasmic adaptor that enhances MuSK phosphorylation. DOK7 is one of
    the genes in which pathogenic CMS variants are frequently observed, and it
    presents as a limb-girdle myasthenia with proximal and truncal weakness
    and frequent scoliosis. Cholinesterase inhibitors are generally
    ineffective and sometimes worsen symptoms, whereas ephedrine and
    salbutamol are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective AChR clustering | DOK7 | CMS10"
    explanation: >-
      Table 1 of this review assigns DOK7 to CMS10 within the CMS caused by
      defective AChR clustering pathomechanistic group, the assignment quoted
      here being the review's own gene-to-subtype-number mapping.
- name: CMS11
  display_name: RAPSN-related congenital myasthenic syndrome (CMS11)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 11
    term:
      id: MONDO:0014588
      label: congenital myasthenic syndrome 11
  genes:
  - preferred_term: RAPSN
    term:
      id: hgnc:9863
      label: RAPSN
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Endplate AChR deficiency caused by biallelic variants in RAPSN, the
    submembranous scaffold that binds the phosphorylated AChR beta-1 subunit
    to form endplate AChR clusters. Onset is typically neonatal with
    fluctuating lid ptosis, bulbar signs, neck muscle weakness and mild limb
    weakness, with episodic worsening in adults. Cholinesterase inhibitors,
    ephedrine, salbutamol and amifampridine are all generally effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Endplate AChR deficiency | RAPSN | CMS11"
    explanation: >-
      Table 1 of this review assigns RAPSN to CMS11 within the Endplate AChR
      deficiency pathomechanistic group, the assignment quoted here being the
      review's own gene-to-subtype-number mapping.
- name: CMS12
  display_name: GFPT1-related congenital myasthenic syndrome (CMS12)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 12
    term:
      id: MONDO:0012518
      label: congenital myasthenic syndrome 12
  genes:
  - preferred_term: GFPT1
    term:
      id: hgnc:4241
      label: GFPT1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Glycosylation-deficient CMS caused by biallelic variants in GFPT1, which
    controls the rate-limiting step of the hexosamine pathway feeding N-linked
    glycosylation. Muscle biopsy shows tubular aggregates and serum creatine
    kinase is raised to about three times the upper limit of normal.
    Cholinesterase inhibitors and salbutamol are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "~3 times in tubular aggregates in GFPT1-CMS and DOK7-CMS"
    explanation: >-
      Sources the creatine kinase elevation quoted in this row's description.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Glycosylation-deficient CMS | GFPT1 | CMS12"
    explanation: >-
      Table 1 of this review assigns GFPT1 to CMS12 within the
      Glycosylation-deficient CMS pathomechanistic group, the assignment quoted
      here being the review's own gene-to-subtype-number mapping.
- name: CMS13
  display_name: DPAGT1-related congenital myasthenic syndrome (CMS13)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 13
    term:
      id: MONDO:0013883
      label: congenital myasthenic syndrome 13
  genes:
  - preferred_term: DPAGT1
    term:
      id: hgnc:2995
      label: DPAGT1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Glycosylation-deficient CMS caused by biallelic variants in DPAGT1, which
    catalyses the first committed step of N-linked glycosylation. Muscle
    biopsy shows tubular aggregates or rimmed vacuoles. This is the
    limb-girdle myasthenic disease allelic to the systemic DPAGT1 congenital
    disorder of glycosylation, which has its own MONDO term and its own KB
    entry.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Glycosylation-deficient CMS | DPAGT1 | CMS13"
    explanation: >-
      Table 1 of this review assigns DPAGT1 to CMS13 within the
      Glycosylation-deficient CMS pathomechanistic group, the assignment quoted
      here being the review's own gene-to-subtype-number mapping.
- name: CMS17
  display_name: LRP4-related congenital myasthenic syndrome (CMS17)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 17
    term:
      id: MONDO:0014578
      label: congenital myasthenic syndrome 17
  genes:
  - preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective AChR clustering, from biallelic variants in LRP4,
    the agrin co-receptor: two LRP4 molecules bind two MuSK molecules to form
    a heterotetrameric receptor complex, and agrin binding to LRP4 induces
    MuSK phosphorylation. Cholinesterase inhibitors worsen symptoms in
    LRP4-CMS.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective AChR clustering | LRP4 | CMS17 | 1 | AR | decrement"
    explanation: >-
      Table 1 of this review assigns LRP4 to CMS17 within the CMS caused by
      defective AChR clustering pathomechanistic group, with the inheritance
      pattern and the low-frequency repetitive-nerve-stimulation finding quoted
      here.
- name: CMS19
  display_name: COL13A1-related congenital myasthenic syndrome (CMS19)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 19
    term:
      id: MONDO:0014745
      label: congenital myasthenic syndrome 19
  genes:
  - preferred_term: COL13A1
    term:
      id: hgnc:2190
      label: COL13A1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by biallelic variants in COL13A1, a single-pass transmembrane
    collagen enriched at the neuromuscular junction that is essential for the
    maturation and maintenance of endplate AChRs. All reported patients
    developed respiratory distress and weak sucking at birth, with facial,
    bulbar, respiratory and truncal weakness while the limb muscles are
    relatively spared. Cholinesterase inhibitors are ineffective, whereas
    salbutamol and amifampridine are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Synaptic CMS | COL13A1 | CMS19 | 41 | AR | decrement"
    explanation: >-
      Table 1 of this review assigns COL13A1 to CMS19 within the Synaptic CMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
- name: CMS20
  display_name: SLC5A7-related congenital myasthenic syndrome (CMS20)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 20
    term:
      id: MONDO:0014939
      label: congenital myasthenic syndrome 20
  genes:
  - preferred_term: SLC5A7
    term:
      id: hgnc:14025
      label: SLC5A7
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective recycling of acetylcholine, from biallelic
    loss-of-function variants in SLC5A7, the high-affinity choline transporter
    that takes choline up into the nerve terminal. Hemiallelic frameshifting
    variants of the same gene instead cause autosomal dominant distal
    hereditary motor neuropathy type VIIA, and why comparable reductions in
    transporter activity give two different phenotypes remains unknown. The
    presentation is neonatal-onset episodic apnea with hypotonia, weakness and
    weak crying. Cholinesterase inhibitors are effective and ephedrine adds
    benefit, whereas amifampridine is ineffective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective recycling of ACh | SLC5A7 | CMS20 | 12 | AR | decrement at rest or only after isometric muscle contraction"
    explanation: >-
      Table 1 of this review assigns SLC5A7 to CMS20 within the CMS caused by
      defective recycling of ACh pathomechanistic group, with the inheritance
      pattern and the low-frequency repetitive-nerve-stimulation finding quoted
      here.
- name: CMS21
  display_name: SLC18A3-related congenital myasthenic syndrome (CMS21)
  classification: gene_defined
  subtype_term:
    preferred_term: congenital myasthenic syndrome 21
    term:
      id: MONDO:0014983
      label: congenital myasthenic syndrome 21
  genes:
  - preferred_term: SLC18A3
    term:
      id: hgnc:10936
      label: SLC18A3
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective recycling of acetylcholine, from biallelic
    variants in SLC18A3, the vesicular acetylcholine transporter that loads
    newly synthesized acetylcholine into synaptic vesicles. SLC18A3 lies
    within the first intron of CHAT, a nested arrangement conserved as far
    back as C. elegans. Patients show severe weakness at birth with hypotonia,
    arthrogryposis and respiratory distress, and a decremental CMAP may appear
    only after isometric contraction. Cholinesterase inhibitors, ephedrine and
    amifampridine are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective recycling of ACh | SLC18A3 | CMS21 | 7 | AR | decrement at rest or only after isometric muscle contraction"
    explanation: >-
      Table 1 of this review assigns SLC18A3 to CMS21 within the CMS caused by
      defective recycling of ACh pathomechanistic group, with the inheritance
      pattern and the low-frequency repetitive-nerve-stimulation finding quoted
      here.
- name: CMS22
  display_name: PREPL-related congenital myasthenic syndrome (CMS22)
  classification: gene_defined
  subtype_term:
    preferred_term: myasthenic syndrome, congenital, 22
    term:
      id: MONDO:0044299
      label: myasthenic syndrome, congenital, 22
  genes:
  - preferred_term: PREPL
    term:
      id: hgnc:30228
      label: PREPL
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective recycling of acetylcholine, from loss-of-function
    variants in PREPL, a serine peptidase whose physiological substrate is
    unknown. PREPL loss does not cause endplate AChR deficiency; it inhibits
    refilling of acetylcholine into synaptic vesicles, reduces the number of
    releasable quanta and lowers the probability of vesicular release. PREPL
    and SLC3A1 are encoded on opposite strands and overlap at their 3-prime
    ends, so a deletion spanning both gives hypotonia-cystinuria syndrome. Ten
    reported patients, including those with the contiguous deletion, were
    initially diagnosed as Prader-Willi syndrome. Cholinesterase inhibitors
    are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective recycling of ACh | PREPL | CMS22 | 18 | AR | decrement"
    explanation: >-
      Table 1 of this review assigns PREPL to CMS22 within the CMS caused by
      defective recycling of ACh pathomechanistic group, with the inheritance
      pattern and the low-frequency repetitive-nerve-stimulation finding quoted
      here.
- name: CMS23
  display_name: SLC25A1-related congenital myasthenic syndrome (CMS23)
  classification: gene_defined
  subtype_term:
    preferred_term: myasthenic syndrome, congenital, 23, presynaptic
    term:
      id: MONDO:0032596
      label: myasthenic syndrome, congenital, 23, presynaptic
  genes:
  - preferred_term: SLC25A1
    term:
      id: hgnc:10979
      label: SLC25A1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective nerve terminal formation, from biallelic variants
    in SLC25A1, a mitochondrial inner-membrane transporter whose variants also
    cause combined D-2- and L-2-hydroxyglutaric aciduria. Knockdown in
    zebrafish disturbs axonal elongation of spinal motor neurons and
    compromises neuromuscular junction formation, so the myasthenia is
    predicted to arise presynaptically. Limb myasthenia and palpebral ptosis
    are the shared clinical features. Cholinesterase inhibitors and
    amifampridine are generally ineffective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective nerve terminal formation | SLC25A1 | CMS23 | 19 | AR | decrement"
    explanation: >-
      Table 1 of this review assigns SLC25A1 to CMS23 within the CMS caused by
      defective nerve terminal formation pathomechanistic group, with the
      inheritance pattern and the low-frequency repetitive-nerve-stimulation
      finding quoted here.
- name: CMS24
  display_name: MYO9A-related congenital myasthenic syndrome (CMS24)
  classification: gene_defined
  subtype_term:
    preferred_term: myasthenic syndrome, congenital, 24, presynaptic
    term:
      id: MONDO:0032597
      label: myasthenic syndrome, congenital, 24, presynaptic
  genes:
  - preferred_term: MYO9A
    term:
      id: hgnc:7608
      label: MYO9A
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    CMS caused by defective nerve terminal formation, from biallelic
    loss-of-function variants in MYO9A, an unconventional myosin carrying a
    Rho GTPase-activating domain that regulates intracellular transport in
    peripheral nerve. Knockdown of the two zebrafish orthologues shortens and
    abnormally branches spinal motor axons and impairs neuromuscular
    transmission. Reported patients had reduced fetal movement, neonatal
    ptosis, later swallowing difficulty, episodic apnea and developmental
    delay. Cholinesterase inhibitors are effective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "CMS caused by defective nerve terminal formation | MYO9A | CMS24 | 3 | AR | decrement"
    explanation: >-
      Table 1 of this review assigns MYO9A to CMS24 within the CMS caused by
      defective nerve terminal formation pathomechanistic group, with the
      inheritance pattern and the low-frequency repetitive-nerve-stimulation
      finding quoted here.
- name: CMS25
  display_name: VAMP1-related congenital myasthenic syndrome (CMS25)
  classification: gene_defined
  subtype_term:
    preferred_term: myasthenic syndrome, congenital, 25, presynaptic
    term:
      id: MONDO:0032675
      label: myasthenic syndrome, congenital, 25, presynaptic
  genes:
  - preferred_term: VAMP1
    term:
      id: hgnc:12642
      label: VAMP1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Lambert-Eaton-like CMS caused by biallelic loss-of-function variants in
    VAMP1, which encodes synaptobrevin-1, the vesicle SNARE. Because the
    lesion is in vesicle fusion itself, low-frequency repetitive nerve
    stimulation produces a decrement while high-frequency stimulation produces
    an increment, as in Lambert-Eaton myasthenic syndrome. Cholinesterase
    inhibitors are effective; amifampridine has not been given and its effect
    is unknown.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "LEMS-like CMS | VAMP1 | CMS25 | 9 | AR | decrement"
    explanation: >-
      Table 1 of this review assigns VAMP1 to CMS25 within the LEMS-like CMS
      pathomechanistic group, with the inheritance pattern and the low-frequency
      repetitive-nerve-stimulation finding quoted here.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_nmj_transmission_failure_model
  hypothesis_label: Canonical NMJ Transmission Failure Model
  status: CANONICAL
  description: >-
    Congenital myasthenic syndromes are caused by germline pathogenic variants
    in genes encoding proteins of the neuromuscular junction. Regardless of
    whether the primary lesion is presynaptic (impaired ACh synthesis, packaging,
    or release), synaptic (basal-lamina / endplate AChE anchoring), postsynaptic
    (AChR deficiency or abnormal channel kinetics, or impaired AChR clustering),
    or in the N-glycosylation pathway, the converging consequence is a reduced
    safety factor of neuromuscular transmission — the endplate potential fails to
    reliably reach the threshold needed to trigger a muscle fiber action
    potential, especially during sustained or repetitive activity. This
    manifests electrophysiologically as a decremental CMAP response on
    low-frequency repetitive nerve stimulation and increased jitter/blocking on
    single-fiber EMG, and clinically as fatigable muscle weakness. The
    mechanistic subtype predicts the pharmacological response: cholinesterase
    inhibitors help most groups but are contraindicated in some (e.g. COLQ /
    endplate AChE deficiency and slow-channel CMS), whereas salbutamol/ephedrine
    are broadly beneficial.
pathophysiology:
- name: Impaired Neuromuscular Junction Transmission
  conforms_to: "neuromuscular_transmission_failure#Loss of the Safety Factor of Neuromuscular Transmission"
  description: >-
    The shared terminal mechanism of all CMS subtypes. A defect in any
    component of the motor endplate — presynaptic ACh handling, synaptic AChE
    anchoring, postsynaptic AChR density/kinetics, AChR clustering, or NMJ
    glycoprotein glycosylation — reduces the safety factor of cholinergic
    synaptic transmission. The endplate potential generated by ACh release
    becomes insufficient to consistently trigger a postsynaptic muscle fiber
    action potential, and this insufficiency worsens with repetitive activity,
    producing fatigable weakness.
  cell_types:
  - preferred_term: Skeletal muscle fiber (postsynaptic motor endplate)
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: Motor neuron (presynaptic terminal)
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Cholinergic synaptic transmission at the NMJ
    term:
      id: GO:0007271
      label: synaptic transmission, cholinergic
    modifier: DECREASED
  - preferred_term: Neuromuscular synaptic transmission
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
    modifier: DECREASED
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ)."
    explanation: Establishes impaired NMJ transmission as the unifying pathomechanism across all CMS genes.
  - reference: PMID:37239850
    reference_title: "Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission."
    explanation: Confirms that disrupted NMJ transmission is the common terminal mechanism despite phenotypic diversity.
  downstream:
  - target: Neck Muscle Weakness
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records neck muscle weakness as a very frequent phenotype in
      congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000467 | Neck muscle weakness | Very frequent (99-80%)"
      explanation: Orphanet records neck muscle weakness as very frequent in CMS.
  - target: Dysphagia
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records dysphagia as a very frequent bulbar phenotype in
      congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002015 | Dysphagia | Very frequent (99-80%)"
      explanation: Orphanet records dysphagia as very frequent in CMS.
  - target: Poor Suck
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records poor suck as a very frequent early feeding phenotype in
      congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002033 | Poor suck | Very frequent (99-80%)"
      explanation: Orphanet records poor suck as very frequent in CMS.
  - target: Feeding Difficulties
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records feeding difficulties as a very frequent phenotype in
      congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011968 | Feeding difficulties | Very frequent (99-80%)"
      explanation: Orphanet records feeding difficulties as very frequent in CMS.
  - target: Ataxia
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records ataxia as a frequent neurologic phenotype in congenital
      myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001251 | Ataxia | Frequent (79-30%)"
      explanation: Orphanet records ataxia as frequent in CMS.
  - target: Gait Disturbance
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records gait disturbance as a frequent neurologic phenotype in
      congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001288 | Gait disturbance | Frequent (79-30%)"
      explanation: Orphanet records gait disturbance as frequent in CMS.
  - target: Central Sleep Apnea
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records central sleep apnea as a frequent respiratory phenotype
      in congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0010536 | Central sleep apnea | Frequent (79-30%)"
      explanation: Orphanet records central sleep apnea as frequent in CMS.
  - target: Choking Episodes
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records choking episodes as a frequent feeding/respiratory
      phenotype in congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0030842 | Choking episodes | Frequent (79-30%)"
      explanation: Orphanet records choking episodes as frequent in CMS.
  - target: Arthrogryposis Multiplex Congenita
    causal_link_type: UNKNOWN
    description: >-
      Orphanet records arthrogryposis multiplex congenita as a frequent
      musculoskeletal phenotype in congenital myasthenic syndrome.
    evidence:
    - reference: ORPHA:590
      reference_title: Congenital myasthenic syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002804 | Arthrogryposis multiplex congenita | Frequent (79-30%)"
      explanation: Orphanet records arthrogryposis multiplex congenita as frequent in CMS.
- name: Presynaptic Acetylcholine Handling Defect
  conforms_to: "neuromuscular_transmission_failure#Reduced Quantal Acetylcholine Release"
  description: >-
    The acetylcholine-handling arm of presynaptic CMS: the lesion lies in the
    supply of transmitter rather than in the release machinery. Choline
    acetyltransferase (CHAT) synthesizes ACh, the high-affinity choline
    transporter (SLC5A7) recovers choline into the terminal, the vesicular ACh
    transporter (SLC18A3) loads it into synaptic vesicles, and PREPL is
    required for those vesicles to be refilled. A defect at any of these steps
    lowers the quantal content of ACh release and so the endplate potential.
    In this group a decrement on low-frequency stimulation is elicited at rest
    in some patients, but only after exercise or high-frequency stimulation in
    the others. The downstream fusion step is modeled separately in Defective
    SNARE-Mediated Synaptic Vesicle Fusion, and terminal development in
    Defective Motor Nerve Terminal Formation.
  cell_types:
  - preferred_term: Motor neuron presynaptic terminal
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Acetylcholine biosynthetic process
    term:
      id: GO:0008292
      label: acetylcholine biosynthetic process
    modifier: DECREASED
  genes:
  - preferred_term: CHAT
    term:
      id: hgnc:1912
      label: CHAT
  - preferred_term: SLC5A7
    term:
      id: hgnc:14025
      label: SLC5A7
  - preferred_term: SLC18A3
    term:
      id: hgnc:10936
      label: SLC18A3
  - preferred_term: PREPL
    term:
      id: hgnc:30228
      label: PREPL
  evidence:
  - reference: PMID:37212067
    reference_title: "Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling, in its packaging into synaptic vesicles, or its subsequent release into the synaptic cleft."
    explanation: Defines the presynaptic ACh-handling defect at the nerve terminal.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      Defective acetylcholine synthesis, packaging, or release at the nerve
      terminal reduces the safety margin of neuromuscular transmission.
- name: Endplate Acetylcholinesterase Deficiency
  description: >-
    In synaptic (basal-lamina) CMS, loss of COLQ removes the collagen tail that
    anchors acetylcholinesterase in the synaptic cleft. The resulting endplate
    AChE deficiency prolongs ACh dwell time, causing cationic overload and
    depolarization block / endplate myopathy. Because residual AChE activity is
    already absent, cholinesterase inhibitors provide no benefit and may be
    harmful.
  cell_types:
  - preferred_term: Skeletal muscle fiber endplate
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  genes:
  - preferred_term: COLQ
    term:
      id: hgnc:2226
      label: COLQ
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency."
    explanation: Establishes endplate AChE deficiency as the synaptic CMS mechanism caused by COLQ loss.
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no benefit from esterase inhibitor treatment, while treatment with ephedrine and salbutamol was objectively efficient in all cases."
    explanation: Confirms the mechanistically predicted lack of AChE-inhibitor benefit in endplate AChE deficiency.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      Loss of endplate acetylcholinesterase prolongs ACh dwell time, causing
      cationic overload and depolarization block that impairs transmission.
- name: Postsynaptic AChR Deficiency, Kinetic Defect, and Impaired Clustering
  conforms_to: "neuromuscular_transmission_failure#Reduced Postsynaptic Endplate Response to Acetylcholine"
  description: >-
    The largest mechanistic group. Variants in AChR subunit genes (CHRNE,
    CHRNA1, CHRNB1, CHRND) reduce endplate AChR density (primary AChR deficiency)
    or alter channel gating kinetics — prolonged openings in slow-channel CMS
    (cationic overload, endplate degeneration) or abbreviated openings in
    fast-channel CMS (reduced response to ACh). Variants in the
    agrin-LRP4-MuSK-DOK7-rapsyn signaling axis (AGRN, LRP4, MUSK, DOK7, RAPSN)
    impair AChR clustering and endplate development/maintenance.
  cell_types:
  - preferred_term: Skeletal muscle fiber postsynaptic membrane
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Skeletal muscle acetylcholine-gated channel clustering
    term:
      id: GO:0071340
      label: skeletal muscle acetylcholine-gated channel clustering
    modifier: DECREASED
  - preferred_term: Neuromuscular junction development
    term:
      id: GO:0007528
      label: neuromuscular junction development
    modifier: ABNORMAL
  genes:
  - preferred_term: CHRNA1
    term:
      id: hgnc:1955
      label: CHRNA1
  - preferred_term: CHRNB1
    term:
      id: hgnc:1961
      label: CHRNB1
  - preferred_term: CHRND
    term:
      id: hgnc:1965
      label: CHRND
  - preferred_term: CHRNE
    term:
      id: hgnc:1966
      label: CHRNE
  - preferred_term: RAPSN
    term:
      id: hgnc:9863
      label: RAPSN
  - preferred_term: DOK7
    term:
      id: hgnc:26594
      label: DOK7
  - preferred_term: MUSK
    term:
      id: hgnc:7525
      label: MUSK
  - preferred_term: AGRN
    term:
      id: hgnc:329
      label: AGRN
  - preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%)."
    explanation: Identifies the dominant postsynaptic AChR-subunit and clustering-pathway genotypes.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      Reduced postsynaptic AChR density, altered channel gating, or impaired
      AChR clustering diminishes the endplate response to acetylcholine.
- name: NMJ Glycoprotein Glycosylation Defect
  description: >-
    In glycosylation-related CMS, variants in the N-linked glycosylation pathway
    (GFPT1, DPAGT1, ALG2, ALG14, GMPPB) reduce glycosylation of multiple NMJ
    glycoproteins including the AChR, producing a combined endplate defect with a
    characteristic limb-girdle distribution and frequently tubular aggregates on
    muscle biopsy.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  genes:
  - preferred_term: GFPT1
    term:
      id: hgnc:4241
      label: GFPT1
  - preferred_term: DPAGT1
    term:
      id: hgnc:2995
      label: DPAGT1
  - preferred_term: GMPPB
    term:
      id: hgnc:22932
      label: GMPPB
  evidence:
  - reference: PMID:37721175
    reference_title: "Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects"
    explanation: Establishes the N-glycosylation pathway genes as a mechanistic cause of NMJ dysfunction.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      Hypoglycosylation of NMJ glycoproteins (including the AChR) produces a
      combined endplate defect that impairs neuromuscular transmission.
- name: Defective SNARE-Mediated Synaptic Vesicle Fusion
  conforms_to: "neuromuscular_transmission_failure#Reduced Quantal Acetylcholine Release"
  description: >-
    Calcium entering the motor nerve terminal through the P/Q-type calcium
    channel binds the two C2B domains of synaptotagmin-2 and triggers assembly
    of the SNARE complex - SNAP25, syntaxin and the vesicle SNARE
    synaptobrevin-1 (VAMP1) - which fuses acetylcholine-laden synaptic
    vesicles with the presynaptic membrane. Variants in SYT2 or VAMP1 break
    that calcium-to-fusion coupling, so fewer quanta are released per nerve
    impulse. The result is a Lambert-Eaton-like electrophysiology, with a
    decrement on low-frequency repetitive nerve stimulation and an increment
    at high frequency, which is why amifampridine, which enhances calcium
    entry into the nerve terminal, is effective in this group. This node is
    distinct from the upstream acetylcholine synthesis and vesicle-loading
    defects: here the vesicles are filled, but they do not fuse on cue.
  cell_types:
  - preferred_term: Motor neuron presynaptic terminal
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Acetylcholine secretion at the nerve terminal
    term:
      id: GO:0014055
      label: acetylcholine secretion, neurotransmission
    modifier: DECREASED
  - preferred_term: Calcium-ion regulated exocytosis of synaptic vesicles
    term:
      id: GO:0017156
      label: calcium-ion regulated exocytosis
    modifier: DECREASED
  genes:
  - preferred_term: SYT2
    term:
      id: hgnc:11510
      label: SYT2
  - preferred_term: VAMP1
    term:
      id: hgnc:12642
      label: VAMP1
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The calcium ions bind to two C2B domains of synaptotagmin 2 (SYT2), and activate the SNARE complex to fuse synaptic vesicles containing ACh to the presynaptic membrane"
    explanation: >-
      States the calcium-to-SNARE-to-fusion step this node models.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "SYT2-CMS, SNAP25-CMS, VAMP1-CMS, UNC13A-CMS, RPH3A-CMS, and LAMA5-CMS are characterized by defects in the SNARE complex, and phenotypically similar to Lambert-Eaton myasthenic syndrome (LEMS)"
    explanation: >-
      Groups the SNARE-defect CMS genes and gives the Lambert-Eaton-like
      phenotype this node predicts.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      Defective calcium-triggered fusion of acetylcholine-laden vesicles reduces
      the quantal content of each nerve impulse, lowering the endplate potential
      and the safety factor of neuromuscular transmission.
- name: Defective Motor Nerve Terminal Formation
  description: >-
    A distinct presynaptic lesion in which the nerve terminal itself is built
    wrongly, rather than the acetylcholine cycle or the fusion machinery
    failing within an otherwise normal terminal. MYO9A, an unconventional
    myosin with a Rho GTPase-activating domain, regulates intracellular
    transport in peripheral nerve; SLC25A1 is a mitochondrial inner-membrane
    transporter. Knockdown of either in zebrafish disturbs the elongation and
    branching of spinal motor axons and compromises neuromuscular junction
    formation, so the myasthenia in CMS23 and CMS24 is attributed to defective
    nerve terminal development. Cholinesterase inhibitors are effective in
    MYO9A-CMS, whereas both cholinesterase inhibitors and amifampridine are
    generally ineffective in SLC25A1-CMS.
  cell_types:
  - preferred_term: Motor neuron presynaptic terminal
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Presynapse assembly at the motor endplate
    term:
      id: GO:0099054
      label: presynapse assembly
    modifier: ABNORMAL
  - preferred_term: Neuromuscular junction development
    term:
      id: GO:0007528
      label: neuromuscular junction development
    modifier: ABNORMAL
  genes:
  - preferred_term: SLC25A1
    term:
      id: hgnc:10979
      label: SLC25A1
  - preferred_term: MYO9A
    term:
      id: hgnc:7608
      label: MYO9A
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Knockdown of two orthologs, myo9aa/ab, in zebrafish causes shortening and abnormal branching of spinal motor neurons, and defective NMJ signal transmission"
    explanation: >-
      Links MYO9A loss to abnormal motor axon morphology and failed
      neuromuscular transmission.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Knockdown of Slc25a1 in zebrafish causes aberration in the axonal elongation of spinal motor neurons and compromise the formation of the NMJ"
    explanation: >-
      Links SLC25A1 loss to the same defect in motor axon elongation and NMJ
      formation.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      A malformed motor nerve terminal cannot establish or sustain a normal
      endplate, reducing the safety factor of neuromuscular transmission.
- name: Endplate Collagen XIII Deficiency
  description: >-
    Collagen XIII is a single-pass transmembrane collagen enriched at the
    neuromuscular junction that is required for the maturation and maintenance
    of endplate acetylcholine receptors. Biallelic COL13A1 variants reduce
    AChR clustering, and Col13a1-deficient mice form the junction abnormally.
    The mechanism therefore sits in the synaptic compartment alongside the
    COLQ lesion but is not an acetylcholinesterase-anchoring defect, which is
    why the two synaptic subtypes differ in their drug response:
    cholinesterase inhibitors are contraindicated in COLQ-CMS and merely
    ineffective in COL13A1-CMS, while salbutamol is reported to help in both.
  cell_types:
  - preferred_term: Skeletal muscle fiber endplate
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: Skeletal muscle acetylcholine-gated channel clustering
    term:
      id: GO:0071340
      label: skeletal muscle acetylcholine-gated channel clustering
    modifier: DECREASED
  genes:
  - preferred_term: COL13A1
    term:
      id: hgnc:2190
      label: COL13A1
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Introduction of the pathogenic variants into C2C12 myotubes reduced AChR clustering"
    explanation: >-
      Shows the reported COL13A1 variants impair AChR clustering in a myotube
      model.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Col13a1-deficient mice show abnormal formation of the NMJ"
    explanation: >-
      Mouse knockout reproduces abnormal neuromuscular junction formation.
  downstream:
  - target: Impaired Neuromuscular Junction Transmission
    description: >-
      Loss of collagen XIII leaves endplate acetylcholine receptors immature and
      poorly maintained, reducing the endplate response to acetylcholine and the
      safety factor of neuromuscular transmission.
phenotypes:
- category: Neurologic
  name: Fatigable Muscle Weakness
  diagnostic: true
  description: >-
    The cardinal manifestation of CMS: abnormal fatigability and fluctuating or
    permanent weakness of extra-ocular, facial, bulbar, axial, respiratory, or
    limb muscles, worsening with exertion.
  phenotype_term:
    preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: PMID:30808424
    reference_title: "Congenital myasthenic syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay."
    explanation: Establishes fatigable/fluctuating weakness across muscle groups as the core CMS phenotype.
- category: Neurologic
  name: Increased Muscle Fatigability
  phenotype_term:
    preferred_term: Increased muscle fatigability
    term:
      id: HP:0003750
      label: Increased muscle fatiguability
  evidence:
  - reference: PMID:30808424
    reference_title: "Congenital myasthenic syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay."
    explanation: Documents abnormal fatigability as a defining CMS feature.
- category: HEENT
  name: Ptosis
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy."
    explanation: Ptosis is a common presenting ocular sign in CMS.
- category: HEENT
  name: Ophthalmoparesis
  phenotype_term:
    preferred_term: Ophthalmoparesis
    term:
      id: HP:0000597
      label: Ophthalmoparesis
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy."
    explanation: Ophthalmoparesis is a common ocular manifestation of CMS.
- category: Musculoskeletal
  name: Limb-Girdle Muscle Weakness
  description: >-
    A proximal, limb-girdle distribution of weakness is characteristic of the
    DOK7, RAPSN, COLQ, and glycosylation (GFPT1, GMPPB) subtypes.
  phenotype_term:
    preferred_term: Limb-girdle muscle weakness
    term:
      id: HP:0003325
      label: Limb-girdle muscle weakness
  evidence:
  - reference: PMID:38907197
    reference_title: "DOK7 congenital myasthenic syndrome: case series and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3"
    explanation: Limb-girdle weakness was the most common manifestation in a DOK7-CMS series (6/7 patients).
- category: Respiratory
  name: Sudden Episodic Apnea
  description: >-
    Episodic, sometimes life-threatening, apneic crises are characteristic of
    CHAT-CMS (CMS with episodic apnea), as well as COLQ- and SCN4A-CMS.
  phenotype_term:
    preferred_term: Sudden episodic apnea
    term:
      id: HP:0002882
      label: Sudden episodic apnea
    temporality: RECURRENT
  evidence:
  - reference: PMID:37212067
    reference_title: "Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presynaptic CMS usually presents during the prenatal or neonatal period, with a severe phenotype including congenital arthrogryposis, developmental delay, and apnoeic crisis."
    explanation: Documents apneic crises as a feature of (presynaptic) CMS.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >-
    Respiratory muscle involvement can necessitate ventilatory support;
    long-term ventilation was required in 55% of slow-channel CMS and 36% of
    DOK7 patients in a large adult cohort.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation"
    explanation: Quantifies respiratory insufficiency requiring ventilation in the most severely affected subtypes.
- category: Neurologic
  name: Bifacial Weakness
  phenotype_term:
    preferred_term: Facial muscle weakness
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:38907197
    reference_title: "DOK7 congenital myasthenic syndrome: case series and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2"
    explanation: Bifacial weakness was observed in a DOK7-CMS case series.
- category: Neurologic
  name: Bulbar Weakness
  phenotype_term:
    preferred_term: Bulbar palsy
    term:
      id: HP:0001283
      label: Bulbar palsy
  evidence:
  - reference: PMID:30808424
    reference_title: "Congenital myasthenic syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles"
    explanation: Bulbar muscle weakness is part of the CMS clinical spectrum.
- category: Neurologic
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30808424
    reference_title: "Congenital myasthenic syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay."
    explanation: Hypotonia is a recognized CMS manifestation, particularly in infantile presentations.
- category: Neurologic
  name: Motor Developmental Delay
  description: >-
    Delayed motor milestones are common, particularly in early-onset subtypes;
    detected in ~52% of a COLQ-CMS cohort.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed developmental motor milestones were detected in 13 patients (∼ 52%)"
    explanation: Quantifies motor developmental delay in a genetically confirmed COLQ-CMS cohort.
- category: Diagnostic
  name: Decremental RNS Response
  diagnostic: true
  description: >-
    A decremental compound muscle action potential response (>10%) on
    low-frequency repetitive nerve stimulation is the electrophysiological
    hallmark of impaired NMJ transmission and is required for diagnosis.
  phenotype_term:
    preferred_term: Decremental CMAP response to repetitive nerve stimulation
    term:
      id: HP:0003403
      label: "EMG: decremental response of compound muscle action potential to repetitive nerve stimulation"
  evidence:
  - reference: PMID:38964204
    reference_title: "Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement."
    explanation: Documents a pathologic decremental RNS response in the majority of tested CMS patients.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS."
    explanation: Establishes the decremental RNS response as the required diagnostic electrophysiology.
- category: Musculoskeletal
  name: Neck Muscle Weakness
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Neck muscle weakness
    term:
      id: HP:0000467
      label: Neck muscle weakness
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000467 | Neck muscle weakness | Very frequent (99-80%)"
    explanation: Orphanet records neck muscle weakness as very frequent in CMS.
- category: Gastrointestinal
  name: Dysphagia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002015 | Dysphagia | Very frequent (99-80%)"
    explanation: Orphanet records dysphagia as very frequent in CMS.
- category: Gastrointestinal
  name: Poor Suck
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Poor suck
    term:
      id: HP:0002033
      label: Poor suck
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002033 | Poor suck | Very frequent (99-80%)"
    explanation: Orphanet records poor suck as very frequent in CMS.
- category: Gastrointestinal
  name: Feeding Difficulties
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011968 | Feeding difficulties | Very frequent (99-80%)"
    explanation: Orphanet records feeding difficulties as very frequent in CMS.
- category: Neurologic
  name: Ataxia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Frequent (79-30%)"
    explanation: Orphanet records ataxia as frequent in CMS.
- category: Neurologic
  name: Gait Disturbance
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001288 | Gait disturbance | Frequent (79-30%)"
    explanation: Orphanet records gait disturbance as frequent in CMS.
- category: Respiratory
  name: Central Sleep Apnea
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Central sleep apnea
    term:
      id: HP:0010536
      label: Central sleep apnea
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010536 | Central sleep apnea | Frequent (79-30%)"
    explanation: Orphanet records central sleep apnea as frequent in CMS.
- category: Respiratory
  name: Choking Episodes
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Choking episodes
    term:
      id: HP:0030842
      label: Choking episodes
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030842 | Choking episodes | Frequent (79-30%)"
    explanation: Orphanet records choking episodes as frequent in CMS.
- category: Musculoskeletal
  name: Arthrogryposis Multiplex Congenita
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: ORPHA:590
    reference_title: Congenital myasthenic syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002804 | Arthrogryposis multiplex congenita | Frequent (79-30%)"
    explanation: Orphanet records arthrogryposis multiplex congenita as frequent in CMS.
genetic:
- name: CHRNE
  gene_term:
    preferred_term: CHRNE
    term:
      id: hgnc:1966
      label: CHRNE
  association: Causal
  subtype: CMS4
  notes: >-
    CHRNE encodes the epsilon subunit of the adult muscle acetylcholine
    receptor. Recessive low-expressor and null variants cause primary AChR
    deficiency (the most common CMS genotype in several cohorts); other CHRNE
    variants cause slow- or fast-channel kinetic CMS.
  evidence:
  - reference: PMID:37721175
    reference_title: "Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the individual CMS genes, the most commonly affected gene was CHRNE (39.4%)"
    explanation: CHRNE was the single most common CMS gene in the Indian cohort.
- name: DOK7
  gene_term:
    preferred_term: DOK7
    term:
      id: hgnc:26594
      label: DOK7
  association: Causal
  subtype: CMS10
  notes: >-
    DOK7 is a cytoplasmic adaptor required for MuSK activation and AChR
    clustering. Recessive variants cause a postsynaptic limb-girdle CMS;
    c.1124_1127dupTGCC is a recurrent variant. DOK7-CMS responds to salbutamol
    but typically not to cholinesterase inhibitors.
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by variants in DOK7 (18.7%) and RAPSN (14%)"
    explanation: DOK7 is the second most common CMS genotype in the French adult cohort.
  - reference: PMID:38907197
    reference_title: "DOK7 congenital myasthenic syndrome: case series and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "c.1124_1127dupTGCC is the most common variant; three patients had this variant."
    explanation: Identifies the recurrent DOK7 frameshift variant.
- name: RAPSN
  gene_term:
    preferred_term: RAPSN
    term:
      id: hgnc:9863
      label: RAPSN
  association: Causal
  subtype: CMS11
  notes: >-
    RAPSN encodes rapsyn, which clusters AChR at the endplate. Recessive
    variants cause a postsynaptic CMS often severe in early childhood that
    subsequently improves; responsive to cholinesterase inhibitors.
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RAPSN patients, often severely affected in early childhood, subsequently improved."
    explanation: Describes the characteristic RAPSN-CMS natural history.
- name: COLQ
  gene_term:
    preferred_term: COLQ
    term:
      id: hgnc:2226
      label: COLQ
  association: Causal
  subtype: CMS5
  notes: >-
    COLQ encodes the collagen-like tail subunit that anchors acetylcholinesterase
    in the synaptic basal lamina. Biallelic loss causes synaptic CMS with
    endplate AChE deficiency.
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency."
    explanation: COLQ is the prototypical synaptic basal-lamina CMS gene.
- name: CHAT
  gene_term:
    preferred_term: CHAT
    term:
      id: hgnc:1912
      label: CHAT
  association: Causal
  subtype: Presynaptic
  notes: >-
    CHAT encodes choline acetyltransferase, the enzyme that synthesizes ACh.
    It is the commonest presynaptic CMS gene and the classic cause of CMS with
    episodic apnea (sudden, sometimes fatal, apneic crises in infancy).
  evidence:
  - reference: PMID:37212067
    reference_title: "Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They can result from a dysfunction in acetylcholine (ACh) synthesis or recycling"
    explanation: CHAT-mediated ACh synthesis defect underlies the commonest presynaptic CMS.
- name: MUSK
  gene_term:
    preferred_term: MUSK
    term:
      id: hgnc:7525
      label: MUSK
  association: Causal
  subtype: CMS9
  notes: >-
    MUSK encodes the muscle-specific receptor tyrosine kinase, the central hub of
    agrin-LRP4-MuSK-DOK7-rapsyn signaling that drives AChR clustering. MUSK-CMS
    has a variable phenotype and a notably high rate of ICU admission.
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%)"
    explanation: MUSK-CMS had one of the highest ICU-admission rates in the French cohort.
- name: GFPT1
  gene_term:
    preferred_term: GFPT1
    term:
      id: hgnc:4241
      label: GFPT1
  association: Causal
  subtype: CMS12
  notes: >-
    GFPT1 controls the rate-limiting step of the hexosamine pathway feeding
    N-glycosylation. Recessive variants cause a limb-girdle glycosylation CMS,
    often with tubular aggregates on muscle biopsy.
  evidence:
  - reference: PMID:37721175
    reference_title: "Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%)"
    explanation: GFPT1 is a recurrent glycosylation-pathway CMS gene in the Indian cohort.
- name: DPAGT1
  gene_term:
    preferred_term: DPAGT1
    term:
      id: hgnc:2995
      label: DPAGT1
  association: Causal
  subtype: CMS13
  notes: >-
    DPAGT1 catalyzes the first committed step of N-linked glycosylation.
    Recessive variants cause a limb-girdle glycosylation CMS; p.T380I is a
    suspected founder allele in the Indian subcontinent.
  evidence:
  - reference: PMID:37721175
    reference_title: "Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DPAGT1 p.T380I and DES c.1023+5G>A, for which founder haplotypes are suspected."
    explanation: Identifies a suspected DPAGT1 founder variant in this population.
- name: CHRNA1
  gene_term:
    preferred_term: CHRNA1
    term:
      id: hgnc:1955
      label: CHRNA1
  association: Causal
  subtype: Postsynaptic
  notes: >-
    CHRNA1 encodes the alpha subunit of the muscle AChR. Variants cause
    postsynaptic CMS (including slow- and fast-channel kinetic forms); the most
    severe loss-of-function alleles cause the separately curated prenatal-lethal
    CHRNA1 fetal akinesia disorder.
- name: CHRNB1
  gene_term:
    preferred_term: CHRNB1
    term:
      id: hgnc:1961
      label: CHRNB1
  association: Causal
  subtype: Postsynaptic
  notes: >-
    CHRNB1 encodes the beta subunit of the muscle AChR; variants cause
    postsynaptic kinetic/deficiency CMS.
- name: CHRND
  gene_term:
    preferred_term: CHRND
    term:
      id: hgnc:1965
      label: CHRND
  association: Causal
  subtype: Postsynaptic
  notes: >-
    CHRND encodes the delta subunit of the muscle AChR; variants cause
    postsynaptic kinetic/deficiency CMS, often with prominent ocular involvement.
- name: AGRN
  gene_term:
    preferred_term: AGRN
    term:
      id: hgnc:329
      label: AGRN
  association: Causal
  subtype: CMS8
  notes: >-
    AGRN encodes agrin, the motor-neuron-derived proteoglycan that activates the
    LRP4-MuSK-DOK7-rapsyn clustering pathway. Recessive variants cause a
    postsynaptic CMS with a variable phenotype.
- name: LRP4
  gene_term:
    preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  association: Causal
  subtype: CMS17
  notes: >-
    LRP4 is the agrin co-receptor that activates MuSK. Recessive variants are a
    rare cause of postsynaptic CMS via impaired AChR clustering.
- name: GMPPB
  gene_term:
    preferred_term: GMPPB
    term:
      id: hgnc:22932
      label: GMPPB
  association: Causal
  subtype: Glycosylation
  notes: >-
    GMPPB supplies GDP-mannose for glycosylation. Variants cause a glycosylation
    CMS that overlaps with limb-girdle muscular dystrophy (a "myasthenic-myopathic"
    presentation, frequently with elevated CK).
  evidence:
  - reference: PMID:37721175
    reference_title: "Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myopathy and muscular dystrophy genes such as GMPPB and DES, presenting as gradually progressive limb girdle CMS, expand the phenotypic spectrum."
    explanation: Documents the limb-girdle myopathic GMPPB-CMS presentation.
- name: COL13A1
  gene_term:
    preferred_term: COL13A1
    term:
      id: hgnc:2190
      label: COL13A1
  association: Causal
  subtype: CMS19
  notes: >-
    COL13A1 encodes a single-pass transmembrane collagen enriched at the
    neuromuscular junction that is required for the maturation and maintenance
    of endplate acetylcholine receptors. Biallelic variants cause CMS19, a
    synaptic-compartment CMS in which cholinesterase inhibitors are
    ineffective but salbutamol and amifampridine help.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Introduction of the pathogenic variants into C2C12 myotubes reduced AChR clustering"
    explanation: >-
      Shows that the reported COL13A1 variants impair AChR clustering in a
      myotube model.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients developed respiratory distress and weak sucking at birth"
    explanation: >-
      Describes the uniform neonatal presentation of COL13A1-CMS.
- name: SLC5A7
  gene_term:
    preferred_term: SLC5A7
    term:
      id: hgnc:14025
      label: SLC5A7
  association: Causal
  subtype: CMS20
  notes: >-
    SLC5A7 encodes the high-affinity choline transporter that takes choline
    back up into the motor nerve terminal for acetylcholine resynthesis.
    Biallelic loss-of-function variants cause CMS20 with neonatal episodic
    apnea; hemiallelic frameshifting variants of the same gene instead cause
    autosomal dominant distal hereditary motor neuropathy type VIIA.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "High affinity choline transporter (ChT, SLC5A7) expressed at the nerve terminal membrane uptakes choline to the nerve terminal"
    explanation: >-
      States the presynaptic transport step that SLC5A7 carries out.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Later, recessive pathogenic variants of SLC5A7 were reported to cause CMS"
    explanation: >-
      Establishes recessive SLC5A7 variants as a cause of CMS.
- name: SLC18A3
  gene_term:
    preferred_term: SLC18A3
    term:
      id: hgnc:10936
      label: SLC18A3
  association: Causal
  subtype: CMS21
  notes: >-
    SLC18A3 encodes the vesicular acetylcholine transporter, which loads newly
    synthesized acetylcholine into synaptic vesicles, and is encoded within
    the first intron of CHAT. Biallelic variants cause CMS21, presenting with
    severe neonatal weakness, arthrogryposis and respiratory distress.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Vesicular acetylcholine transporter (vAChT, SLC18A3) transports synthesized ACh to the synaptic vesicle"
    explanation: >-
      States the vesicular loading step that SLC18A3 carries out.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Loss-of-function variants of SLC18A3 also cause CMS"
    explanation: >-
      Establishes loss-of-function SLC18A3 variants as a cause of CMS.
- name: PREPL
  gene_term:
    preferred_term: PREPL
    term:
      id: hgnc:30228
      label: PREPL
  association: Causal
  subtype: CMS22
  notes: >-
    PREPL encodes a serine peptidase of unknown physiological substrate whose
    loss impairs refilling of synaptic vesicles with acetylcholine. Biallelic
    loss-of-function variants cause CMS22; because PREPL overlaps SLC3A1 at
    its 3-prime end, a deletion spanning both genes gives hypotonia-cystinuria
    syndrome instead.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Loss-of-function variants of PREPL do not cause endplate AChR deficiency, but inhibit refilling of ACh to synaptic vesicles, reduce the number of releasable ACh quanta, and decrease the probability of vesicular release"
    explanation: >-
      States the presynaptic mechanism of PREPL loss and excludes an
      AChR-deficiency mechanism.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ten patients with PREPL-CMS including HCS were initially diagnosed as Prader-Willi syndrome"
    explanation: >-
      Records the characteristic initial misdiagnosis in PREPL-CMS.
- name: SLC25A1
  gene_term:
    preferred_term: SLC25A1
    term:
      id: hgnc:10979
      label: SLC25A1
  association: Causal
  subtype: CMS23
  notes: >-
    SLC25A1 encodes a mitochondrial inner-membrane transporter. Biallelic
    variants cause CMS23, attributed to defective motor nerve terminal
    formation; variants in the same gene also cause combined D-2- and
    L-2-hydroxyglutaric aciduria. Cholinesterase inhibitors and amifampridine
    are generally ineffective.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Knockdown of Slc25a1 in zebrafish causes aberration in the axonal elongation of spinal motor neurons and compromise the formation of the NMJ"
    explanation: >-
      Zebrafish knockdown links SLC25A1 loss to defective motor axon and NMJ
      formation.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "SLC25A1-CMS is thus predicted to be caused by presynaptic defects"
    explanation: >-
      Assigns SLC25A1-CMS to the presynaptic compartment.
- name: MYO9A
  gene_term:
    preferred_term: MYO9A
    term:
      id: hgnc:7608
      label: MYO9A
  association: Causal
  subtype: CMS24
  notes: >-
    MYO9A encodes an unconventional myosin with a Rho GTPase-activating domain
    that regulates intracellular transport in peripheral nerve. Biallelic
    loss-of-function variants cause CMS24 through defective motor nerve
    terminal formation.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Biallelic loss-of-function variants of MYO9A cause CMS"
    explanation: >-
      Establishes biallelic MYO9A loss of function as a cause of CMS.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Knockdown of two orthologs, myo9aa/ab, in zebrafish causes shortening and abnormal branching of spinal motor neurons, and defective NMJ signal transmission"
    explanation: >-
      Zebrafish knockdown links MYO9A loss to abnormal motor axons and failed
      NMJ transmission.
- name: VAMP1
  gene_term:
    preferred_term: VAMP1
    term:
      id: hgnc:12642
      label: VAMP1
  association: Causal
  subtype: CMS25
  notes: >-
    VAMP1 encodes synaptobrevin-1, the vesicle SNARE. Biallelic
    loss-of-function variants cause CMS25, a Lambert-Eaton-like CMS in which
    low-frequency repetitive nerve stimulation gives a decrement and
    high-frequency stimulation an increment.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Biallelic loss-of-function variant of VAMP1 encoding another component of the SNARE complex, synaptobrevin1, cause a neonatal onset CMS"
    explanation: >-
      Establishes biallelic VAMP1 loss of function as a cause of neonatal-onset
      CMS.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: "Vamp1-deficient mice showed marked shrinkage of motor endplate and reduction in endplate potentials, which is electrophysiologically similar to LEMS"
    explanation: >-
      Mouse knockout reproduces the Lambert-Eaton-like endplate physiology.
- name: SYT2
  gene_term:
    preferred_term: SYT2
    term:
      id: hgnc:11510
      label: SYT2
  association: Causal
  subtype: Presynaptic
  notes: >-
    SYT2 encodes synaptotagmin-2, the fast calcium sensor that couples the
    presynaptic calcium transient to SNARE-mediated vesicle fusion.
    Hemiallelic and biallelic variants cause CMS7A and CMS7B respectively,
    which are curated as their own Disease entry
    (kb/disorders/Congenital_Myasthenic_Syndrome_7.yaml, MONDO:0014468); SYT2
    is recorded here so the umbrella entry's gene list is complete.
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Synaptotagmin 2 (SYT2) senses Ca2+ ions entering into the nerve terminal through P/Q-type calcium channel and triggers the formation of the SNARE complex that releases ACh in synaptic vesicles to the synaptic space"
    explanation: >-
      States the presynaptic calcium-sensing and SNARE-triggering step that SYT2
      carries out.
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hemiallelic pathogenic variants were identified in SYT2 in patients with CMS resembling LEMS"
    explanation: >-
      Establishes SYT2 variants as a cause of Lambert-Eaton-like CMS.
treatments:
- name: Acetylcholinesterase Inhibitor Therapy
  description: >-
    Pyridostigmine and related cholinesterase inhibitors prolong ACh action at
    the endplate and benefit most CMS subtypes (e.g. AChR deficiency, RAPSN,
    glycosylation CMS). They are CONTRAINDICATED in endplate AChE deficiency
    (COLQ) and in slow-channel CMS, where they can worsen the cationic-overload
    endplate myopathy. Therapy selection is therefore genotype-guided.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: acetylcholinesterase inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS."
    explanation: Establishes both the broad efficacy and the subtype-specific contraindication of cholinesterase inhibitors.
- name: Beta-2 Adrenergic Agonist Therapy (Salbutamol)
  description: >-
    Salbutamol (albuterol) is broadly beneficial in CMS, including subtypes that
    do not respond to cholinesterase inhibitors (COLQ, DOK7). It is recommended
    as first-line therapy for DOK7-CMS.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: salbutamol
      term:
        id: CHEBI:2549
        label: albuterol
  evidence:
  - reference: PMID:38907197
    reference_title: "DOK7 congenital myasthenic syndrome: case series and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients."
    explanation: Establishes salbutamol as first-line therapy for DOK7-CMS.
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment with ephedrine and salbutamol was objectively efficient in all cases."
    explanation: Documents objective salbutamol benefit in COLQ-CMS where AChE inhibitors fail.
- name: Ephedrine Therapy
  description: >-
    Ephedrine, a sympathomimetic, is effective in many CMS subtypes including
    endplate AChE deficiency (COLQ); historically used before salbutamol became a
    preferred alternative.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ephedrine
      term:
        id: CHEBI:15407
        label: (-)-ephedrine
  evidence:
  - reference: PMID:38475910
    reference_title: "COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment with ephedrine and salbutamol was objectively efficient in all cases."
    explanation: Documents objective ephedrine benefit in COLQ-CMS.
- name: Amifampridine (3,4-Diaminopyridine) Therapy
  description: >-
    Amifampridine (3,4-diaminopyridine) is a potassium-channel blocker that
    enhances presynaptic ACh release, beneficial in several CMS subtypes
    (notably presynaptic and fast-channel forms), but not effective in all.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amifampridine
      term:
        id: CHEBI:135948
        label: amifampridine
  evidence:
  - reference: PMID:36835142
    reference_title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS."
    explanation: Establishes amifampridine as effective in most, but not all, CMS subtypes.
- name: Noninvasive Ventilation
  description: >-
    Respiratory support, including noninvasive ventilation, is used for
    respiratory insufficiency and apneic crises; long-term ventilation is needed
    in the most severely affected subtypes (slow-channel CMS, DOK7).
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: noninvasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  evidence:
  - reference: PMID:38696726
    reference_title: "Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation"
    explanation: Documents the need for ventilatory support in severe CMS subtypes.
- name: Genetic Counseling
  description: >-
    Counseling for affected individuals and families, given the mostly autosomal
    recessive inheritance (with autosomal dominant slow-channel CMS and some
    presynaptic forms). Molecular diagnosis is essential to guide genotype-specific
    therapy.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
clinical_trials:
- name: NCT06436742
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Phase 1b randomized, double-blind, placebo-controlled study of ARGX-119, an
    agonist antibody targeting MuSK, in adults with genetically confirmed
    DOK7-CMS; primary objective safety/tolerability, with exploratory efficacy
    including the 6-minute walk test.
  target_phenotypes:
  - preferred_term: Limb-girdle muscle weakness
    term:
      id: HP:0003325
      label: Limb-girdle muscle weakness
  evidence:
  - reference: clinicaltrials:NCT06436742
    reference_title: "A Phase 1b, Double-Blinded, Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Efficacy of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes"
    supports: SUPPORT
    snippet: "ARGX-119"
    explanation: Phase 1b trial of ARGX-119 in DOK7-CMS, an emerging targeted therapy for the postsynaptic clustering pathway.
references:
- reference: PMID:20301347
  title: "Congenital Myasthenic Syndromes Overview."
  tags:
  - GeneReviews
- reference: PMID:36835142
  title: "Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review."
datasets:
- accession: ega:EGAS00001000693
  title: Neuromics / RD-Connect - congenital myasthenic syndrome
  description: This study contains omics datasets from the Neuromics project (www.rd-neuromics.eu) on rare neuromuscular and neurodegenerative disorders. Data includes BAM and VCF files from whole-exome sequencing and standardised phenotypic data mapped to the human phenotype ontology (HPO). In some cases proteomic, transcriptomic and metabolomic data may also be available. This study groups together datasets from individuals with a congenital myasthenic syndrome phenotype and also includes some unaffected family members. Search under the Neuromics name to find related studies for other neuromuscular and neurodegenerative disorders.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Congenital Myasthenic Syndrome"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
notes: >-
  Subtype enumeration and scope (2026-09-20). This umbrella entry now enumerates
  the gene-defined, numbered CMS subtypes as `has_subtypes` rows, each bound to
  its own MONDO term and carrying the causal gene, alongside the four
  pre-existing rows that group them by NMJ compartment. The compartment rows
  carry `children` lists naming their members, so the two schemes coexist
  without duplicating content: the compartment is the mechanistic and
  therapeutic axis, the number is MONDO's and OMIM's gene-defined axis.

  Anchor check. The entry's `disease_term`, MONDO:0018940, was re-verified
  against MONDO before this pass: it is the umbrella class ("Congenital
  myasthenic syndrome (CMS) is a group of genetic disorders of impaired
  neuromuscular transmission at the motor endplate characterized by fatigable
  muscle weakness"), and every numbered subtype enumerated here is among its 37
  is_a descendants. It is not a leaf disease standing in for the family, so no
  re-anchoring was needed.

  What is deliberately NOT a row here. Four gene-defined CMS concepts have their
  own Disease entries and are not duplicated as subtype rows: CHAT-CMS (CMS6,
  MONDO:0009689), SYT2-CMS (CMS7, MONDO:0014468, covering CMS7A and CMS7B),
  ALG14-CMS (CMS15, MONDO:0014542), and the prenatal-lethal CHRNA1 fetal
  akinesia disorder. CHAT and SYT2 are still recorded in `genetic:` so the
  umbrella's gene list is complete. Two more numbered CMS terms are curated
  under a different parent and are cross-referenced from the relevant
  compartment row rather than duplicated here: CMS14 (ALG2, MONDO:0014543) is a
  `has_subtypes` row of
  kb/disorders/ALG2-Congenital_Disorder_of_Glycosylation.yaml, and CMS18
  (SNAP25, MONDO:0014590) is the `disease_term` of
  kb/disorders/SNAP25_Encephalopathy.yaml, whose notes explain MONDO's lagging
  label. Of all the numbered CMS terms, only CMS16 (SCN4A, MONDO:0013620) is
  genuinely absent from this KB: a grep of kb/ finds neither that CURIE nor the
  string CMS16. CMS4A, CMS4B and CMS4C are is_a children of the CMS4 row's own
  term, MONDO:1040021, and are covered by it. GMPPB-CMS has no numbered CMS
  designation and no term among the 37 is_a descendants of MONDO:0018940, so it
  is recorded only in `genetic:` and on the Glycosylation compartment row.

  Observations on MONDO, recorded rather than acted on. (1) MONDO's grouping
  classes for the synaptic and glycosylation compartments, MONDO:0020346 and
  MONDO:0018144, are both obsolete with no live replacement found by a
  synonym-inclusive search, so those two compartment rows are left unbound while
  the presynaptic and postsynaptic rows bind MONDO:0700466 and MONDO:0020344.
  (2) MONDO classifies CMS19 (COL13A1) as both presynaptic and postsynaptic
  CMS; PMID:36835142 Table 1 files COL13A1 as synaptic CMS, and this entry
  follows the review. (3) MONDO:0009689, whose primary label is "congenital
  myasthenic syndrome 6" and whose gene is CHAT, carries the bare synonym
  "CMS1A", which is the primary label of a different term, MONDO:0011088
  (CHRNA1). (4) MONDO:0044299 (CMS22, PREPL) is not filed under MONDO:0700466
  even though PMID:36835142 groups PREPL with CHAT, SLC18A3 and SLC5A7 as
  presynaptic CMS caused by defective recycling of acetylcholine.

📚

References & Deep Research

References

PMID:20301347

Congenital Myasthenic Syndromes Overview.

No top-level findings curated for this source.

PMID:36835142

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 25 citations 2026-06-15T23:45:14.619348

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Congenital Myasthenic Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Congenital Myasthenic Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Congenital Myasthenic Syndrome (CMS): Comprehensive Disease Characteristics Report (2023–2024 prioritized)

Target disease

Disease name: Congenital myasthenic syndromes (CMS)
Category: Mendelian (genetically heterogeneous NMJ disorders)
MONDO ID: Not retrieved in the available evidence (not present in the fetched full texts).

Executive summary

Congenital myasthenic syndromes (CMS) are inherited disorders of neuromuscular junction (NMJ) transmission that typically present in infancy/childhood with fatigable weakness but can present in adolescence/adulthood. Contemporary large cohorts (France n=235 adults; India n=156; Belgium n=37) quantify genotype frequencies, diagnostic delays, and long-term disability/ventilation needs, and support a genotype-guided symptomatic treatment paradigm in which acetylcholinesterase inhibitors, β2-adrenergic agonists (salbutamol/albuterol, ephedrine), and amifampridine are variably helpful—and can be harmful in some genetic subtypes. (polavarapu2024clinicalandgenetic pages 1-2, theuriet2024congenitalmyasthenicsyndromes pages 1-3, smeets2024congenitalmyasthenicsyndromes pages 1-2)

Source	Year/month	Design	N	Key genotype findings	Key phenotype/outcome/treatment findings	URL/DOI
Theuriet et al., Brain	2024-05	French nationwide retrospective adult cohort	235	Pathogenic variants in 19 genes; most common genotypes: CHRNE-low expressor 23.8%, DOK7 18.7%, RAPSN 14%. Clinical clusters: ocular (CHRNE-LE, CHRND, FCCMS), distal (SCCMS), limb-girdle (RAPSN, COLQ, DOK7, GMPPB, GFPT1), variable phenotype (MUSK, AGRN). (theuriet2024congenitalmyasthenicsyndromes pages 1-3)	Mean follow-up 34 years; diagnosis made in adulthood in 139/235 despite childhood onset in most. ICU admission >20% in RAPSN 54.8%, MUSK 50%, DOK7 38.6%, AGRN 25.0%. At last visit, ventilation required in 55% of SCCMS and 36.3% of DOK7 patients; wheelchair use in 36.3% DOK7, 25% GMPPB, 20% GFPT1; 6 deaths. Authors concluded therapy had a “striking” positive impact and prognosis was favorable for most patients. (theuriet2024congenitalmyasthenicsyndromes pages 1-3)	https://doi.org/10.1093/brain/awae124
Polavarapu et al., Brain (Indian cohort)	2024-09 (advance online 2023-09-18)	Large single-country genetically characterized cohort	156 patients / 141 families	Variants in 17 CMS-associated genes in 132/141 families (93.6%); distribution: postsynaptic 62.4%, glycosylation 21.3%, synaptic basal lamina 4.3%, presynaptic 2.8%, other NMJ genes (DES, TEFM) 2.8%. Most common genes: CHRNE 39.4%, DOK7 14.4%, DPAGT1 9.8%, GFPT1 7.6%, MUSK 6.1%, GMPPB 5.3%, COLQ 4.5%; 22 recurrent variants, including suspected founder alleles. (polavarapu2024clinicalandgenetic pages 1-2)	Age at onset ranged from congenital to fourth decade; mean onset 6.6 years; mean diagnosis age 19 years; mean diagnostic delay 12.5 years. Study emphasized major geographic variability in CMS genotype frequencies and the increasing contribution of glycosylation genes in India. (polavarapu2024clinicalandgenetic pages 1-2)	https://doi.org/10.1093/brain/awad315
Smeets et al., Pediatric Neurology (Belgium)	2024-09	National retrospective pediatric/adult cohort	37	Pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, GMPPB; CHRNE most common. Most CMS variants recessive; dominant inheritance noted for slow-channel syndromes and presynaptic SNAP25/SYT2-related disease. (smeets2024congenitalmyasthenicsyndromes pages 1-2)	Estimated Belgian prevalence 3.19 per 1,000,000. Most had onset at birth/infancy/childhood, but 7 adult-onset cases were identified (CHRNE, DOK7, MUSK, CHRND, GMPPB). RNS performed in 23 patients; 18/23 showed pathologic decrement. Authors noted treatment responses were usually predictable from genotype and stressed molecular diagnosis to tailor therapy. (smeets2024congenitalmyasthenicsyndromes pages 1-2)	https://doi.org/10.1016/j.pediatrneurol.2024.06.002
Ohno et al., International Journal of Molecular Sciences	2023-02	Comprehensive review	35 genes / 442 cited articles	Defined CMS as caused by germline pathogenic variants in 35 genes: AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1; classified into 14 groups. (ohno2023clinicalandpathologic pages 23-24, ohno2023clinicalandpathologic pages 1-3)	Stated that RNS-elicited CMAP measurement is required for diagnosis and that clinical/electrophysiologic features alone cannot identify the defective molecule; genetic testing is always required. Most CMS present before age 2, though onset can occur later. Cholinesterase inhibitors help many groups but are contraindicated in some; ephedrine, salbutamol/albuterol, amifampridine are effective in many but not all subtypes. Review also highlights episodic apnea in CHAT-, COLQ-, SCN4A-CMS and elevated CK in GMPPB-, GFPT1-, SCCMS. (ohno2023clinicalandpathologic pages 23-24, ohno2023clinicalandpathologic pages 1-3, ohno2023clinicalandpathologic media 068f9c05)	https://doi.org/10.3390/ijms24043730
O’Connor et al., International Journal of Molecular Sciences	2023-05	Review on mitochondrial involvement in CMS/NMJ disease	Review	Highlighted SLC25A1 and TEFM as mitochondria-associated genes reported in suspected CMS; proposed a “mitochondrial CMS” subcategory. Noted that mitochondrial defects may impair NMJ transmission at both pre- and postsynapse. (o’connor2023mitochondrialmutationscan pages 1-2)	Reported that mitochondrial disease and CMS can overlap clinically and that electrophysiological studies found NMJ abnormalities in >25% of a cohort with genetically confirmed primary mitochondrial disease. Emphasized treatment importance because drugs that help one CMS subtype may worsen another; mentioned AChE inhibitors, 3,4-DAP, and β2-agonists (salbutamol, ephedrine) as subtype-dependent options. (o’connor2023mitochondrialmutationscan pages 1-2)	https://doi.org/10.3390/ijms24108505
Pugliese et al., Journal of Neuromuscular Diseases	2023-09	Focused review of presynaptic CMS and animal models	Review	Presynaptic CMS comprise roughly 5–10% of all CMS; CHAT is the commonest presynaptic gene, accounting for 4–5% of all CMS. Mechanisms include impaired ACh synthesis/recycling, vesicle packaging, release, and presynaptic endplate development/maintenance. (pugliese2023presynapticcongenitalmyasthenic pages 1-3)	Presynaptic CMS usually present prenatally/neonatally with severe phenotypes including arthrogryposis, developmental delay, and apneic crises, but milder proximal-weakness phenotypes also occur. Diagnosis integrates history/exam, RNS decrement, SFEMG jitter/blocking, and confirmatory sequencing. Review summarizes in vivo models in zebrafish, mouse, C. elegans, and Drosophila for mechanism and therapy studies. (pugliese2023presynapticcongenitalmyasthenic pages 1-3)	https://doi.org/10.3233/JND-221646
Hesami et al., Orphanet Journal of Rare Diseases (COLQ cohort)	2024-03	Retrospective genetically confirmed subtype cohort	26	COLQ-CMS due to 14 variants, including 8 novel variants; variant classes included 6 missense, 3 frameshift, 3 nonsense, 1 synonymous, 1 CNV. COLQ encodes the collagen-like tail of acetylcholinesterase and causes synaptic CMS with endplate AChE deficiency. (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)	Mean follow-up 9 years. Symptom onset from birth to 15 years; delayed motor milestones in ~52%; sluggish pupils in ~30%. Low-frequency RNS showed significant decrement in all tested patients; double CMAP present in ~75%. No benefit from esterase inhibitors; ephedrine and salbutamol were objectively effective in all cases. (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)	https://doi.org/10.1186/s13023-024-03116-x
Ziaadini et al., BMC Neurology (DOK7 series)	2024-06	Case series with literature review	7	Genetically confirmed DOK7-CMS; most common variant in this series was c.1124_1127dupTGCC (3 patients). DOK7 is a common postsynaptic CMS gene associated with limb-girdle presentations and variable age at onset. (ziaadini2024dok7congenitalmyasthenic pages 1-2)	Mean onset 12.5 years (birth to 33 years). Common manifestations: limb-girdle weakness 6/7, fluctuating symptoms 5/7, ptosis 4/7, bifacial weakness 3/7, reduced extraocular movement 3/7, bulbar symptoms 2/7, dyspnea 2/7. 3-Hz RNS decrement in 5/6 tested. Authors reported salbutamol was the most effective treatment and recommended it as first-line for DOK7 patients. (ziaadini2024dok7congenitalmyasthenic pages 1-2)	https://doi.org/10.1186/s12883-024-03713-0

Table: This table compiles the most relevant 2023–2024 CMS cohorts and reviews, emphasizing sample size, geography, genotype distribution, and clinically actionable phenotype/treatment findings. It is useful for quickly comparing broad CMS overviews with subtype-specific cohorts such as COLQ- and DOK7-related disease.

1. Disease information

1.1 Concise overview (key concepts/definitions)

CMS are “a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ)” (Ohno et al., 2023; review). (ohno2023clinicalandpathologic pages 1-3)

Key clinical concept: despite the historical term “congenital,” onset can be variable; the 2023 IJMS review notes that while “Most CMS patients develop the disease before age 2 years,” CMS “can develop at any age including adolescence and adulthood,” including transient neonatal presentations with later relapse. (ohno2023clinicalandpathologic pages 1-3)

1.2 Key identifiers and coding systems

OMIM (disease-level): CMS is referenced as “CMS (OMIM #603,034)” in a 2024 COLQ-CMS cohort paper. (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)
OMIM (gene-level example): COLQ is referenced as OMIM #603,033 in the same source. (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)
Orphanet / ICD-10/ICD-11 / MeSH / MONDO: Not explicitly present in retrieved full-text evidence; therefore not reliably extractable here.

1.3 Common synonyms / alternative names

“Congenital myasthenic syndromes”
“Congenital myasthenic syndrome”
“Endplate myopathies” (CMS described as “motor endplate … endplate myopathies” in a review). (finsterer2019congenitalmyasthenicsyndromes pages 1-2)

1.4 Evidence sources

This report primarily uses aggregated disease-level resources (highly cited reviews) and multi-center cohorts (France, India, Belgium), plus gene-subtype cohorts (COLQ-CMS; DOK7-CMS) and ClinicalTrials.gov registry records. (polavarapu2024clinicalandgenetic pages 1-2, theuriet2024congenitalmyasthenicsyndromes pages 1-3, smeets2024congenitalmyasthenicsyndromes pages 1-2, hesami2024colqcongenitalmyasthenicsyndrome pages 1-2, ziaadini2024dok7congenitalmyasthenic pages 1-2, NCT01203592 chunk 1, NCT06078553 chunk 1, NCT06436742 chunk 1)

2. Etiology

2.1 Disease causal factors

Primary cause: germline pathogenic variants in NMJ-expressed genes (Mendelian, usually autosomal recessive). The 2023 IJMS review enumerates 35 CMS genes and emphasizes shared “defective neuromuscular signal transduction” due to NMJ molecular defects. (ohno2023clinicalandpathologic pages 1-3)

Representative causal genes (from 2023 review; 35 genes): AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1. (ohno2023clinicalandpathologic pages 1-3)

Subtype classification (current understanding): CMS are commonly categorized by the NMJ location of the defective protein—presynaptic, synaptic, postsynaptic—plus a group of glycosylation-related disorders; this framing is used across cohorts and reviews. (smeets2024congenitalmyasthenicsyndromes pages 1-2, pugliese2023presynapticcongenitalmyasthenic pages 1-3)

Inheritance: “Most CMS patients show autosomal recessive inheritance or require biallelic pathogenic variants,” while dominant/de novo inheritance is reported for slow-channel CMS (SCCMS) and certain presynaptic genes (e.g., SNAP25) and SYT2 in some cases. (ohno2023clinicalandpathologic pages 1-3, smeets2024congenitalmyasthenicsyndromes pages 1-2)

2.2 Risk factors

Genetic risk factors: the causal pathogenic variant(s) themselves. Cohort-level genotype frequencies provide practical “risk” context among diagnosed cases: - France nationwide adult cohort (n=235): CHRNE low-expressor 23.8%, DOK7 18.7%, RAPSN 14%. (theuriet2024congenitalmyasthenicsyndromes pages 1-3) - India cohort (n=156): CHRNE 39.4%, DOK7 14.4%, DPAGT1 9.8%, GFPT1 7.6%, MUSK 6.1%, GMPPB 5.3%, COLQ 4.5%. (polavarapu2024clinicalandgenetic pages 1-2)

Environmental/infectious risk factors: Not supported as primary causes in retrieved evidence; CMS are genetic disorders.

2.3 Protective factors

No genetic or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

Not identified in the retrieved evidence.

3. Phenotypes (clinical spectrum)

3.1 Core phenotype types

CMS manifestations are fatigable weakness affecting ocular, bulbar, respiratory, axial, and limb muscles. A review summarizes: “CMS are clinically characterised by abnormal fatigability, or transient or permanent weakness of extra-ocular, facial, bulbar, truncal, respiratory, or limb muscles.” (finsterer2019congenitalmyasthenicsyndromes pages 1-2)

Common/important phenotype patterns - Ocular involvement: ptosis, ophthalmoparesis (frequent). (smeets2024congenitalmyasthenicsyndromes pages 1-2, hesami2024colqcongenitalmyasthenicsyndrome pages 1-2) - Limb-girdle phenotype: emphasized for DOK7-CMS and other subtypes; “limb-girdle weakness” was present in 6/7 DOK7 cases in a 2024 series. (ziaadini2024dok7congenitalmyasthenic pages 1-2) - Episodic apnea: “Episodic apnea is frequently reported in CHAT-CMS, COLQ-CMS, and SCN4A-CMS.” (ohno2023clinicalandpathologic pages 1-3) - CNS/developmental involvement: some genes associate with developmental delay; the 2023 review lists multiple genes where developmental delay has been reported (e.g., CHAT, SNAP25, DPAGT1, SLC25A1, PURA). (ohno2023clinicalandpathologic pages 1-3)

3.2 Age of onset, severity, progression

Typical onset is infancy/early childhood, but adult-onset occurs (cohort evidence): 7/37 Belgian cases had adult-onset (genes included CHRNE, DOK7, MUSK, CHRND, GMPPB). (smeets2024congenitalmyasthenicsyndromes pages 1-2)
DOK7 case series: onset ranged “from birth to as late as the age of 33” with mean onset 12.5 years. (ziaadini2024dok7congenitalmyasthenic pages 1-2)

3.3 Frequency and phenotype statistics from recent cohorts

Belgium (n=37): RNS performed in 23; 18/23 showed pathological decrement. (smeets2024congenitalmyasthenicsyndromes pages 1-2)
COLQ-CMS Iran (n=26): delayed motor milestones ~52%; sluggish pupils ~30%; double CMAP ~75%. (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)

3.4 Quality of life impact

Formal QoL outcome instruments are being collected in current natural history studies (see Diagnostics/Treatment and Trials below), including EQ-5D-5L and PROMIS measures, reflecting recognized QoL burden. (NCT06078553 chunk 1)

3.5 Suggested HPO terms (examples; non-exhaustive)

Based on phenotypes explicitly reported in the retrieved evidence: - Ptosis (HP:0000508) - External ophthalmoplegia / Ophthalmoparesis (HP:0000544 / HP:0000598) - Muscle weakness (HP:0001324) - Limb-girdle muscle weakness (HP:0003750) - Fatigable weakness / Abnormal fatigability (commonly mapped to fatigable muscle weakness concepts) - Respiratory insufficiency / Dyspnea (HP:0002093 / HP:0002094) - Bulbar dysfunction / Dysphagia (HP:0002110) - Episodic apnea (HP:0002104) - Motor delay / Delayed developmental milestones (HP:0001263)

4. Genetic / molecular information

4.1 Causal genes and subtype structure

The 2023 IJMS review emphasizes 35 established CMS genes and organizes them into 14 groups “according to the pathomechanical, clinical, and therapeutic features.” (ohno2023clinicalandpathologic pages 1-3)

4.2 Pathogenic variant classes (examples from 2024 primary literature)

COLQ-CMS Iranian cohort (n=26): “We detected 14 variants (eight novel variants), including six missense, three frameshift, three nonsense, one synonymous and one copy number variation (CNV), in the COLQ gene.” (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)

Founder/recurrent variants (population-specific): - India cohort: identified “22 recurrent variants… eight… geographically specific to the Indian subcontinent,” and suspected founder haplotypes for DPAGT1 p.T380I and DES c.1023+5G>A. (polavarapu2024clinicalandgenetic pages 1-2) - DOK7 series: c.1124_1127dupTGCC was the most common variant (3/7). (ziaadini2024dok7congenitalmyasthenic pages 1-2)

4.3 Modifier genes / protective variants

Not identified in the retrieved evidence.

4.4 Epigenetic information and chromosomal abnormalities

Not identified in the retrieved evidence.

5. Environmental information

CMS are genetic disorders; no specific toxins, lifestyle, or infectious triggers were identified in the retrieved evidence.

6. Mechanism / pathophysiology

6.1 Core causal chain (NMJ physiology to symptoms)

A unifying mechanism is “a pathomechanism that disrupts neuromuscular transmission” at the NMJ. (o’connor2023mitochondrialmutationscan pages 1-2)

Causal chain (general): 1) Germline pathogenic variant in NMJ gene → 2) impaired ACh synthesis/packaging/release, synaptic basal-lamina signaling, or postsynaptic receptor clustering/channel kinetics → 3) reduced safety factor of neuromuscular transmission (decrement on low-frequency RNS; increased jitter on SFEMG) → 4) fatigable weakness ± respiratory/bulbar crises. (pugliese2023presynapticcongenitalmyasthenic pages 1-3, ohno2023clinicalandpathologic pages 1-3)

6.2 Mechanistic categories (current classification)

Presynaptic CMS: defects in “acetylcholine (ACh) synthesis or recycling, … packaging into synaptic vesicles, or … release into the synaptic cleft.” (pugliese2023presynapticcongenitalmyasthenic pages 1-3)
Synaptic (basal lamina) CMS: exemplified by COLQ-CMS (AChE anchoring/basal lamina). (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)
Postsynaptic CMS: includes AChR deficiency/kinetic defects and endplate development/maintenance genes (e.g., DOK7/MUSK pathway). (smeets2024congenitalmyasthenicsyndromes pages 1-2, ziaadini2024dok7congenitalmyasthenic pages 1-2)
Glycosylation-related CMS: “combination defects of the NMJ” affecting multiple components. (smeets2024congenitalmyasthenicsyndromes pages 1-2)
Mitochondrial involvement: “two mitochondrial genes—SLC25A1 and TEFM—have been reported in patients with suspected CMS,” leading to proposals for “mitochondrial CMS.” (o’connor2023mitochondrialmutationscan pages 1-2)

6.3 GO (biological process) suggestions (examples)

Chemical synaptic transmission; neuromuscular junction development/organization; acetylcholine metabolic process; synaptic vesicle exocytosis; protein glycosylation; acetylcholine receptor signaling pathway (mechanistically aligned to presynaptic/synaptic/postsynaptic and glycosylation CMS categories). (pugliese2023presynapticcongenitalmyasthenic pages 1-3, ohno2023clinicalandpathologic pages 1-3)

6.4 Cell Ontology (CL) suggestions

Motor neuron (CL:0000100)
Skeletal muscle myofiber (skeletal muscle cell)
Schwann cell (terminal Schwann cells participate in NMJ biology, though not CMS-specific in retrieved evidence)

7. Anatomical structures affected

7.1 Organ/system level

Primary system: neuromuscular junction in skeletal muscle (motor endplate). (finsterer2019congenitalmyasthenicsyndromes pages 1-2, ohno2023clinicalandpathologic pages 1-3)

7.2 Tissue/cell level

Skeletal muscle and motor nerve terminals at NMJ (presynaptic terminal; synaptic cleft/basal lamina; postsynaptic membrane). (pugliese2023presynapticcongenitalmyasthenic pages 1-3, hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)

7.3 Subcellular level (examples)

Synaptic vesicles / SNARE machinery implicated for some presynaptic CMS genes; presynaptic CMS mechanisms include vesicle packaging/release. (pugliese2023presynapticcongenitalmyasthenic pages 1-3, ohno2023clinicalandpathologic pages 1-3)

7.4 UBERON suggestions

Neuromuscular junction
Skeletal muscle
Diaphragm / respiratory muscles (respiratory involvement documented in cohorts). (theuriet2024congenitalmyasthenicsyndromes pages 1-3)

8. Temporal development

8.1 Onset patterns

Often infancy/early childhood; adult-onset is increasingly recognized (Belgian cohort; DOK7 series). (smeets2024congenitalmyasthenicsyndromes pages 1-2, ziaadini2024dok7congenitalmyasthenic pages 1-2)

8.2 Progression/course

Long-term adult cohort data show heterogeneous trajectories: “Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another… particularly in AGRN, DOK7 and COLQ.” (theuriet2024congenitalmyasthenicsyndromes pages 1-3)

9. Inheritance and population

9.1 Epidemiology (statistics)

Belgium prevalence estimate: 37 identified patients, “estimated prevalence of 3.19 per 1,000,000.” (smeets2024congenitalmyasthenicsyndromes pages 1-2)
Reviews note variability and under-ascertainment; presynaptic CMS review cites prevalence “estimated at 1.8 to 14.8 per million under those aged 18 years.” (pugliese2023presynapticcongenitalmyasthenic pages 1-3)

9.2 Population genetics / founder effects

India cohort: 22 recurrent variants; 8 geographically specific; founder haplotypes suspected for certain variants. (polavarapu2024clinicalandgenetic pages 1-2)

9.3 Sex ratio and demographics

French adult cohort: 123/235 female (52.3%). (theuriet2024congenitalmyasthenicsyndromes pages 1-3)

10. Diagnostics

10.1 Core diagnostic concept

Electrophysiologic evidence of impaired NMJ transmission and confirmatory genetics.

Key quote (2023 IJMS review): “Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS… genetic studies are always required for accurate diagnosis.” (ohno2023clinicalandpathologic pages 1-3)

10.2 Clinical tests / electrophysiology

Repetitive nerve stimulation (RNS): pathologic decrement is common (Belgium: 18/23 tested). (smeets2024congenitalmyasthenicsyndromes pages 1-2)
Single-fiber EMG (SFEMG): can show “abnormal jitter and blocking” (review). (pugliese2023presynapticcongenitalmyasthenic pages 1-3)
Double CMAP: characteristic in COLQ-CMS cohort (~75%). (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)

10.3 Laboratory/immunology to distinguish from autoimmune myasthenia gravis

COLQ-CMS cohort describes diagnosis including “absence of acetylcholine receptor or muscle-specific tyrosine kinase antibodies” and lack of immunosuppressive response, supporting CMS vs autoimmune MG differentiation. (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)

10.4 Genetic testing strategies (real-world implementation)

Belgium: diagnosis via targeted gene panels, single-gene testing, WES, mendeliome sequencing. (smeets2024congenitalmyasthenicsyndromes pages 1-2)
India: gene panels or hotspot screening followed by WES; high diagnostic yield (93.6% of families with CMS-associated genes). (polavarapu2024clinicalandgenetic pages 1-2)

10.5 Differential diagnosis

CMS can be mistaken for “nonspecific myopathies” and other neuromuscular disorders; DOK7 series highlights misdiagnosis risk when neurophysiology is not straightforward. (ziaadini2024dok7congenitalmyasthenic pages 1-2)

11. Outcome / prognosis

11.1 Long-term outcomes (2024 high-authority cohort)

A large French nationwide cohort of genetically confirmed adult CMS patients (n=235) provides long-term outcome statistics: - Mean follow-up 34 years. - ICU admission proportions >20% for RAPSN (54.8%), MUSK (50%), DOK7 (38.6%), AGRN (25%). - At last visit: ventilation required in 55% SCCMS and 36.3% DOK7; wheelchair dependence 36.3% DOK7, 25% GMPPB, 20% GFPT1. - Six deaths. - Conclusion: “the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit,” and “The positive impact of therapy was striking.” (theuriet2024congenitalmyasthenicsyndromes pages 1-3)

12. Treatment

12.1 Genotype-guided symptomatic therapy (core concept)

Therapy selection must be genotype- and mechanism-specific; multiple sources highlight that a medication can help one subtype and worsen another.

Key quote (2023 mitochondrial/NMJ review): “Many CMS subtypes are responsive to treatment, but drugs that may result in improvement for one genetic subtype of CMS can be detrimental for another type.” (o’connor2023mitochondrialmutationscan pages 1-2)

Key quote (Belgium cohort): “Most treatment responses were predictable based on the genotype.” (smeets2024congenitalmyasthenicsyndromes pages 1-2)

12.2 Major drug classes and examples (applications and real-world implementation)

1) Acetylcholinesterase inhibitors (AChE inhibitors; e.g., pyridostigmine) - Broadly used; however, “cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS.” (ohno2023clinicalandpathologic pages 1-3) - COLQ-CMS cohort: “There was no benefit from esterase inhibitor treatment.” (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2)

2) β2-adrenergic agonists (salbutamol/albuterol) and sympathomimetics (ephedrine) - COLQ-CMS cohort: “treatment with ephedrine and salbutamol was objectively efficient in all cases.” (hesami2024colqcongenitalmyasthenicsyndrome pages 1-2) - DOK7-CMS series: “Salbutamol was the most effective… We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients.” (ziaadini2024dok7congenitalmyasthenic pages 1-2) - Clinical trial evidence (albuterol): Phase 1 open-label single-group trial tested oral albuterol in CMS, motivated by ephedrine unavailability, with structured functional outcomes over 3 years; actual enrollment 21, completed 2013 (ClinicalTrials.gov NCT01203592). (NCT01203592 chunk 1)

3) Amifampridine / 3,4-diaminopyridine (3,4-DAP) - Expanded-access (treatment use) program NCT03062631 provided oral 3,4-DAP with safety monitoring (chemistry and ECG) for CMS patients, with broad age eligibility and seizure/arrhythmia exclusions. (NCT03062631 chunk 1)

12.3 Emerging/experimental therapies and trials (2023–2024 emphasis)

ARGX-119 (argenx) for DOK7-CMS: Phase 1b randomized, double-blind, placebo-controlled trial (NCT06436742) in adults with genetically confirmed DOK7-CMS; primary objective safety/tolerability; exploratory efficacy includes 6-minute walk test change; estimated enrollment 16; IV infusions with open-label extension option. (NCT06436742 chunk 1)
Genotype-specific natural history study: NCT06078553 recruits CMS due to DOK7, MUSK, AGRN, or LRP4 (n~100), capturing QMG, MG-ADL, PROMIS, EQ-5D-5L, mobility tests and other PROs to support outcome measure validation and future interventional studies. (NCT06078553 chunk 1)

12.4 MAXO terms (suggested)

Acetylcholinesterase inhibitor therapy
Beta-2 adrenergic agonist therapy
Amifampridine therapy (potassium channel blocker / presynaptic release enhancer)
Ventilatory support (for respiratory insufficiency)
Physical therapy / rehabilitation (not directly evidenced in retrieved texts but standard supportive care; not asserted here as evidence-based without retrieved citations)

13. Prevention

Primary prevention is not applicable in the conventional sense for inherited CMS. The retrieved evidence does not provide specific guideline statements on carrier screening, prenatal testing, or PGT; therefore these cannot be cited here.

14. Other species / natural disease

No naturally occurring non-human CMS data were identified in the retrieved evidence.

15. Model organisms

Presynaptic CMS review reports extensive use of in vivo models to study NMJ biology and therapies, including zebrafish (morpholinos and CRISPR/Cas9), mouse models (tissue-specific and whole-body knockouts), C. elegans (ACh NMJ with conserved machinery), and Drosophila (synaptic conservation but glutamatergic NMJ, affecting model suitability). (pugliese2023presynapticcongenitalmyasthenic pages 1-3)

Visual evidence (table)

Ohno et al. (2023) provide a gene-by-gene “Electrophysiological features and therapies” summary (Table 1), retrieved as cropped table images; this table supports genotype-specific electrophysiology and therapy expectations across CMS categories. (ohno2023clinicalandpathologic media 068f9c05, ohno2023clinicalandpathologic media 6f6d529d, ohno2023clinicalandpathologic media 7690dc2c, ohno2023clinicalandpathologic media 29d820b1)

Notes on evidence gaps

MONDO/MeSH/ICD/Orphanet IDs, detailed ClinVar variant-level frequencies, and robust QoL scores from interventional trials were not present in the retrieved full texts and therefore are not asserted.
PMIDs were not consistently available in the retrieved full-text excerpts; DOIs/URLs and publication metadata are provided from the sources.

References

(polavarapu2024clinicalandgenetic pages 1-2): Kiran Polavarapu, Balaraju Sunitha, Ana Töpf, Veeramani Preethish-Kumar, Rachel Thompson, Seena Vengalil, Saraswati Nashi, Mainak Bardhan, Sai Bhargava Sanka, Akshata Huddar, Gopikrishnan Unnikrishnan, Gautham Arunachal, Manu Santhappan Girija, Anna Porter, Yoshiteru Azuma, Paulo José Lorenzoni, Dipti Baskar, Ram Murthy Anjanappa, Madassu Keertipriya, Hansashree Padmanabh, Ganaraja Valakunja Harikrishna, Steve Laurie, Leslie Matalonga, Rita Horvath, Atchayaram Nalini, and Hanns Lochmüller. Clinical and genetic characterisation of a large indian congenital myasthenic syndrome cohort. Brain : a journal of neurology, 147:281-296, Sep 2024. URL: https://doi.org/10.1093/brain/awad315, doi:10.1093/brain/awad315. This article has 18 citations.
(theuriet2024congenitalmyasthenicsyndromes pages 1-3): Julian Theuriet, Marion Masingue, Anthony Behin, Ana Ferreiro, Guillaume Bassez, Pauline Jaubert, Oriana Tarabay, Frédéric Fer, Antoine Pegat, Françoise Bouhour, Juliette Svahn, Philippe Petiot, Laurentiu Jomir, Guy Chauplannaz, Catherine Cornut-Chauvinc, Véronique Manel, Emmanuelle Salort-Campana, Shahram Attarian, Etienne Fortanier, Annie Verschueren, Ludivine Kouton, Jean-Philippe Camdessanché, Céline Tard, Armelle Magot, Yann Péréon, Jean-Baptiste Noury, Marie-Christine Minot-Myhie, Maud Perie, Frederic Taithe, Yacine Farhat, Anne-Laure Millet, Pascal Cintas, Guilhem Solé, Marco Spinazzi, Florence Esselin, Dimitri Renard, Sabrina Sacconi, Andra Ezaru, Edoardo Malfatti, Martial Mallaret, Laurent Magy, Eva Diab, Philippe Merle, Maud Michaud, Maxime Fournier, Aleksandra Nadaj Pakleza, Jean-Baptiste Chanson, Claire Lefeuvre, Pascal Laforet, Pascale Richard, Damien Sternberg, Rocio-Nur Villar-Quiles, Tanya Stojkovic, and Bruno Eymard. Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis. Brain, 147:3849-3862, May 2024. URL: https://doi.org/10.1093/brain/awae124, doi:10.1093/brain/awae124. This article has 23 citations and is from a highest quality peer-reviewed journal.
(smeets2024congenitalmyasthenicsyndromes pages 1-2): Nathalie Smeets, Alexander Gheldof, Bart Dequeker, Margaux Poleur, Sofia Maldonado Slootjes, Vinciane Van Parijs, Nicolas Deconinck, Pauline Dontaine, Alicia Alonso-Jimenez, Jan De Bleecker, Willem De Ridder, Sarah Herdewyn, Stéphanie Paquay, Arnaud Vanlander, Liesbeth De Waele, Geertrui Peirens, Diane Beysen, Kristl G. Claeys, Nicolas Dubuisson, Isabelle Hansen, Gauthier Remiche, Sara Seneca, Véronique Bissay, and Luc Régal. Congenital myasthenic syndromes in belgium: genetic and clinical characterization of pediatric and adult patients. Pediatric Neurology, 158:57-65, Sep 2024. URL: https://doi.org/10.1016/j.pediatrneurol.2024.06.002, doi:10.1016/j.pediatrneurol.2024.06.002. This article has 8 citations and is from a peer-reviewed journal.
(ohno2023clinicalandpathologic pages 23-24): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 119 citations.
(ohno2023clinicalandpathologic pages 1-3): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 119 citations.
(ohno2023clinicalandpathologic media 068f9c05): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 119 citations.
(o’connor2023mitochondrialmutationscan pages 1-2): Kaela O’Connor, Sally Spendiff, Hanns Lochmüller, and Rita Horvath. Mitochondrial mutations can alter neuromuscular transmission in congenital myasthenic syndrome and mitochondrial disease. International Journal of Molecular Sciences, 24:8505, May 2023. URL: https://doi.org/10.3390/ijms24108505, doi:10.3390/ijms24108505. This article has 14 citations.
(pugliese2023presynapticcongenitalmyasthenic pages 1-3): Alessia Pugliese, Stephen H. Holland, Carmelo Rodolico, Hanns Lochmüller, and Sally Spendiff. Presynaptic congenital myasthenic syndromes: understanding clinical phenotypes through in vivo models. Journal of Neuromuscular Diseases, 10:731-759, Sep 2023. URL: https://doi.org/10.3233/jnd-221646, doi:10.3233/jnd-221646. This article has 18 citations and is from a peer-reviewed journal.
(hesami2024colqcongenitalmyasthenicsyndrome pages 1-2): Omid Hesami, Mahtab Ramezani, Aida Ghasemi, Farzad Fatehi, Ali Asghar Okhovat, Bentolhoda Ziaadini, Ariana Kariminejad, and Shahriar Nafissi. Colq-congenital myasthenic syndrome in an iranian cohort: the clinical and genetics spectrum. Orphanet Journal of Rare Diseases, Mar 2024. URL: https://doi.org/10.1186/s13023-024-03116-x, doi:10.1186/s13023-024-03116-x. This article has 4 citations and is from a peer-reviewed journal.
(ziaadini2024dok7congenitalmyasthenic pages 1-2): Bentolhoda Ziaadini, Bardyia Ghaderi Yazdi, Elham Dirandeh, Reza Boostani, Narges Karimi, Akram Panahi, Ariana Kariminejad, Mahsa Fadaee, Fatemeh Ahangari, and Shahriar Nafissi. Dok7 congenital myasthenic syndrome: case series and review of literature. BMC Neurology, Jun 2024. URL: https://doi.org/10.1186/s12883-024-03713-0, doi:10.1186/s12883-024-03713-0. This article has 7 citations and is from a peer-reviewed journal.
(finsterer2019congenitalmyasthenicsyndromes pages 1-2): Josef Finsterer. Congenital myasthenic syndromes. Orphanet Journal of Rare Diseases, Feb 2019. URL: https://doi.org/10.1186/s13023-019-1025-5, doi:10.1186/s13023-019-1025-5. This article has 237 citations and is from a peer-reviewed journal.
(NCT01203592 chunk 1): Andrew Engel. Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes. Mayo Clinic. 2010. ClinicalTrials.gov Identifier: NCT01203592
(NCT06078553 chunk 1): A Natural History Study in Participants With Congenital Myasthenic Syndromes (CMS) Due to Mutations in DOK7, MUSK, AGRN, or LRP4. argenx. 2024. ClinicalTrials.gov Identifier: NCT06078553
(NCT06436742 chunk 1): A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS). argenx. 2024. ClinicalTrials.gov Identifier: NCT06436742
(NCT03062631 chunk 1): Ricardo Maselli. Treatment Use of 3,4 Diaminopyridine in Congenital Myasthenia. Ricardo Maselli. ClinicalTrials.gov Identifier: NCT03062631
(ohno2023clinicalandpathologic media 6f6d529d): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 119 citations.
(ohno2023clinicalandpathologic media 7690dc2c): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 119 citations.
(ohno2023clinicalandpathologic media 29d820b1): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 119 citations.

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Mechanistic Hypotheses

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Phenotypes

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Medical Actions

Related Datasets

Clinical Trials

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References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Congenital Myasthenic Syndrome (CMS): Comprehensive Disease Characteristics Report (2023–2024 prioritized)

Target disease

Executive summary

1. Disease information

1.1 Concise overview (key concepts/definitions)

1.2 Key identifiers and coding systems

1.3 Common synonyms / alternative names

1.4 Evidence sources

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Core phenotype types

3.2 Age of onset, severity, progression

3.3 Frequency and phenotype statistics from recent cohorts

3.4 Quality of life impact

3.5 Suggested HPO terms (examples; non-exhaustive)

4. Genetic / molecular information

4.1 Causal genes and subtype structure

4.2 Pathogenic variant classes (examples from 2024 primary literature)

4.3 Modifier genes / protective variants

4.4 Epigenetic information and chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Core causal chain (NMJ physiology to symptoms)

6.2 Mechanistic categories (current classification)

6.3 GO (biological process) suggestions (examples)

6.4 Cell Ontology (CL) suggestions

7. Anatomical structures affected

7.1 Organ/system level

7.2 Tissue/cell level

7.3 Subcellular level (examples)

7.4 UBERON suggestions

8. Temporal development

8.1 Onset patterns

8.2 Progression/course

9. Inheritance and population

9.1 Epidemiology (statistics)

9.2 Population genetics / founder effects

9.3 Sex ratio and demographics

10. Diagnostics

10.1 Core diagnostic concept

10.2 Clinical tests / electrophysiology