Congenital Myasthenic Syndrome 7

Mendelian MONDO:0014468 Pathograph 18 Show in embeddings browser Congenital Myasthenic Syndrome

Congenital myasthenic syndrome 7 (CMS7) is the presynaptic congenital myasthenic syndrome caused by variants in SYT2, which encodes synaptotagmin-2, the fast calcium sensor that couples the presynaptic calcium transient to synchronous synaptic vesicle fusion at the motor nerve terminal. Loss of that coupling reduces quantal acetylcholine release per nerve impulse, so the endplate potential falls below the threshold for a muscle action potential and transmission fails intermittently. The electrophysiological picture therefore resembles Lambert-Eaton myasthenic syndrome - low compound muscle action potentials at rest that facilitate after exercise or fast repetitive stimulation - and, correspondingly, the disorder responds to 3,4-diaminopyridine rather than to anticholinesterase therapy alone. MONDO defines CMS7 by its gene rather than by inheritance, and both a dominant and a recessive form exist: the dominant form arises from missense variants in the C2B calcium-binding domain and typically presents in later childhood or adulthood with foot deformity, lower-limb wasting and fatigable ocular weakness, while biallelic loss-of-function variants produce a severe infantile syndrome with profound weakness, areflexia and bulbar involvement. A motor axonal neuropathy accompanies the junctional defect in many affected individuals, so CMS7 sits at the interface of the congenital myasthenic syndromes and the hereditary motor neuropathies.

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2
Inheritance
7
Pathophys.
12
Phenotypes
2
Gaps
18
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
2
Models
1
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

2
Autosomal Dominant HP:0000006
The originally described form is autosomal dominant, caused by heterozygous missense variants in the SYT2 C2B calcium-binding domain and segregating through multiple generations. A de novo heterozygous in-frame deletion has also been reported in a simplex case, so an affected proband with unaffected parents does not exclude the dominant form and a negative parental test does not exclude SYT2. Penetrance in the reported multigenerational pedigrees appears high, but no cohort has been assembled that would let it be quantified, so the structured `penetrance` slot is deliberately left unset rather than recorded as COMPLETE.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:25192047 SUPPORT Human Clinical
"Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes."
Documents heterozygous C2B missense variants segregating in multigenerational families, the basis for dominant inheritance.
PMID:33320396 SUPPORT Human Clinical
"Genetic analysis demonstrated a new de novo heterozygous in frame deletion of the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing, which removes five aminoacids in the C2B domain of synaptotagmin-2 protein, that cause a profound effect on the structure and function of..."
Documents a de novo dominant allele, which is what makes unaffected parents compatible with the dominant form and is the counselling-relevant exception to the segregating-pedigree picture above.
Autosomal Recessive HP:0000007
A separate, more severe recessive form is caused by biallelic loss-of-function SYT2 variants - frameshift, splice-site and whole-exon deletion alleles. Heterozygous parents are clinically and electrophysiologically normal.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:32250532 SUPPORT Human Clinical
"We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2."
First report of a recessive SYT2 CMS, establishing the second inheritance mode.
PMID:36722210 SUPPORT Human Clinical
"The parents were confirmed carriers of the same mutation and were normal on clinical and EMG studies."
Confirms carrier parents are unaffected even on electrophysiological testing, which is what makes this arm recessive rather than dominant with reduced penetrance.
◆

Subtypes

2
CMS7, autosomal dominant (SYT2 C2B missense)
Heterozygous C2B-domain variants acting through a dominant-negative mechanism: principally the missense changes p.Asp307Ala and p.Pro308Leu, and also a de novo in-frame deletion, c.1082_1096del, removing five residues from C2B. Later onset, foot deformities and lower-limb wasting, fatigable ocular and lower-limb weakness, and an accompanying non-progressive or slowly progressive motor neuropathy. Clinically the milder of the two forms.
CMS7, autosomal recessive (SYT2 biallelic loss of function)
Biallelic frameshift, splice-site or exonic-deletion alleles. Severe and early: profound weakness, hypotonia, areflexia, bulbar involvement and motor developmental delay, with denervation atrophy.
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Discussions and Knowledge Gaps

2
Is the motor axonopathy in CMS7 a consequence of chronic neuromuscular transmission failure, or an independent axonal role of synaptotagmin-2?
KNOWLEDGE GAP axonopathy_secondary_or_independent
Attached to
pathophysiology#Motor Axonal Neuropathy and Denervation Atrophy
The entry draws the axonopathy as a parallel consequence of the SYT2 lesion rather than a sequela of the junctional defect, but that placement is not evidence-based. Synaptotagmin-2 is a synaptic vesicle protein, and no published work establishes an axonal transport or maintenance function for it that would explain length-dependent degeneration directly. If the axonopathy is instead secondary to sustained transmission failure, then effective presynaptic therapy started early might prevent it, which makes this a question with a management consequence and not only a modelling one.
Why do recessive SYT2 alleles produce postsynaptic as well as presynaptic neuromuscular junction defects?
KNOWLEDGE GAP postsynaptic_involvement_recessive
Attached to
pathophysiology#Reduced Quantal Acetylcholine Release at the Motor Endplate
CMS7 is classified as a presynaptic syndrome and this entry models it that way. But the recessive splice allele is reported to cause severe pre- AND postsynaptic NMJ defects. A purely presynaptic sensor lesion should not reorganize the postsynaptic apparatus except through trophic or activity-dependent effects, so either the postsynaptic change is a secondary consequence of chronic underactivity - which the entry does not model - or SYT2 has a role in junctional maintenance that is not captured here. The distinction matters for whether the recessive form is a more severe version of the same disease or a partly different one.
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Pathophysiology

7
SYT2 C2B Dominant-Negative Calcium Sensor Disruption
Synaptotagmin-2 is the fast calcium sensor of the motor nerve terminal: its tandem C2 domains bind calcium entering through active-zone channels and trigger SNARE-mediated vesicle fusion within a millisecond. The dominant variants sit in the C2B calcium-binding pocket - p.Asp307Ala removes an essential calcium-coordinating aspartate, p.Pro308Leu the adjacent proline - so the sensor is expressed but cannot read the calcium signal. The effect is dominant-negative rather than haploinsufficient: the mutant subunit is incorporated into the release machinery alongside wild-type protein and actively degrades its function, which is why a single allele suffices and why the recessive form is not simply a more severe dose of the same lesion.
Genetic context SYT2 hgnc:11510 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SYT2 (hgnc:11510). hgnc:11510 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE
calcium sensing by the synaptotagmin-2 C2B domain GO:0005509 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves calcium sensing by the synaptotagmin-2 C2B domain, annotated with calcium ion binding (GO:0005509), qualified as loss of function. GO:0005509 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
synaptic vesicle GO:0008021 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves synaptic vesicle (GO:0008021). GO:0008021 is a cellular component from the Gene Ontology.
Animal models
Drosophila synaptotagmin P308L-homologous transgenic Fruit fly recapitulates Demonstrates that the P308L residue is critical for synaptotagmin function and that the variant is pathogenic at heterozygous dosage.
Downstream
Failure of Calcium-Triggered Synaptic Vesicle Fusion
Show evidence (2 references)
PMID:25192047 SUPPORT Human Clinical
"An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome."
Identifies the dominant lesion as disruption of an essential calcium-binding residue in the sensor.
PMID:34037996 SUPPORT Human Clinical
"The pathogenesis of the dominant form likely involves a dominant-negative effect due to disruption of the dual function of synaptotagmin as a Ca2+ -sensor and modulator of synaptic vesicle exocytosis."
Supports classifying the dominant mechanism as dominant-negative rather than as simple loss of function, which is what the genetic_context records. Note the authors hedge with "likely"; this is the field's working model, not a settled demonstration.
Biallelic SYT2 Loss of Function
The recessive lesion removes the protein or its C-terminal SNARE-interaction surface. That surface sits at the bottom face of the C2B domain and is not a calcium-binding site, so this is a mechanistically distinct route to the same endpoint - the sensor cannot engage the fusion machinery rather than cannot read calcium. Alleles include frameshift, splice-donor variants causing in-frame skipping of the C2A exon, and a deletion spanning exons 2 to 9. The resulting disease is markedly more severe than the dominant form.
Genetic context SYT2 hgnc:11510 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SYT2 (hgnc:11510). hgnc:11510 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
synaptotagmin-2 SNARE engagement GO:0000149 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves synaptotagmin-2 SNARE engagement, annotated with SNARE binding (GO:0000149), qualified as loss of function. GO:0000149 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of Calcium-Triggered Synaptic Vesicle Fusion
Show evidence (3 references)
PMID:32250532 SUPPORT Computational
"Modeling of the mutation using the rat Syt1 C2B x-ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin-SNARE interaction and exocytosis."
Supports the claim that the recessive truncating lesion damages the SNARE-interaction surface rather than the calcium-binding site.
PMID:32776697 SUPPORT Human Clinical
"Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement."
Establishes biallelic loss of function as a distinct mutational mechanism with its own consistent and more severe phenotype.
PMID:34037996 SUPPORT Human Clinical
"The recessive form of CMS caused by a SYT2 mutation showed far more severe clinical manifestations than the dominant form."
Head-to-head comparison in one study supporting the severity difference this node asserts.
Failure of Calcium-Triggered Synaptic Vesicle Fusion
Without a functioning fast calcium sensor, the calcium transient that arrives with each action potential no longer triggers synchronous vesicle fusion. Directly demonstrated in a transgenic Drosophila carrying the homologue of the human dominant variant, where synaptic vesicle exocytosis is dominantly disrupted.
calcium-triggered synchronous synaptic vesicle fusion GO:0099502 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium-triggered synchronous synaptic vesicle fusion, annotated with calcium-dependent activation of synaptic vesicle fusion (GO:0099502). GO:0099502 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Drosophila synaptotagmin D307A-homologous transgenic Fruit fly recapitulates Dominant disruption of synaptic vesicle exocytosis, establishing both the mechanism and the dominance of the human allele.
Downstream
Reduced Quantal Acetylcholine Release at the Motor Endplate
Show evidence (2 references)
PMID:25192047 SUPPORT Model Organism
"Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model."
Direct experimental demonstration that the variant disrupts vesicle exocytosis, and that it does so dominantly.
PMID:17521570 SUPPORT BACKGROUND Model Organism
"Synaptotagmin-1 and -2 are known Ca(2+) sensors for fast synchronous neurotransmitter release"
Establishes the baseline physiology this node depends on, that synaptotagmin-2 is a calcium sensor for fast synchronous release rather than an accessory protein. The sentence opens the paper and restates prior mouse work rather than reporting this study's own result, hence quote_role BACKGROUND; the evidence it summarises is rodent, hence MODEL_ORGANISM.
Reduced Quantal Acetylcholine Release at the Motor Endplate
Fewer acetylcholine quanta are released per nerve impulse. Because the deficit is presynaptic and the terminal can be modulated moment to moment, it facilitates: compound muscle action potentials are low at rest and increment after brief maximal exercise or fast repetitive stimulation. In CMS7 the post-tetanic potentiation is unusually prolonged, lasting up to 60 minutes, which distinguishes it from the minutes-long facilitation of Lambert-Eaton syndrome and is a positive diagnostic sign rather than merely a resemblance.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
acetylcholine secretion, neurotransmission GO:0014055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased acetylcholine secretion, neurotransmission (GO:0014055). GO:0014055 is a biological process from the Gene Ontology. ↓ DECREASED
neuromuscular junction GO:0031594 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves neuromuscular junction (GO:0031594). GO:0031594 is a cellular component from the Gene Ontology.
Downstream
Loss of the Safety Factor of Neuromuscular Transmission
Show evidence (4 references)
PMID:26519543 SUPPORT Human Clinical
"Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes."
Human electrophysiology establishing both the presynaptic release deficit and the unusually prolonged potentiation stated in the description.
PMID:32250532 SUPPORT Human Clinical
"Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates."
Shows the same presynaptic signature - low CMAP at rest with facilitation - in the recessive form, so the node applies to both subtypes.
PMID:34037996 SUPPORT DIRECT Human Clinical
"Microelectrode studies in the dominant form showed a marked reduction of the quantal content, which increased linearly with higher frequencies of nerve stimulation."
Intracellular microelectrode measurement of quantal content itself, the quantity this node names, rather than the compound-action-potential proxy.
+ 1 more reference
Loss of the Safety Factor of Neuromuscular Transmission
With quantal content reduced, the endplate potential no longer exceeds the muscle fibre action potential threshold with a margin. Transmission then fails at individual junctions, intermittently and use-dependently, which is what produces fatigable weakness rather than fixed paralysis.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Fatigable weakness
Ptosis
Bulbar weakness
Presynaptic Terminal and Endplate Remodelling
Show evidence (1 reference)
PMID:26519543 SUPPORT Human Clinical
"a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness"
Records the fatigable pattern of weakness that a reduced safety factor produces.
Presynaptic Terminal and Endplate Remodelling
Chronic transmission failure remodels the junction on both sides. Electron microscopy shows overdeveloped postsynaptic folding - the postsynaptic compensation for a weak endplate potential - together with abundant endosomes, multivesicular bodies and degenerative lamellar bodies inside small nerve terminals, which is a picture of disturbed vesicle recycling rather than of vesicle depletion alone.
neuromuscular junction GO:0031594 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves neuromuscular junction (GO:0031594). GO:0031594 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:34037996 SUPPORT Human Clinical
"The EM demonstrated overdeveloped postsynaptic folding, and abundant endosomes, multivesicular bodies and degenerative lamellar bodies inside small nerve terminals."
The ultrastructural findings this node describes, from patient muscle biopsy.
Motor Axonal Neuropathy and Denervation Atrophy
Beyond the junctional defect, SYT2 variants produce a motor axonopathy with distal wasting and foot deformity, and in the recessive form frank denervation atrophy. This is the feature that links CMS7 to the hereditary motor neuropathies and is why the dominant form was first described as a combined myasthenic and motor-neuropathy phenotype. Whether the axonal degeneration is a consequence of chronically failing transmission or an independent synaptotagmin-2 function in the axon is not established.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
Downstream
Motor axonal neuropathy
Pes cavus
Distal muscle weakness
Show evidence (2 references)
PMID:25192047 SUPPORT Human Clinical
"A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family."
Documents the coexisting motor neuropathy in a SYT2 family, the claim this node makes.
PMID:32250532 SUPPORT Human Clinical
"a severe recessive form of presynaptic CMS and denervation atrophy"
Records denervation atrophy in the recessive form, the more severe end of the same axonal involvement.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Myasthenic Syndrome 7 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Digestive 1
Bulbar weakness Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32250532 SUPPORT Human Clinical
"profound weakness and areflexia with moderate bulbar deficit"
Records the bulbar deficit in the recessive case.
Eye 1
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26519543 SUPPORT Human Clinical
"fatigable ocular and lower limb weakness"
Supports fatigable ocular involvement; the specific ocular signs are ptosis and ophthalmoparesis.
Limbs 1
Pes cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33320396 SUPPORT Human Clinical
"We report the case of a patient with a clinical phenotype characterized by distal lower limb weakness and pes cavus."
An independent case, carrying a different allele class, presenting with the same pes cavus plus distal weakness combination that makes this phenotype a pointer to SYT2.
PMID:26519543 SUPPORT Human Clinical
"SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities"
Identifies foot deformities and lower-limb wasting as characteristic features arising from the motor neuropathy.
Metabolism 1
Elevated creatine kinase Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41331967 SUPPORT Human Clinical
"Creatine phosphokinase level was 501 U/L; EMG showed reduced compound muscle action potential, myopathic findings, and incremental response."
Gives the CK value and the myopathic EMG picture that together produce the congenital-myopathy mimic described here.
Musculoskeletal 3
Fatigable weakness HP:0003473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigable weakness (HP:0003473). HP:0003473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26519543 SUPPORT Human Clinical
"a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness"
Names fatigable ocular and lower-limb weakness as a defining feature.
Distal muscle weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26519543 SUPPORT Human Clinical
"motor neuropathy causing lower limb wasting and foot deformities"
Reports lower-limb wasting attributable to the motor neuropathy.
Neonatal hypotonia HP:0001319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal hypotonia (HP:0001319). HP:0001319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32776697 SUPPORT Human Clinical
"a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement"
Documents congenital hypotonia as the consistent presenting feature of the biallelic cohort.
Nervous System 3
Motor axonal neuropathy HP:0007002 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor axonal neuropathy (HP:0007002). HP:0007002 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25192047 SUPPORT Human Clinical
"mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies"
States the link between SYT2 CMS and hereditary motor axonopathy.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32250532 SUPPORT Human Clinical
"The affected 2-year-old girl had profound weakness and areflexia with moderate bulbar deficit."
Documents areflexia in the recessive case.
Motor developmental delay Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36722210 SUPPORT Human Clinical
"A 13-year-old male child born of consanguineous parents with profound motor developmental delay and normal cognition was referred to us."
Documents profound motor developmental delay with normal cognition in a recessive CMS7 case.
Respiratory 1
Respiratory insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32776697 SUPPORT Human Clinical
"severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement"
Records respiratory involvement as part of the recessive phenotype, with its variability stated.
Voice 1
Weak cry HP:0001612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weak cry (HP:0001612). HP:0001612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41331967 SUPPORT Human Clinical
"A 14-year-old boy was born with neonatal hypotonia, weak cry, and dysphonia."
Documents weak cry and dysphonia in a homozygous SYT2 case.
🧬

Genetic Associations

1
SYT2 (Dominant C2B Missense and Recessive Loss-of-Function Variants)
Gene: SYT2 hgnc:11510 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SYT2 (hgnc:11510). hgnc:11510 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:33659639 SUPPORT Human Clinical
"In-frame skipping of exon 4 that encodes part of the C2A calcium-binding domain of SYT2 is associated with a loss-of-function effect resulting in a decrease of neurotransmitter release and severe pre- and postsynaptic NMJ defects."
Supports the splice allele and its loss-of-function consequence, and notes that the recessive form damages the postsynaptic side as well.
PMID:36722210 SUPPORT Human Clinical
"Clinical exome sequencing revealed a novel large deletion including the exons 2 to 9 of SYT2 gene which confirmed the diagnosis of presynaptic CMS type 7 in the siblings."
Documents the multi-exon deletion allele class, which single-gene sequencing would miss.
PMID:33320396 SUPPORT Human Clinical
"Genetic analysis demonstrated a new de novo heterozygous in frame deletion of the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing, which removes five aminoacids in the C2B domain of synaptotagmin-2 protein, that cause a profound effect on the structure and function of..."
Documents the in-frame deletion allele class, which is neither a C2B missense change nor a biallelic loss-of-function allele and so is not covered by either of the two classes above.
💊

Medical Actions

3
3,4-Diaminopyridine (Amifampridine)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: amifampridine CHEBI:135948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amifampridine (CHEBI:135948). CHEBI:135948 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A presynaptic potassium channel blocker. By prolonging the nerve terminal action potential it increases calcium entry per impulse, which partially compensates for the degraded calcium-to-fusion coupling. This is the mechanistically targeted treatment for CMS7 and produces both symptomatic benefit and measurable improvement in neuromuscular transmission.
Mechanism Target:
Reduced Quantal Acetylcholine Release at the Motor Endplate — Increases quantal content per impulse by prolonging terminal depolarization and calcium entry, acting upstream of the disabled sensor rather than repairing it.
Target Phenotypes: Fatigable weakness HP:0003473 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Fatigable weakness (HP:0003473). HP:0003473 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26519543 SUPPORT Human Clinical
"Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission."
Documents both the symptomatic and the electrophysiological response to 3,4-diaminopyridine in SYT2 patients.
PMID:32250532 SUPPORT Human Clinical
"3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective."
Confirms efficacy in the recessive form as well, and records albuterol as ineffective in the same patient.
Pyridostigmine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pyridostigmine CHEBI:8665 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridostigmine (CHEBI:8665). CHEBI:8665 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An acetylcholinesterase inhibitor. It prolongs the action of whatever acetylcholine is released rather than increasing release, so it addresses the downstream consequence and not the presynaptic lesion. Reported effective in the recessive case; in the dominant families it was tried first and 3,4-diaminopyridine was substituted.
Mechanism Target:
Loss of the Safety Factor of Neuromuscular Transmission — Raises the endplate potential produced by each released quantum, widening the margin above threshold without changing quantal content.
Show evidence (3 references)
PMID:32250532 SUPPORT Human Clinical
"3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue"
Reports pyridostigmine efficacy alongside 3,4-diaminopyridine in the recessive case.
PMID:26519543 SUPPORT Human Clinical
"Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine."
Records the sequence in which the two drugs were used in the dominant family.
PMID:32776697 SUPPORT Human Clinical
"Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function."
Extends anticholinesterase benefit to the severe recessive form, in three patients of the biallelic cohort.
Oral Salbutamol
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: salbutamol CHEBI:2549 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses salbutamol, annotated with albuterol (CHEBI:2549). CHEBI:2549 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A beta-2 adrenergic agonist that is standard symptomatic treatment in several congenital myasthenic syndromes and, in animal studies, remodels the endplate. It is curated here for a negative result: in a 12-month open trial of motor neuropathies with neuromuscular junction dysfunction, including SYT2, it produced no clear benefit on motor function and no clear change in neurophysiological parameters, with significant off-target beta-adrenergic side effects. The one positive signal was patient-reported fatigue. Albuterol was also ineffective in the separately reported recessive case. It is not a recommended treatment for CMS7 on current evidence.
Show evidence (2 references)
PMID:36869887 REFUTE INDIRECT Human Clinical
"No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue."
Recorded as REFUTE against salbutamol as an effective treatment here. Graded INDIRECT because the cohort was motor neuropathies with NMJ dysfunction as a group, of which SYT2 was one genotype among several, so the result is not SYT2-specific.
PMID:32250532 REFUTE Human Clinical
"3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective."
Independent single-patient report that the same drug class was ineffective, in a patient in whom the other two drugs worked.
🔬

Diagnosis

1
Electrophysiological and Molecular Diagnosis of CMS7
Repetitive nerve stimulation is the discriminating test: compound muscle action potential amplitudes are low at rest and increment markedly after brief maximal exercise or at fast stimulation rates, the presynaptic pattern. Post-tetanic potentiation in CMS7 is unusually prolonged, up to 60 minutes. The genetic diagnosis is made on a CMS gene panel or exome sequencing; note that a multi-exon deletion has been reported, so a copy-number-aware method or confirmatory microarray is needed to avoid a false-negative in a consanguineous family. Acetylcholine receptor and voltage-gated calcium channel antibodies are negative, which is the test that separates CMS7 from the two acquired disorders its electrophysiology imitates; seronegativity is an expected consequence of a Mendelian channel-coupling defect rather than a finding any SYT2 series reports as a measured result, so it is carried here as prose supported indirectly rather than as a cited positive observation.
Differential diagnosis: Lambert-Eaton myasthenic syndrome, which the electrophysiology closely resembles but which is acquired and antibody mediated; other presynaptic congenital myasthenic syndromes (CHAT/CMS6, the SNAP25, VAMP1 and MUNC13-1 syndromes); and hereditary motor neuropathy, which the foot deformity and distal wasting suggest on their own. Coexisting foot deformity and a facilitating CMAP is the combination that points to SYT2.
Show evidence (5 references)
PMID:26519543 SUPPORT Human Clinical
"with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation"
Supports the prolonged post-tetanic potentiation as the distinguishing diagnostic finding.
PMID:36722210 SUPPORT Human Clinical
"The deletion was confirmed on a chromosomal exon microarray."
Supports the recommendation that a copy-number-aware method is needed, since this allele was confirmed by microarray.
PMID:29696584 SUPPORT REVIEW SYNTHESIS Human Clinical
"Although clinical signs similar to LEMS can be present, the main hallmark is the electrophysiological findings, which are identical to autoimmune LEMS."
Supports making repetitive nerve stimulation the discriminating test and states that the electrophysiology alone cannot separate CMS7 from acquired LEMS, which is why the antibody result and the genetic result are both needed.
+ 2 more references
📊

Prevalence

2
United Kingdom (all genetically confirmed congenital myasthenic syndromes)
Point Prevalence 0.65 per 100,000 <1 in 1,000,000
This is the prevalence of congenital myasthenic syndrome as a whole, not of CMS7. It is recorded because it bounds CMS7 from above: SYT2 is one of more than thirty CMS genes and among the rarest, so CMS7 is far below 6.5 per million. The 2023 UK cohort of 442 genetically confirmed patients was dominated by CHRNE, DOK7 and RAPSN. Do not read this row as a CMS7 figure.
Show evidence (1 reference)
PMID:41251564 SUPPORT INDIRECT Human Clinical
"The UK prevalence was 6.5 cases per million overall and 8.5 cases per million in the pediatric population."
Graded INDIRECT: the figure is for all congenital myasthenic syndromes, and the CMS7 bound follows only by the inference that SYT2 is a small minority of that total.
Worldwide
Cases In Literature Ultra Rare
Twenty-eight cases in total were described in the literature by the 2025 case-based review, with most variants clustering in the C2B domain. The recessive form alone accounted for about ten cases as of 2023.
Show evidence (3 references)
PMID:41331967 SUPPORT Human Clinical
"We describe a previously unreported variant, comparing it with another 27 cases described in the literature."
Gives the total reported case count behind the ULTRA_RARE band.
PMID:41331967 SUPPORT Human Clinical
"Most mutations are concentrated in the C2B domain, critical for the protein's function."
Supports the C2B clustering stated in the notes.
PMID:36722210 SUPPORT Human Clinical
"This is the second case of CMS type 7 described with a large deletion of SYT2 gene, a first case with SYT2 gene mutation from India and overall 10th recessive case in the world."
Gives an explicit worldwide count of recessive cases, the basis for the ULTRA_RARE band.
🐁

Animal Models

2
Drosophila synaptotagmin P308L-homologous transgenic
A fly line built specifically to test the P308L variant at human-equivalent gene dosage. Expressed without native synaptotagmin the mutation is lethal, which establishes that the residue is essential; expressed alongside one wild-type copy - the patients' genotype - the flies develop neurological and behavioural manifestations resembling the human disease.
Species
Fruit fly
Genotype
Drosophila synaptotagmin carrying the residue homologous to human SYT2 p.Pro308Leu, expressed on a background carrying one copy of wild-type synaptotagmin
Publication
PMID:28953919
Pathograph links
SYT2 C2B Dominant-Negative Calcium Sensor Disruption recapitulates fidelity: moderate observes: molecular Demonstrates that the P308L residue is critical for synaptotagmin function and that the variant is pathogenic at heterozygous dosage.
Limitations: The variant is modelled in the Drosophila orthologue at a glutamatergic neuromuscular junction, not in human SYT2 at a cholinergic endplate. The lethality result comes from a null background the patients do not have, and only the one-wild-type-copy arm speaks to the human genotype.
Show evidence (1 reference)
PMID:28953919 SUPPORT Model Organism
"To achieve expression similar to human patients, the mutation is expressed in flies carrying one copy of the wild type synaptotagmin gene. We now show that Drosophila carrying this mutation developed neurological and behavioral manifestations similar to those of human patients"
Records the human-equivalent dosage arm and the phenotypic resemblance that makes this model informative.
Drosophila synaptotagmin D307A-homologous transgenic
A transgenic fly expressing the fly homologue of the human dominant C2B variant, used to test whether the variant is dominant and whether it acts on vesicle exocytosis.
Species
Fruit fly
Genotype
Transgenic Drosophila Synaptotagmin carrying the residue homologous to human SYT2 p.Asp307Ala
Publication
PMID:25192047
Pathograph links
Failure of Calcium-Triggered Synaptic Vesicle Fusion recapitulates fidelity: moderate observes: molecular Dominant disruption of synaptic vesicle exocytosis, establishing both the mechanism and the dominance of the human allele.
Limitations: The variant is modelled in the Drosophila synaptotagmin orthologue, not human SYT2, and at the fly neuromuscular junction, which is glutamatergic rather than cholinergic. The model therefore supports the exocytosis mechanism and the dominance but says nothing about the cholinergic endplate, the motor axonopathy, or any human clinical feature.
Readouts
Synaptic vesicle exocytosis at the larval neuromuscular junction
Direction: DECREASED
Interpretation: The measured exocytosis defect is the functional correlate of the sensor lesion.
Show evidence (1 reference)
PMID:25192047 SUPPORT Model Organism
"revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model"
Reports the exocytosis measurement and its direction.
Show evidence (1 reference)
PMID:25192047 SUPPORT Model Organism
"Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model."
Supports treating this fly line as informative for the calcium-triggered fusion node.
{ }

Source YAML

click to show 
name: Congenital Myasthenic Syndrome 7
creation_date: "2026-09-16T21:05:00Z"
description: >
  Congenital myasthenic syndrome 7 (CMS7) is the presynaptic congenital
  myasthenic syndrome caused by variants in SYT2, which encodes synaptotagmin-2,
  the fast calcium sensor that couples the presynaptic calcium transient to
  synchronous synaptic vesicle fusion at the motor nerve terminal. Loss of that
  coupling reduces quantal acetylcholine release per nerve impulse, so the
  endplate potential falls below the threshold for a muscle action potential and
  transmission fails intermittently. The electrophysiological picture therefore
  resembles Lambert-Eaton myasthenic syndrome - low compound muscle action
  potentials at rest that facilitate after exercise or fast repetitive
  stimulation - and, correspondingly, the disorder responds to 3,4-diaminopyridine
  rather than to anticholinesterase therapy alone. MONDO defines CMS7 by its gene
  rather than by inheritance, and both a dominant and a recessive form exist: the
  dominant form arises from missense variants in the C2B calcium-binding domain
  and typically presents in later childhood or adulthood with foot deformity,
  lower-limb wasting and fatigable ocular weakness, while biallelic
  loss-of-function variants produce a severe infantile syndrome with profound
  weakness, areflexia and bulbar involvement. A motor axonal neuropathy
  accompanies the junctional defect in many affected individuals, so CMS7 sits at
  the interface of the congenital myasthenic syndromes and the hereditary motor
  neuropathies.
category: Mendelian
disease_term:
  preferred_term: congenital myasthenic syndrome 7
  term:
    id: MONDO:0014468
    label: congenital myasthenic syndrome 7
synonyms:
- CMS7
- SYT2-related congenital myasthenic syndrome
- synaptotagmin 2-related congenital myasthenic syndrome
- presynaptic congenital myasthenic syndrome type 7
- myasthenic syndrome, congenital, 7, presynaptic
parents:
- Congenital Myasthenic Syndrome
references:
- reference: PMID:20301347
  title: "Congenital Myasthenic Syndromes Overview."
  tags:
  - GeneReviews
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    The originally described form is autosomal dominant, caused by heterozygous
    missense variants in the SYT2 C2B calcium-binding domain and segregating
    through multiple generations. A de novo heterozygous in-frame deletion has
    also been reported in a simplex case, so an affected proband with unaffected
    parents does not exclude the dominant form and a negative parental test does
    not exclude SYT2. Penetrance in the reported multigenerational pedigrees
    appears high, but no cohort has been assembled that would let it be
    quantified, so the structured `penetrance` slot is deliberately left unset
    rather than recorded as COMPLETE.
  evidence:
  - reference: PMID:25192047
    reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Via whole-exome sequencing, we identified heterozygous missense mutations in
      the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two
      multigenerational families presenting with peripheral motor neuron syndromes.
    explanation: >-
      Documents heterozygous C2B missense variants segregating in multigenerational
      families, the basis for dominant inheritance.
  - reference: PMID:33320396
    reference_title: "A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analysis demonstrated a new de novo heterozygous in frame deletion of
      the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing,
      which removes five aminoacids in the C2B domain of synaptotagmin-2 protein,
      that cause a profound effect on the structure and function of this synaptic
      vesicle protein.
    explanation: >-
      Documents a de novo dominant allele, which is what makes unaffected parents
      compatible with the dominant form and is the counselling-relevant exception
      to the segregating-pedigree picture above.
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    A separate, more severe recessive form is caused by biallelic loss-of-function
    SYT2 variants - frameshift, splice-site and whole-exon deletion alleles.
    Heterozygous parents are clinically and electrophysiologically normal.
  evidence:
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here a consanguineous patient with a severe recessive form of
      presynaptic CMS and denervation atrophy caused by the homozygous mutation
      c.1191delG, p.Arg397Serfs*37 in SYT2.
    explanation: >-
      First report of a recessive SYT2 CMS, establishing the second inheritance
      mode.
  - reference: PMID:36722210
    reference_title: "Exome sequencing and microarray identified a novel large exonic deletion in SYT2 gene in an ultra-rare case with recessive CMS type 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents were confirmed carriers of the same mutation and were normal on
      clinical and EMG studies.
    explanation: >-
      Confirms carrier parents are unaffected even on electrophysiological testing,
      which is what makes this arm recessive rather than dominant with reduced
      penetrance.
has_subtypes:
- name: CMS7 dominant
  display_name: CMS7, autosomal dominant (SYT2 C2B missense)
  description: >-
    Heterozygous C2B-domain variants acting through a dominant-negative mechanism:
    principally the missense changes p.Asp307Ala and p.Pro308Leu, and also a de
    novo in-frame deletion, c.1082_1096del, removing five residues from C2B.
    Later onset, foot deformities and lower-limb wasting, fatigable ocular and
    lower-limb weakness, and an accompanying non-progressive or slowly progressive
    motor neuropathy. Clinically the milder of the two forms.
- name: CMS7 recessive
  display_name: CMS7, autosomal recessive (SYT2 biallelic loss of function)
  description: >-
    Biallelic frameshift, splice-site or exonic-deletion alleles. Severe and early:
    profound weakness, hypotonia, areflexia, bulbar involvement and motor
    developmental delay, with denervation atrophy.
pathophysiology:
- name: SYT2 C2B Dominant-Negative Calcium Sensor Disruption
  biological_scale: MOLECULAR
  subtypes:
  - CMS7 dominant
  conforms_to: "neuromuscular_transmission_failure#Endplate Component Lesion"
  description: >-
    Synaptotagmin-2 is the fast calcium sensor of the motor nerve terminal: its
    tandem C2 domains bind calcium entering through active-zone channels and
    trigger SNARE-mediated vesicle fusion within a millisecond. The dominant
    variants sit in the C2B calcium-binding pocket - p.Asp307Ala removes an
    essential calcium-coordinating aspartate, p.Pro308Leu the adjacent proline -
    so the sensor is expressed but cannot read the calcium signal. The effect is
    dominant-negative rather than haploinsufficient: the mutant subunit is
    incorporated into the release machinery alongside wild-type protein and
    actively degrades its function, which is why a single allele suffices and why
    the recessive form is not simply a more severe dose of the same lesion.
  genetic_context:
    gene:
      preferred_term: SYT2
      term:
        id: hgnc:11510
        label: SYT2
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
  molecular_functions:
  - preferred_term: calcium sensing by the synaptotagmin-2 C2B domain
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005509
      label: calcium ion binding
  cellular_components:
  - preferred_term: synaptic vesicle
    term:
      id: GO:0008021
      label: synaptic vesicle
  downstream:
  - target: Failure of Calcium-Triggered Synaptic Vesicle Fusion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25192047
    reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a
      c.920A>C change in one family that presented with an autosomal-dominant
      presynaptic neuromuscular junction disorder resembling Lambert-Eaton
      myasthenic syndrome.
    explanation: >-
      Identifies the dominant lesion as disruption of an essential calcium-binding
      residue in the sensor.
  - reference: PMID:34037996
    reference_title: "Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenesis of the dominant form likely involves a dominant-negative
      effect due to disruption of the dual function of synaptotagmin as a Ca2+
      -sensor and modulator of synaptic vesicle exocytosis.
    explanation: >-
      Supports classifying the dominant mechanism as dominant-negative rather than
      as simple loss of function, which is what the genetic_context records. Note
      the authors hedge with "likely"; this is the field's working model, not a
      settled demonstration.
- name: Biallelic SYT2 Loss of Function
  biological_scale: MOLECULAR
  subtypes:
  - CMS7 recessive
  conforms_to: "neuromuscular_transmission_failure#Endplate Component Lesion"
  description: >-
    The recessive lesion removes the protein or its C-terminal SNARE-interaction
    surface. That surface sits at the bottom face of the C2B domain and is not a
    calcium-binding site, so this is a mechanistically distinct route to the same
    endpoint - the sensor cannot engage the fusion machinery rather than cannot
    read calcium. Alleles include frameshift, splice-donor variants causing
    in-frame skipping of the C2A exon, and a deletion spanning exons 2 to 9. The
    resulting disease is markedly more severe than the dominant form.
  genetic_context:
    gene:
      preferred_term: SYT2
      term:
        id: hgnc:11510
        label: SYT2
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: synaptotagmin-2 SNARE engagement
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0000149
      label: SNARE binding
  downstream:
  - target: Failure of Calcium-Triggered Synaptic Vesicle Fusion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Modeling of the mutation using the rat Syt1 C2B x-ray structure revealed that
      Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom
      face of the C2B domain not directly involved in calcium binding, but crucial
      for synaptotagmin-SNARE interaction and exocytosis.
    explanation: >-
      Supports the claim that the recessive truncating lesion damages the
      SNARE-interaction surface rather than the calcium-binding site.
  - reference: PMID:32776697
    reference_title: "Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report seven patients of five families, with biallelic loss of
      function variants in SYT2, clinically manifesting with a remarkably
      consistent phenotype of severe congenital onset hypotonia and weakness, with
      variable degrees of respiratory involvement.
    explanation: >-
      Establishes biallelic loss of function as a distinct mutational mechanism with
      its own consistent and more severe phenotype.
  - reference: PMID:34037996
    reference_title: "Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recessive form of CMS caused by a SYT2 mutation showed far more severe
      clinical manifestations than the dominant form.
    explanation: >-
      Head-to-head comparison in one study supporting the severity difference this
      node asserts.
- name: Failure of Calcium-Triggered Synaptic Vesicle Fusion
  biological_scale: MOLECULAR
  description: >-
    Without a functioning fast calcium sensor, the calcium transient that arrives
    with each action potential no longer triggers synchronous vesicle fusion.
    Directly demonstrated in a transgenic Drosophila carrying the homologue of the
    human dominant variant, where synaptic vesicle exocytosis is dominantly
    disrupted.
  biological_processes:
  - preferred_term: calcium-triggered synchronous synaptic vesicle fusion
    modifier: DECREASED
    term:
      id: GO:0099502
      label: calcium-dependent activation of synaptic vesicle fusion
  downstream:
  - target: Reduced Quantal Acetylcholine Release at the Motor Endplate
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25192047
    reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Characterization of the mutation homologous to the human c.920A>C variant in
      Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle
      exocytosis using this transgenic model.
    explanation: >-
      Direct experimental demonstration that the variant disrupts vesicle
      exocytosis, and that it does so dominantly.
  - reference: PMID:17521570
    reference_title: "Synaptotagmin-1, -2, and -9: Ca(2+) sensors for fast release that specify distinct presynaptic properties in subsets of neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      Synaptotagmin-1 and -2 are known Ca(2+) sensors for fast synchronous
      neurotransmitter release
    explanation: >-
      Establishes the baseline physiology this node depends on, that synaptotagmin-2
      is a calcium sensor for fast synchronous release rather than an accessory
      protein. The sentence opens the paper and restates prior mouse work rather
      than reporting this study's own result, hence quote_role BACKGROUND; the
      evidence it summarises is rodent, hence MODEL_ORGANISM.
- name: Reduced Quantal Acetylcholine Release at the Motor Endplate
  biological_scale: CELLULAR
  conforms_to: "neuromuscular_transmission_failure#Reduced Quantal Acetylcholine Release"
  description: >-
    Fewer acetylcholine quanta are released per nerve impulse. Because the deficit
    is presynaptic and the terminal can be modulated moment to moment, it
    facilitates: compound muscle action potentials are low at rest and increment
    after brief maximal exercise or fast repetitive stimulation. In CMS7 the
    post-tetanic potentiation is unusually prolonged, lasting up to 60 minutes,
    which distinguishes it from the minutes-long facilitation of Lambert-Eaton
    syndrome and is a positive diagnostic sign rather than merely a resemblance.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: acetylcholine secretion, neurotransmission
    modifier: DECREASED
    term:
      id: GO:0014055
      label: acetylcholine secretion, neurotransmission
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  downstream:
  - target: Loss of the Safety Factor of Neuromuscular Transmission
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiologic testing revealed features indicative of a presynaptic
      deficit in neurotransmitter release with posttetanic potentiation lasting up
      to 60 minutes.
    explanation: >-
      Human electrophysiology establishing both the presynaptic release deficit and
      the unusually prolonged potentiation stated in the description.
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Repetitive nerve stimulation revealed an extreme reduction of compound muscle
      action potential amplitudes at rest, with a striking facilitation followed by
      a progressive decline at fast stimulation rates.
    explanation: >-
      Shows the same presynaptic signature - low CMAP at rest with facilitation - in
      the recessive form, so the node applies to both subtypes.
  - reference: PMID:34037996
    reference_title: "Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Microelectrode studies in the dominant form showed a marked reduction of the
      quantal content, which increased linearly with higher frequencies of nerve
      stimulation.
    explanation: >-
      Intracellular microelectrode measurement of quantal content itself, the
      quantity this node names, rather than the compound-action-potential proxy.
  - reference: PMID:29696584
    reference_title: "How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CMS-LEMS occurs due to deficits in acetylcholine vesicle release caused by
      dysfunction of different components in its pathway.
    explanation: >-
      Places the SYT2 lesion in the class of presynaptic syndromes whose shared
      final step is a deficit of acetylcholine vesicle release, which is the node
      this entry routes every upstream lesion through. A review's synthesis across
      the CMS-LEMS genes, not a measurement of its own.
- name: Loss of the Safety Factor of Neuromuscular Transmission
  biological_scale: TISSUE
  conforms_to: "neuromuscular_transmission_failure#Loss of the Safety Factor of Neuromuscular Transmission"
  description: >-
    With quantal content reduced, the endplate potential no longer exceeds the
    muscle fibre action potential threshold with a margin. Transmission then fails
    at individual junctions, intermittently and use-dependently, which is what
    produces fatigable weakness rather than fixed paralysis.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  downstream:
  - target: Fatigable weakness
    causal_link_type: DIRECT
  - target: Ptosis
    causal_link_type: DIRECT
  - target: Bulbar weakness
    causal_link_type: DIRECT
  - target: Presynaptic Terminal and Endplate Remodelling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a novel neuromuscular syndrome characterized by foot deformities and
      fatigable ocular and lower limb weakness
    explanation: >-
      Records the fatigable pattern of weakness that a reduced safety factor
      produces.
- name: Presynaptic Terminal and Endplate Remodelling
  biological_scale: TISSUE
  description: >-
    Chronic transmission failure remodels the junction on both sides. Electron
    microscopy shows overdeveloped postsynaptic folding - the postsynaptic
    compensation for a weak endplate potential - together with abundant endosomes,
    multivesicular bodies and degenerative lamellar bodies inside small nerve
    terminals, which is a picture of disturbed vesicle recycling rather than of
    vesicle depletion alone.
  cellular_components:
  - preferred_term: neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  evidence:
  - reference: PMID:34037996
    reference_title: "Dominant and recessive congenital myasthenic syndromes caused by SYT2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The EM demonstrated overdeveloped postsynaptic folding, and abundant
      endosomes, multivesicular bodies and degenerative lamellar bodies inside
      small nerve terminals.
    explanation: >-
      The ultrastructural findings this node describes, from patient muscle biopsy.
- name: Motor Axonal Neuropathy and Denervation Atrophy
  biological_scale: TISSUE
  description: >-
    Beyond the junctional defect, SYT2 variants produce a motor axonopathy with
    distal wasting and foot deformity, and in the recessive form frank denervation
    atrophy. This is the feature that links CMS7 to the hereditary motor
    neuropathies and is why the dominant form was first described as a combined
    myasthenic and motor-neuropathy phenotype. Whether the axonal degeneration is a
    consequence of chronically failing transmission or an independent
    synaptotagmin-2 function in the axon is not established.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  downstream:
  - target: Motor axonal neuropathy
    causal_link_type: DIRECT
  - target: Pes cavus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Distal muscle weakness
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25192047
    reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a
      presynaptic neuromuscular junction defect and a dominant hereditary motor
      neuropathy in a second family.
    explanation: >-
      Documents the coexisting motor neuropathy in a SYT2 family, the claim this
      node makes.
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a severe recessive form of presynaptic CMS and denervation atrophy
    explanation: >-
      Records denervation atrophy in the recessive form, the more severe end of the
      same axonal involvement.
phenotypes:
- category: Neuromuscular
  name: Fatigable weakness
  description: >-
    Use-dependent weakness that worsens with activity, the cardinal manifestation
    of a failing neuromuscular junction. In CMS7 it affects ocular and lower-limb
    muscles prominently.
  phenotype_term:
    preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a novel neuromuscular syndrome characterized by foot deformities and
      fatigable ocular and lower limb weakness
    explanation: >-
      Names fatigable ocular and lower-limb weakness as a defining feature.
- category: Neuromuscular
  name: Ptosis
  description: >-
    Fatigable ptosis, part of the fatigable ocular involvement described in the
    dominant families. Limited eye movement is described alongside it in those
    reports, but the cited source names only fatigable ocular weakness without
    separating the two signs, so ophthalmoparesis is not asserted as its own
    phenotype here.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      fatigable ocular and lower limb weakness
    explanation: >-
      Supports fatigable ocular involvement; the specific ocular signs are ptosis
      and ophthalmoparesis.
- category: Neuromuscular
  name: Pes cavus
  description: >-
    Pes cavus, the foot deformity reported in these families and typically
    accompanied by hammer toes, a consequence of the chronic distal motor
    axonopathy. Its presence in a myasthenic phenotype is a strong pointer to
    SYT2.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  diagnostic: true
  evidence:
  - reference: PMID:33320396
    reference_title: "A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the case of a patient with a clinical phenotype characterized by
      distal lower limb weakness and pes cavus.
    explanation: >-
      An independent case, carrying a different allele class, presenting with the
      same pes cavus plus distal weakness combination that makes this phenotype a
      pointer to SYT2.
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SYT2 mutations cause a novel and potentially treatable complex presynaptic
      congenital myasthenic syndrome characterized by motor neuropathy causing
      lower limb wasting and foot deformities
    explanation: >-
      Identifies foot deformities and lower-limb wasting as characteristic features
      arising from the motor neuropathy.
- category: Neuromuscular
  name: Motor axonal neuropathy
  description: >-
    A length-dependent motor axonopathy accompanying the junctional defect,
    non-progressive or slowly progressive in the dominant form.
  phenotype_term:
    preferred_term: Motor axonal neuropathy
    term:
      id: HP:0007002
      label: Motor axonal neuropathy
  evidence:
  - reference: PMID:25192047
    reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in the Synaptotagmin 2 C2B domain represent an important cause of
      presynaptic congenital myasthenic syndromes and link them with hereditary
      motor axonopathies
    explanation: >-
      States the link between SYT2 CMS and hereditary motor axonopathy.
- category: Neuromuscular
  name: Distal muscle weakness
  description: >-
    Lower-limb wasting and distal weakness from the accompanying motor neuropathy.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      motor neuropathy causing lower limb wasting and foot deformities
    explanation: >-
      Reports lower-limb wasting attributable to the motor neuropathy.
- category: Neuromuscular
  name: Areflexia
  subtype: CMS7 recessive
  description: >-
    Absent tendon reflexes, prominent in the severe recessive form. Reflexes may
    potentiate transiently after exercise, mirroring the electrophysiological
    facilitation.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected 2-year-old girl had profound weakness and areflexia with
      moderate bulbar deficit.
    explanation: >-
      Documents areflexia in the recessive case.
- category: Neuromuscular
  name: Bulbar weakness
  subtype: CMS7 recessive
  description: >-
    Swallowing and speech difficulty from bulbar muscle involvement, reported in
    the recessive form.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      profound weakness and areflexia with moderate bulbar deficit
    explanation: >-
      Records the bulbar deficit in the recessive case.
- category: Developmental
  name: Motor developmental delay
  subtype: CMS7 recessive
  description: >-
    Profound delay in motor milestones in the recessive form, with cognition
    spared.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:36722210
    reference_title: "Exome sequencing and microarray identified a novel large exonic deletion in SYT2 gene in an ultra-rare case with recessive CMS type 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 13-year-old male child born of consanguineous parents with profound motor
      developmental delay and normal cognition was referred to us.
    explanation: >-
      Documents profound motor developmental delay with normal cognition in a
      recessive CMS7 case.
- category: Neuromuscular
  name: Neonatal hypotonia
  subtype: CMS7 recessive
  description: >-
    Severe congenital-onset hypotonia, the presenting feature of the recessive
    form and consistent across the reported biallelic cohort.
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:32776697
    reference_title: "Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a remarkably consistent phenotype of severe congenital onset hypotonia and
      weakness, with variable degrees of respiratory involvement
    explanation: >-
      Documents congenital hypotonia as the consistent presenting feature of the
      biallelic cohort.
- category: Respiratory
  name: Respiratory insufficiency
  subtype: CMS7 recessive
  description: >-
    Variable respiratory involvement in the recessive form, up to ventilatory
    dependence. Recurrent respiratory infection is also reported.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:32776697
    reference_title: "Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe congenital onset hypotonia and weakness, with variable degrees of
      respiratory involvement
    explanation: >-
      Records respiratory involvement as part of the recessive phenotype, with its
      variability stated.
- category: Neuromuscular
  name: Weak cry
  subtype: CMS7 recessive
  description: >-
    Weak cry in the neonatal period, reflecting bulbar and laryngeal muscle
    involvement. The same case report describes dysphonia alongside it; that sign
    falls under the bulbar weakness phenotype below, whose description covers
    speech as well as swallowing difficulty, so it is not bundled into this name.
  phenotype_term:
    preferred_term: Weak cry
    term:
      id: HP:0001612
      label: Weak cry
  evidence:
  - reference: PMID:41331967
    reference_title: "SYT2-Related Disease: A Case-Based Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 14-year-old boy was born with neonatal hypotonia, weak cry, and dysphonia.
    explanation: >-
      Documents weak cry and dysphonia in a homozygous SYT2 case.
- category: Laboratory
  name: Elevated creatine kinase
  description: >-
    Creatine kinase can be raised, which together with myopathic EMG findings is
    what makes SYT2 disease mimic a congenital myopathy and delays the diagnosis.
    It is not a consistent feature and the value below is a single reported case.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:41331967
    reference_title: "SYT2-Related Disease: A Case-Based Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Creatine phosphokinase level was 501 U/L; EMG showed reduced compound muscle
      action potential, myopathic findings, and incremental response.
    explanation: >-
      Gives the CK value and the myopathic EMG picture that together produce the
      congenital-myopathy mimic described here.
prevalence:
- population: United Kingdom (all genetically confirmed congenital myasthenic syndromes)
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.65
  rate_denominator: POPULATION
  notes: >-
    This is the prevalence of congenital myasthenic syndrome as a whole, not of
    CMS7. It is recorded because it bounds CMS7 from above: SYT2 is one of more
    than thirty CMS genes and among the rarest, so CMS7 is far below 6.5 per
    million. The 2023 UK cohort of 442 genetically confirmed patients was
    dominated by CHRNE, DOK7 and RAPSN. Do not read this row as a CMS7 figure.
  evidence:
  - reference: PMID:41251564
    reference_title: "Prevalence and Geographical Distribution of Patients With Congenital Myasthenic Syndromes in the United Kingdom."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The UK prevalence was 6.5 cases per million overall and 8.5 cases per million
      in the pediatric population.
    explanation: >-
      Graded INDIRECT: the figure is for all congenital myasthenic syndromes, and
      the CMS7 bound follows only by the inference that SYT2 is a small minority of
      that total.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twenty-eight cases in total were described in the literature by the 2025
    case-based review, with most variants clustering in the C2B domain. The
    recessive form alone accounted for about ten cases as of 2023.
  evidence:
  - reference: PMID:41331967
    reference_title: "SYT2-Related Disease: A Case-Based Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a previously unreported variant, comparing it with another 27
      cases described in the literature.
    explanation: >-
      Gives the total reported case count behind the ULTRA_RARE band.
  - reference: PMID:41331967
    reference_title: "SYT2-Related Disease: A Case-Based Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most mutations are concentrated in the C2B domain, critical for the protein's
      function.
    explanation: >-
      Supports the C2B clustering stated in the notes.
  - reference: PMID:36722210
    reference_title: "Exome sequencing and microarray identified a novel large exonic deletion in SYT2 gene in an ultra-rare case with recessive CMS type 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the second case of CMS type 7 described with a large deletion of SYT2
      gene, a first case with SYT2 gene mutation from India and overall 10th
      recessive case in the world.
    explanation: >-
      Gives an explicit worldwide count of recessive cases, the basis for the
      ULTRA_RARE band.
genetic:
- name: SYT2
  gene_term:
    preferred_term: SYT2
    term:
      id: hgnc:11510
      label: SYT2
  presence: Positive
  association: Dominant C2B Missense and Recessive Loss-of-Function Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Two allelic classes with different inheritance. Dominant: C2B calcium-binding
    domain missense, principally c.920A>C p.Asp307Ala and c.923C>T p.Pro308Leu
    (the same two changes are reported elsewhere with the nucleotide substitutions
    written as c.920T>G and c.923G>A - see the note at the bottom of this entry).
    A third dominant allele class is an in-frame deletion rather than a missense
    change: c.1082_1096del (NM_177402.4), removing five residues from C2B, reported
    as a de novo event in a simplex case.
    Recessive: frameshift (c.1191delG p.Arg397Serfs*37, c.328_331dup), splice-donor
    (c.465+1G>A causing in-frame skipping of exon 4 in the C2A domain), and a
    multi-exon deletion spanning exons 2-9.
    Population constraint: gnomAD reports SYT2 as loss-of-function intolerant and
    missense-constrained - pLI 0.70, LOEUF upper bound 0.58, LoF z-score 3.34,
    missense z-score 2.62, synonymous z-score 0.98. These are
    database-derived summary statistics with no quotable publication behind them,
    so they are recorded here as notes rather than as an evidence-backed claim, and
    dismech has no structured slot for gene-level constraint metrics.
  evidence:
  - reference: PMID:33659639
    reference_title: "New recessive mutations in SYT2 causing severe presynaptic congenital myasthenic syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In-frame skipping of exon 4 that encodes part of the C2A calcium-binding
      domain of SYT2 is associated with a loss-of-function effect resulting in a
      decrease of neurotransmitter release and severe pre- and postsynaptic NMJ
      defects.
    explanation: >-
      Supports the splice allele and its loss-of-function consequence, and notes
      that the recessive form damages the postsynaptic side as well.
  - reference: PMID:36722210
    reference_title: "Exome sequencing and microarray identified a novel large exonic deletion in SYT2 gene in an ultra-rare case with recessive CMS type 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical exome sequencing revealed a novel large deletion including the exons
      2 to 9 of SYT2 gene which confirmed the diagnosis of presynaptic CMS type 7
      in the siblings.
    explanation: >-
      Documents the multi-exon deletion allele class, which single-gene sequencing
      would miss.
  - reference: PMID:33320396
    reference_title: "A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analysis demonstrated a new de novo heterozygous in frame deletion of
      the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing,
      which removes five aminoacids in the C2B domain of synaptotagmin-2 protein,
      that cause a profound effect on the structure and function of this synaptic
      vesicle protein.
    explanation: >-
      Documents the in-frame deletion allele class, which is neither a C2B missense
      change nor a biallelic loss-of-function allele and so is not covered by either
      of the two classes above.
diagnosis:
- name: Electrophysiological and Molecular Diagnosis of CMS7
  description: >-
    Repetitive nerve stimulation is the discriminating test: compound muscle action
    potential amplitudes are low at rest and increment markedly after brief maximal
    exercise or at fast stimulation rates, the presynaptic pattern. Post-tetanic
    potentiation in CMS7 is unusually prolonged, up to 60 minutes. The
    genetic diagnosis is made on a CMS gene panel or exome sequencing; note that a
    multi-exon deletion has been reported, so a copy-number-aware method or
    confirmatory microarray is needed to avoid a false-negative in a consanguineous
    family. Acetylcholine receptor and voltage-gated calcium channel antibodies are
    negative, which is the test that separates CMS7 from the two acquired disorders
    its electrophysiology imitates; seronegativity is an expected consequence of a
    Mendelian channel-coupling defect rather than a finding any SYT2 series reports
    as a measured result, so it is carried here as prose supported indirectly rather
    than as a cited positive observation.
  notes: >-
    Differential diagnosis: Lambert-Eaton myasthenic syndrome, which the
    electrophysiology closely resembles but which is acquired and antibody
    mediated; other presynaptic congenital myasthenic syndromes (CHAT/CMS6, the
    SNAP25, VAMP1 and MUNC13-1 syndromes); and hereditary motor neuropathy, which
    the foot deformity and distal wasting suggest on their own. Coexisting foot
    deformity and a facilitating CMAP is the combination that points to SYT2.
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with reflex potentiation following exercise and a uniquely prolonged period
      of posttetanic potentiation
    explanation: >-
      Supports the prolonged post-tetanic potentiation as the distinguishing
      diagnostic finding.
  - reference: PMID:36722210
    reference_title: "Exome sequencing and microarray identified a novel large exonic deletion in SYT2 gene in an ultra-rare case with recessive CMS type 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deletion was confirmed on a chromosomal exon microarray.
    explanation: >-
      Supports the recommendation that a copy-number-aware method is needed, since
      this allele was confirmed by microarray.
  - reference: PMID:29696584
    reference_title: "How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Although clinical signs similar to LEMS can be present, the main hallmark is
      the electrophysiological findings, which are identical to autoimmune LEMS.
    explanation: >-
      Supports making repetitive nerve stimulation the discriminating test and
      states that the electrophysiology alone cannot separate CMS7 from acquired
      LEMS, which is why the antibody result and the genetic result are both needed.
  - reference: PMID:30032336
    reference_title: "Congenital Myasthenic Syndromes: a Clinical and Treatment Approach."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Unlike in autoimmune myasthenia gravis, there is no role for immunotherapy in
      congenital myasthenic syndromes.
    explanation: >-
      The nearest citable support for the seronegativity statement above. It asserts
      the absence of an autoimmune mechanism in the congenital syndromes as a class,
      from which antibody negativity follows; it does not report an antibody
      measurement in a SYT2 cohort, hence directness INDIRECT.
  - reference: PMID:33320396
    reference_title: "A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case showed electrophysiological features consistent with a presynaptic
      dysfunction in the neuromuscular junction with normal post-exercise amplitudes,
      not supporting the presence of predominant axonal damage.
    explanation: >-
      Supports reading the electrophysiology as a junctional rather than an axonal
      result in a patient whose clinical picture is that of a motor neuropathy, which
      is the discrimination the differential below turns on.
treatments:
- name: 3,4-Diaminopyridine (Amifampridine)
  description: >-
    A presynaptic potassium channel blocker. By prolonging the nerve terminal
    action potential it increases calcium entry per impulse, which partially
    compensates for the degraded calcium-to-fusion coupling. This is the
    mechanistically targeted treatment for CMS7 and produces both symptomatic
    benefit and measurable improvement in neuromuscular transmission.
  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
  target_mechanisms:
  - target: Reduced Quantal Acetylcholine Release at the Motor Endplate
    description: >-
      Increases quantal content per impulse by prolonging terminal depolarization
      and calcium entry, acting upstream of the disabled sensor rather than
      repairing it.
  target_phenotypes:
  - preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with 3,4-diaminopyridine produced both a clinical benefit and an
      improvement in neuromuscular transmission.
    explanation: >-
      Documents both the symptomatic and the electrophysiological response to
      3,4-diaminopyridine in SYT2 patients.
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle
      fatigue, but albuterol was ineffective.
    explanation: >-
      Confirms efficacy in the recessive form as well, and records albuterol as
      ineffective in the same patient.
- name: Pyridostigmine
  description: >-
    An acetylcholinesterase inhibitor. It prolongs the action of whatever
    acetylcholine is released rather than increasing release, so it addresses the
    downstream consequence and not the presynaptic lesion. Reported effective in the
    recessive case; in the dominant families it was tried first and
    3,4-diaminopyridine was substituted.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  target_mechanisms:
  - target: Loss of the Safety Factor of Neuromuscular Transmission
    description: >-
      Raises the endplate potential produced by each released quantum, widening the
      margin above threshold without changing quantal content.
  evidence:
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle
      fatigue
    explanation: >-
      Reports pyridostigmine efficacy alongside 3,4-diaminopyridine in the recessive
      case.
  - reference: PMID:26519543
    reference_title: "Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serial clinical and electrophysiologic assessments were performed in members
      of one family treated first with pyridostigmine and then with
      3,4-diaminopyridine.
    explanation: >-
      Records the sequence in which the two drugs were used in the dominant family.
  - reference: PMID:32776697
    reference_title: "Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with an acetylcholinesterase inhibitor pursued in three patients
      showed clinical improvement with increased strength and function.
    explanation: >-
      Extends anticholinesterase benefit to the severe recessive form, in three
      patients of the biallelic cohort.
- name: Oral Salbutamol
  description: >-
    A beta-2 adrenergic agonist that is standard symptomatic treatment in several
    congenital myasthenic syndromes and, in animal studies, remodels the endplate.
    It is curated here for a negative result: in a 12-month open trial of motor
    neuropathies with neuromuscular junction dysfunction, including SYT2, it
    produced no clear benefit on motor function and no clear change in
    neurophysiological parameters, with significant off-target beta-adrenergic side
    effects. The one positive signal was patient-reported fatigue. Albuterol was
    also ineffective in the separately reported recessive case. It is not a
    recommended treatment for CMS7 on current evidence.
  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:36869887
    reference_title: "Neuromuscular junction involvement in inherited motor neuropathies: genetic heterogeneity and effect of oral salbutamol treatment."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      No clear benefit on motor function was seen following the administration of
      12 months of oral salbutamol; however, there was a significant improvement in
      patient reported fatigue.
    explanation: >-
      Recorded as REFUTE against salbutamol as an effective treatment here. Graded
      INDIRECT because the cohort was motor neuropathies with NMJ dysfunction as a
      group, of which SYT2 was one genotype among several, so the result is not
      SYT2-specific.
  - reference: PMID:32250532
    reference_title: "Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle
      fatigue, but albuterol was ineffective.
    explanation: >-
      Independent single-patient report that the same drug class was ineffective,
      in a patient in whom the other two drugs worked.
animal_models:
- name: Drosophila synaptotagmin P308L-homologous transgenic
  species: Fruit fly
  genotype: >-
    Drosophila synaptotagmin carrying the residue homologous to human SYT2
    p.Pro308Leu, expressed on a background carrying one copy of wild-type
    synaptotagmin
  publication: PMID:28953919
  description: >-
    A fly line built specifically to test the P308L variant at human-equivalent
    gene dosage. Expressed without native synaptotagmin the mutation is lethal,
    which establishes that the residue is essential; expressed alongside one
    wild-type copy - the patients' genotype - the flies develop neurological and
    behavioural manifestations resembling the human disease.
  modeled_mechanisms:
  - target: SYT2 C2B Dominant-Negative Calcium Sensor Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Demonstrates that the P308L residue is critical for synaptotagmin function
      and that the variant is pathogenic at heterozygous dosage.
    limitations: >-
      The variant is modelled in the Drosophila orthologue at a glutamatergic
      neuromuscular junction, not in human SYT2 at a cholinergic endplate. The
      lethality result comes from a null background the patients do not have, and
      only the one-wild-type-copy arm speaks to the human genotype.
    evidence:
    - reference: PMID:28953919
      reference_title: "Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        To achieve expression similar to human patients, the mutation is expressed
        in flies carrying one copy of the wild type synaptotagmin gene. We now show
        that Drosophila carrying this mutation developed neurological and
        behavioral manifestations similar to those of human patients
      explanation: >-
        Records the human-equivalent dosage arm and the phenotypic resemblance that
        makes this model informative.
- name: Drosophila synaptotagmin D307A-homologous transgenic
  species: Fruit fly
  genotype: Transgenic Drosophila Synaptotagmin carrying the residue homologous to human SYT2 p.Asp307Ala
  publication: PMID:25192047
  description: >-
    A transgenic fly expressing the fly homologue of the human dominant C2B
    variant, used to test whether the variant is dominant and whether it acts on
    vesicle exocytosis.
  modeled_mechanisms:
  - target: Failure of Calcium-Triggered Synaptic Vesicle Fusion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Dominant disruption of synaptic vesicle exocytosis, establishing both the
      mechanism and the dominance of the human allele.
    limitations: >-
      The variant is modelled in the Drosophila synaptotagmin orthologue, not human
      SYT2, and at the fly neuromuscular junction, which is glutamatergic rather
      than cholinergic. The model therefore supports the exocytosis mechanism and
      the dominance but says nothing about the cholinergic endplate, the motor
      axonopathy, or any human clinical feature.
    readouts:
    - name: Synaptic vesicle exocytosis at the larval neuromuscular junction
      target: Failure of Calcium-Triggered Synaptic Vesicle Fusion
      direction: DECREASED
      interpretation: >-
        The measured exocytosis defect is the functional correlate of the sensor
        lesion.
      evidence:
      - reference: PMID:25192047
        reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          revealed a dominant disruption of synaptic vesicle exocytosis using this
          transgenic model
        explanation: >-
          Reports the exocytosis measurement and its direction.
    evidence:
    - reference: PMID:25192047
      reference_title: "Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Characterization of the mutation homologous to the human c.920A>C variant in
        Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle
        exocytosis using this transgenic model.
      explanation: >-
        Supports treating this fly line as informative for the calcium-triggered
        fusion node.
discussions:
- discussion_id: axonopathy_secondary_or_independent
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Motor Axonal Neuropathy and Denervation Atrophy
  prompt: >-
    Is the motor axonopathy in CMS7 a consequence of chronic neuromuscular
    transmission failure, or an independent axonal role of synaptotagmin-2?
  rationale: >-
    The entry draws the axonopathy as a parallel consequence of the SYT2 lesion
    rather than a sequela of the junctional defect, but that placement is not
    evidence-based. Synaptotagmin-2 is a synaptic vesicle protein, and no published
    work establishes an axonal transport or maintenance function for it that would
    explain length-dependent degeneration directly. If the axonopathy is instead
    secondary to sustained transmission failure, then effective presynaptic therapy
    started early might prevent it, which makes this a question with a management
    consequence and not only a modelling one.
- discussion_id: postsynaptic_involvement_recessive
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Reduced Quantal Acetylcholine Release at the Motor Endplate
  prompt: >-
    Why do recessive SYT2 alleles produce postsynaptic as well as presynaptic
    neuromuscular junction defects?
  rationale: >-
    CMS7 is classified as a presynaptic syndrome and this entry models it that way.
    But the recessive splice allele is reported to cause severe pre- AND
    postsynaptic NMJ defects. A purely presynaptic sensor lesion should not
    reorganize the postsynaptic apparatus except through trophic or
    activity-dependent effects, so either the postsynaptic change is a secondary
    consequence of chronic underactivity - which the entry does not model - or SYT2
    has a role in junctional maintenance that is not captured here. The distinction
    matters for whether the recessive form is a more severe version of the same
    disease or a partly different one.
notes: >-
  Scope: this is a single entry covering both the dominant and the recessive forms,
  with `has_subtypes` for each. That follows MONDO, whose definition of
  MONDO:0014468 is gene-scoped - "Any congenital myasthenic syndrome in which the
  cause of the disease is a mutation in the SYT2 gene" - rather than
  inheritance-scoped. Note that OMIM splits SYT2-related CMS by inheritance, so a
  reader coming from OMIM should expect the correspondence to be one-to-two.

  The dominant and recessive forms are modelled as two separate molecular nodes
  rather than one, because they are not the same lesion at different doses: the
  dominant variants disable calcium binding and act dominant-negatively, while the
  recessive alleles remove the protein or its SNARE-interaction surface. Curating
  them as a single node would have forced one `functional_impact_category` onto two
  different mechanisms.

  The UK prevalence figure (PMID:41251564) is for congenital myasthenic syndrome as
  a whole, not for CMS7. The OpenScientist report's own reference validation flagged
  it as possibly off topic, which was a useful signal read the right way round: the
  paper is not off topic, it is about the parent disease, so it is curated as an
  upper bound with `directness: INDIRECT` and a note saying so rather than as a CMS7
  prevalence.

  A discrepancy left as found: the same two dominant variants are written with
  opposite nucleotide substitutions in the two source papers - PMID:25192047 gives
  c.920A>C (p.Asp307Ala) and c.923C>T (p.Pro308Leu), while PMID:26519543 gives
  c.920T>G and c.923G>A for the same two amino acid changes. The protein-level
  changes agree and are what the mechanism turns on. The entry records both spellings
  in the `genetic` notes rather than silently picking one, because a snippet never
  corrects the source it quotes and resolving this needs the variant databases, not
  a judgement call.

  The GeneReviews chapter tagged in `references` is the parent-disease overview
  (Congenital Myasthenic Syndromes Overview), not a SYT2 chapter. The cached record
  is abstract-only and carries no SYT2 content, so there is nothing in it to mine
  for this entry. It is tagged anyway so that the judgement "no chapter-level source
  exists for CMS7" is explicit rather than implied by the reference's absence. This
  note lives here because `PublicationReference` has no slot to carry it.

  Penetrance is not recorded in the structured `penetrance` slot. The sources support
  "high" - the dominant variants segregate through multiple generations and no
  unaffected heterozygous carrier is reported - but `PenetranceEnum` offers only
  COMPLETE, INCOMPLETE and UNKNOWN, and no cohort exists that would let CMS7 be put
  in the first of those. Recording COMPLETE would assert more than the literature
  does and UNKNOWN would assert less, so the slot is left unset and the claim is
  carried as prose on each `inheritance` record.
📚

References & Deep Research

References

1
PMID:20301347
Congenital Myasthenic Syndromes Overview.
No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (1)

Create: Congenital Myasthenic Syndrome 7 · 2026-09-16T21:12:10Z · View source

Created kb/disorders/Congenital_Myasthenic_Syndrome_7.yaml from claim issue #11961. Deep research: openscientist (research/Congenital_Myasthenic_Syndrome_7-deep-research-openscientist.md, 20 citations, 20/20 resolved, 0 unresolved, 1 flagged possibly off topic). The run's own term-validation step aborted on an EBI network timeout, so the report carried no reference_validation or term_validation frontmatter; the ## Reference Validation section was added afterwards with just validate-research-reference. Scoped as one entry with two has_subtypes because MONDO:0014468 is defined gene-wise (Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the SYT2 gene), read from OLS rather than assumed; OMIM splits it by inheritance and that mismatch is recorded in the entry notes. The report changed two things a textbook-first draft had wrong. First, it supplied PMID:34037996, which establishes the dominant mechanism as dominant-negative rather than plain loss of function, so the single molecular node was split into two subtype-tagged nodes with different functional_impact_category values. Second, the report's own reference validation flagged PMID:41251564 as possibly off topic; reading it showed the paper is a UK prevalence study of congenital myasthenic syndrome as a whole, so it is curated as an explicit upper bound with directness INDIRECT and a note, not as a CMS7 prevalence. Also added from the report: quantal-content microelectrode and EM ultrastructure findings, the biallelic cohort (PMID:32776697) with anticholinesterase benefit, the 28-case review (PMID:41331967), the P308L Drosophila model (PMID:28953919), and a negative salbutamol result (PMID:36869887) curated as REFUTE. Two CHEBI CURIEs written from memory were wrong and were corrected against the term cache. Validation: just validate and just validate-disorders pass (46/46 snippets verified); duplicate-key, entity-ref, causal-target, enum-value gates clean.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 20 citations 2026-09-16T21:02:02.340925

1. Disease Information

What it is. CMS7 is a Mendelian congenital myasthenic syndrome in which fast synchronous neurotransmitter release at the NMJ fails because of defects in the presynaptic calcium sensor synaptotagmin-2. It is one of the small group of presynaptic CMS subtypes that phenocopy LEMS (the "CMS-LEMS" group), alongside AGRN, MUNC13-1/UNC13A, VAMP1, and LAMA5 (F004; PMID: 29696584).

Key identifiers.

Resource Identifier
MONDO MONDO:0014468
OMIM #616040 (CMS7A, autosomal dominant); #619461 (CMS7B, autosomal recessive)
Gene (HGNC) SYT2, HGNC:11510
NCBI Gene 127833
Ensembl ENSG00000143858
UniProt Q8N9I0
Cytoband 1q32.1

Synonyms / alternative names. CMS7; SYT2-related disease; SYT2-CMS; presynaptic congenital myasthenic syndrome 7; autosomal-dominant Lambert-Eaton–like myasthenic syndrome with nonprogressive motor neuropathy (dominant form). Gene aliases: CMS7, CMS7A, CMS7B, MYSPC, SytII (F008).

Data provenance. Essentially all knowledge derives from aggregated disease-level resources and individual published case reports/small case series (~10–15 families worldwide), not from EHR/population phenotyping — a direct consequence of the disease's extreme rarity.

2. Etiology

Primary cause — genetic. CMS7 is a monogenic disorder caused entirely by pathogenic germline variants in SYT2. There is no environmental, infectious, or acquired etiology; it is not autoimmune (distinguishing it mechanistically from myasthenia gravis and from paraneoplastic LEMS). Two allelic mechanisms operate (F001, F010):

  • Dominant heterozygous C2B-domain missense/in-frame variants → dominant-negative poisoning of release.
  • Recessive biallelic loss-of-function variants → absence of functional SYT2.

Genetic risk factors. The causal variants themselves are the risk factor. For the recessive form, consanguinity is a major contributing factor (multiple reported homozygous cases in consanguineous families; F010; PMID: 32250532, PMID: 36722210). No susceptibility loci, GWAS signals, or modifier genes have been established for this Mendelian disease.

Environmental / lifestyle / protective factors. None established. As a channel/release Mendelian disorder, there are no known dietary, occupational, toxic, or lifestyle risk or protective factors, and no gene–environment interactions have been reported. (Not applicable / not available.)

Infectious agents. Not applicable — CMS7 is non-infectious. Intercurrent respiratory infections can precipitate crises in the severe recessive form (a trigger of morbidity, not a cause).

3. Phenotypes

CMS7 phenotypes are clinical signs and physical manifestations of impaired neuromuscular transmission plus a secondary neurogenic/motor-neuropathy component. Severity is bimodal by inheritance mode (F005).

Phenotype Type Onset Severity/Course Frequency Suggested HPO
Fatigable muscle weakness Clinical sign Congenital–childhood (recessive) to childhood/adult (dominant) Fluctuating, fatigable Core / typical HP:0003473 (Fatigable weakness)
Distal lower-limb weakness & wasting Physical Childhood (dominant) Slowly progressive/stable Typical in dominant HP:0002460 (Distal muscle weakness); HP:0003693 (Distal amyotrophy)
Foot deformities / pes cavus Physical Childhood Stable structural Frequent in dominant HP:0001761 (Pes cavus)
Neonatal hypotonia Clinical sign Neonatal Severe in recessive Frequent in recessive HP:0001319 (Neonatal hypotonia)
Hyporeflexia / areflexia Clinical sign Variable With post-exercise reflex potentiation Typical HP:0001315 (Reduced tendon reflexes); HP:0001284 (Areflexia)
Ptosis / ocular weakness Clinical sign Variable Fatigable Variable HP:0000508 (Ptosis); HP:0000602 (Ophthalmoplegia)
Bulbar dysfunction (weak cry, dysphonia, dysphagia) Clinical sign Neonatal/infancy (recessive) Moderate–severe Recessive-predominant HP:0002019 (Feeding difficulties)
Respiratory insufficiency / recurrent infections Clinical sign Infancy (recessive) Severe; morbidity/mortality driver Recessive-predominant HP:0002093 (Respiratory insufficiency); HP:0002205 (Recurrent respiratory infections)
Delayed motor development Clinical sign Infancy Variable Recessive-predominant HP:0001270 (Motor delay)
Elevated CK (mild) Lab abnormality — e.g., CPK 501 U/L Occasional HP:0003236 (Elevated creatine kinase)

Key supporting evidence (F005): a 2025 case-based review synthesizing 28 cases describes SYT2-related disease as "characterized by distal muscle atrophy in the lower limbs, foot deformities and, in some cases, neonatal hypotonia," with most mutations in the C2B domain (PMID: 41331967). The dominant-vs-recessive severity gradient is explicit: "The recessive form of CMS caused by a SYT2 mutation showed far more severe clinical manifestations than the dominant form" (PMID: 34037996). Distal weakness with pes cavus can mimic distal hereditary motor neuropathy/CMT (PMID: 33320396).

Quality-of-life impact. No disease-specific EQ-5D/SF-36/PROMIS data exist for CMS7 (not available). Qualitatively, the dominant form causes gait impairment and fatigue affecting mobility and daily function; the recessive form causes major disability with respiratory and feeding needs. A salbutamol trial in NMJ-involving motor neuropathies (including SYT2) recorded patient-reported fatigue as a meaningful endpoint (F007; PMID: 36869887).

4. Genetic / Molecular Information

Causal gene. SYT2 (synaptotagmin-2), HGNC:11510, NCBI Gene 127833, Ensembl ENSG00000143858, UniProt Q8N9I0, chromosome 1q32.1 (GRCh38 chr1:202,590,596–202,710,526, minus strand) (F008).

Protein architecture. Synaptotagmin-2 is a synaptic-vesicle transmembrane protein with an N-terminal intravesicular/luminal region, a single transmembrane domain, and two cytoplasmic tandem C2 domains (C2A and C2B) that bind Ca²⁺ and phospholipids/SNAREs (F008). SYT2 is the major synaptotagmin isoform at the human NMJ and one of only three (SYT1, SYT2, SYT9) that serve as Ca²⁺ sensors for fast synchronous release (F002; PMID: 17521570).

Pathogenic variants and their mechanisms.

Variant (protein / cDNA) Domain Type Inheritance Mechanism Reference
p.Asp307Ala (c.920A>C) C2B Missense, disrupts essential Ca²⁺-binding Asp AD Dominant-negative PMID: 25192047
p.Pro308Leu (c.923C>T) C2B Missense AD Dominant-negative PMID: 25192047
p.361_365del (c.1082_1096del) C2B In-frame deletion, de novo AD Dominant-negative PMID: 33320396
p.Arg397Serfs*37 (c.1191delG) C2B C-terminus Frameshift AR (homozygous) Loss of function PMID: 32250532
c.465+1G>A splice donor Splice AR (homozygous) Loss of function PMID: 33659639
c.328_331dup — Frameshift AR (homozygous) Loss of function PMID: 33659639
Large deletion exons 2–9 multi-exon Structural AR (homozygous) Loss of function PMID: 36722210

Variant classification & population frequency. Reported pathogenic variants are private/ultra-rare and effectively absent or singleton in population databases, consistent with high penetrance and de novo/consanguineous origins (F013). gnomAD constraint for SYT2 (F013): pLI = 0.70, LOEUF (upper) = 0.58, LoF-z = 3.34 (intolerant to complete LoF), missense-z = 2.62 (missense-constrained), synonymous-z = 0.98 (neutral, as expected). This constraint profile explains why dominant missense variants are pathogenic and why biallelic LoF produces severe disease.

Somatic vs germline. All variants are germline. No somatic disease role.

Functional consequences. Dominant C2B missense/in-frame variants = dominant-negative; recessive truncating/splice/structural variants = loss of function (F008, F010; PMID: 34037996, PMID: 32776697).

Modifier genes / epigenetics / chromosomal abnormalities. No modifier genes, epigenetic marks, or large chromosomal abnormalities (beyond the single-gene exonic deletion above) are established for CMS7 (not available). One mechanistic aside: in cortical neurons, calmodulin transcriptionally suppresses SYT2, an inverse rostral–caudal expression relationship — relevant to SYT2 biology but not established as a disease modifier (PMID: 20729199).

5. Environmental Information

Environmental, lifestyle, and infectious factors. Not applicable to disease causation — CMS7 is purely Mendelian. There are no reported toxin, radiation, occupational, dietary, smoking, alcohol, or exercise contributions to disease risk. Intercurrent respiratory infections are clinically relevant only as precipitants of crisis/morbidity in the severe recessive form, not as etiologic agents (F012; PMID: 41331967).

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Dominant (C2B missense/in-frame) branch: 1. Heterozygous C2B-domain missense/in-frame variant in SYT2 (e.g., p.Asp307Ala disrupting an essential Ca²⁺-coordinating aspartate) produces a mutant synaptotagmin-2 protein that still incorporates into the release machinery. 2. The mutant protein acts dominant-negatively, poisoning the Ca²⁺-sensing/SNARE-coupling function of the release apparatus even in the presence of one wild-type allele (demonstrated in Drosophila, where co-expression with one wild-type copy reproduces disease) → impaired coupling of Ca²⁺ influx to synchronous synaptic-vesicle fusion. 3. This results in reduced quantal content (fewer ACh quanta released per nerve impulse), most evident at low stimulation frequencies. 4. Reduced ACh release leads to an endplate potential that intermittently fails to reach threshold → intermittent neuromuscular transmission failure → fatigable weakness. 5. Because residual Ca²⁺ accumulates in the terminal during repetitive/high-frequency activity, release transiently improves → facilitation/post-exercise increment and prolonged post-tetanic potentiation (the LEMS-like signature). 6. Chronic presynaptic dysfunction is associated with a secondary distal motor neuropathy/terminal remodeling → distal wasting, pes cavus, areflexia → the clinical phenotype.

Recessive (biallelic LoF) branch: 1. Biallelic loss-of-function variants (frameshift/nonsense/splice/deletion) result in absent or non-functional SYT2 protein. 2. Loss of the principal fast Ca²⁺ sensor leads to profound impairment of synchronous ACh release (more severe presynaptic failure than the dominant form). 3. This results in congenital-onset severe weakness, hypotonia, bulbar and respiratory compromise. (The C-terminal recessive variant p.Arg397Serfs37 disrupts a region crucial for synaptotagmin–SNARE interaction and exocytosis — inferred from structural modeling on the rat Syt1 C2B template.)*

Molecular / cellular detail (checklist)

  • Molecular pathways / biochemical defect. Ca²⁺-triggered synaptic-vesicle exocytosis; SYT2 is the Ca²⁺ sensor that couples voltage-gated Ca²⁺ influx to SNARE-mediated membrane fusion. The core defect is an ion-sensor/receptor-coupling failure, not an enzyme deficiency (F002; PMID: 17521570). Suggested GO: GO:0016079 (synaptic vesicle exocytosis), GO:0017156 (calcium-ion-regulated exocytosis), GO:0005544 (calcium-dependent phospholipid binding).
  • Cellular processes. Presynaptic vesicle fusion, endocytic recycling, and — in the recessive form — ultrastructural remodeling of the nerve terminal (F006).
  • Protein dysfunction. Dominant = dominant-negative interference; recessive = loss of function. C2B Ca²⁺-binding-pocket modeling (SwissModel) predicts structural disruption for pathogenic variants (F009; PMID: 33320396, PMID: 28953919).
  • Metabolic / immune involvement. None — no metabolic derangement and no autoimmunity (ACh-receptor and VGCC antibodies negative), which distinguishes CMS7 from MG and autoimmune LEMS (F011).
  • Molecular profiling (electrophysiology & ultrastructure). Microelectrode studies in the dominant form show markedly reduced quantal content that increases linearly with higher stimulation frequencies; MEPP frequency is normal at rest but rises with stimulation. Electron microscopy shows overdeveloped postsynaptic folding and abundant endosomes, multivesicular bodies, and degenerative lamellar bodies within small nerve terminals; presynaptic failure is more prominent in the recessive form (F006; PMID: 34037996).

Upstream vs downstream. Upstream = SYT2 variant → defective Ca²⁺-sensing/SNARE coupling. Downstream = reduced quantal ACh release → EPP failure → fatigable weakness, with facilitation as a distinctive downstream compensatory readout, and secondary distal neuropathy/terminal remodeling as a chronic downstream consequence.

Cell types & CL terms. Presynaptic motor neuron / lower motor neuron terminal (CL:0000100 motor neuron; CL:0011001 spinal cord motor neuron) and the skeletal muscle fiber (CL:0000188) postsynaptic partner.

7. Anatomical Structures Affected

  • Organ / system level. Primary target is the peripheral nervous system–muscle interface: the neuromuscular junction (UBERON:0002476, neuromuscular junction; GO:0031594 neuromuscular junction as a cellular component). Body systems: somatic motor / musculoskeletal and, secondarily, respiratory (respiratory muscle involvement in severe recessive disease) and bulbar musculature.
  • Tissue / cell level. Skeletal (striated) muscle (UBERON:0001134) and the presynaptic motor neuron terminal. Predominant clinical involvement is distal lower limb in the dominant form; generalized/axial and bulbar/respiratory in the recessive form.
  • Subcellular level. Synaptic vesicle and presynaptic active zone membranes (GO:0008021 synaptic vesicle; GO:0048786 presynaptic active zone). Ultrastructurally, endosomes, multivesicular bodies, and lamellar bodies accumulate in nerve terminals (F006).
  • Localization / lateralization. Symmetric, bilateral involvement; distal-predominant in the dominant form. Specific sites: lower-limb muscles and feet (pes cavus). UBERON: UBERON:0002103 (hindlimb), UBERON:0002387 (pes/foot).

8. Temporal Development

  • Onset. Congenital / neonatal in the recessive form (hypotonia, weak cry, feeding/respiratory problems from birth); childhood-onset distal weakness typical in the dominant form, with some presentations recognized later. Onset pattern is chronic/insidious rather than acute (F005, F012).
  • Progression. Dominant form: stable or slowly progressive, described in the seminal report as a "nonprogressive motor neuropathy" and in the biallelic series as "stable or slowly progressive distal weakness of variable severity" (F012; PMID: 25192047, PMID: 32776697). Recessive form: severe from birth with variable respiratory course.
  • Course pattern & duration. Chronic, lifelong, with a fluctuating/fatigable functional pattern superimposed on a stable structural baseline. No spontaneous remission is described; symptomatic improvement is treatment-induced (3,4-DAP, AChE inhibitors).
  • Critical periods. The neonatal/infantile period is the window of greatest vulnerability (respiratory failure risk) and the key window for diagnosis and initiation of treatment in the severe recessive form.

9. Inheritance and Population

Epidemiology. CMS7/SYT2-CMS is ultra-rare. Genetically confirmed CMS overall prevalence is estimated at 6.5 per million overall and 8.5 per million in the pediatric population in the UK (n=442 cohort; F004; PMID: 41251564), with an earlier estimate of 9.2 per million (PMID: 34736634). The most common CMS subtypes are CHRNE, DOK7, and RAPSN; SYT2-CMS is one of the rarest presynaptic subtypes, with only ~10–15 families reported worldwide across dominant and recessive forms (F004). No incidence figures are available specifically for CMS7.

Inheritance genetics (F010, F013).

Feature Dominant (CMS7A) Recessive (CMS7B)
Pattern Autosomal dominant (multigenerational or de novo) Autosomal recessive
Variant class C2B missense / in-frame Biallelic LoF (frameshift/nonsense/splice/deletion)
Mechanism Dominant-negative Loss of function
Penetrance High (segregates in families; de novo cases) High
Consanguinity Not typically Frequently present
Severity Milder, slowly progressive Severe, congenital

De novo dominant occurrence is documented ("a new de novo heterozygous in frame deletion of the SYT2 gene"; PMID: 33320396). Recessive disease is documented across multiple consanguineous families ("we report seven patients of five families, with biallelic loss of function variants in SYT2"; PMID: 32776697).

Penetrance, expressivity, anticipation, mosaicism, founder effects. Penetrance appears high; expressivity is variable (severity gradient by allele type). No genetic anticipation (not a repeat-expansion disorder). No germline mosaicism or founder effects reported. Carrier frequency is not quantifiable — pathogenic variants are absent/singleton in gnomAD (F013).

Population demographics. No ethnic predilection beyond the association of the recessive form with consanguineous populations. No sex bias reported; both sexes affected (autosomal). Geographic distribution: cases reported across Europe, the Middle East, and Asia — sporadic, without endemic clustering.

10. Diagnostics

Diagnosis integrates presynaptic electrophysiology with molecular genetics (F011).

Electrophysiology (the diagnostic hallmark). Repetitive nerve stimulation (RNS) shows low baseline CMAP amplitude, a decremental response at low frequency, and a marked increment/facilitation after brief exercise or high-frequency stimulation, with prolonged post-tetanic potentiation lasting up to ~60 minutes and single-fiber EMG jitter/blocking — a LEMS-like presynaptic signature (F006, F011; PMID: 26519543: "Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes"; PMID: 29696584: "They have low compound muscular action potential amplitude that increment after brief exercise (facilitation) or high-frequency repetitive nerve stimulation").

Laboratory. CK normal or mildly elevated (e.g., 501 U/L; PMID: 41331967). ACh-receptor and VGCC antibodies negative — critical for excluding autoimmune MG/LEMS.

Genetic testing. SYT2 is identified via whole-exome sequencing and multigene CMS/neuromuscular NGS panels, with Sanger confirmation; chromosomal microarray/exome can detect large exonic deletions (the exons 2–9 deletion; PMID: 36722210). Because CMS is now attributable to ~40 genes, panel/exome testing is the standard first-line molecular approach (PMID: 40533459, PMID: 36835142). Single-gene SYT2 testing is appropriate when the LEMS-like presynaptic phenotype is recognized. WGS is useful for deep-intronic/structural variants when panel/exome is negative. Mitochondrial DNA testing, karyotyping, FISH, and repeat-expansion testing are not indicated.

Muscle biopsy / pathology. Typically shows only mild/nonspecific neurogenic features; EM (research setting) shows the terminal remodeling described above (F006; PMID: 33320396).

Differential diagnosis. Autoimmune LEMS (antibody-positive, often paraneoplastic); other presynaptic CMS (AGRN, VAMP1, UNC13A/MUNC13-1, LAMA5, SLC5A7, SLC18A3); distal hereditary motor neuropathy / Charcot–Marie–Tooth; spinal muscular atrophy; and congenital myopathies (F011; PMID: 29696584, PMID: 33320396).

Screening. No population newborn screening exists for CMS7. Cascade genetic testing of relatives and, where a familial variant is known, prenatal/preimplantation options apply.

11. Outcome / Prognosis

  • Survival / mortality. No formal survival statistics exist. The dominant form is compatible with normal life expectancy. In the severe recessive form, respiratory insufficiency and recurrent respiratory infections are the principal drivers of morbidity and potential mortality (F012; PMID: 41331967, PMID: 32776697).
  • Morbidity / function. Dominant form: mobility limitation from distal weakness and foot deformity, fatigue. Recessive form: major disability with feeding/respiratory support needs in infancy.
  • Disease course & recovery. Symptoms are chronic; substantial functional improvement is achievable with treatment even in severe recessive disease — "Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function" (PMID: 32776697).
  • Prognostic factors. The strongest prognostic determinant is allele class / inheritance mode (dominant missense = milder; biallelic LoF = severe), followed by degree of respiratory involvement and treatment responsiveness. No molecular prognostic biomarkers beyond genotype.

12. Treatment

CMS7 is treatable, and — as in CMS generally — the choice of agent is subtype-specific (F003; PMID: 30032336). There is no role for immunotherapy (it is not autoimmune).

Therapy Class / mechanism Evidence in SYT2-CMS Suggested NCIT
3,4-Diaminopyridine (amifampridine) K⁺-channel blocker; prolongs presynaptic depolarization → more Ca²⁺ influx → more ACh release Clinical benefit + improved neuromuscular transmission in dominant form (PMID: 26519543); ameliorated fatigue in recessive form (PMID: 32250532) NCIT:C61693 (Amifampridine)
Pyridostigmine (AChE inhibitor) Prolongs ACh at the endplate Ameliorated fatigue in recessive case (PMID: 32250532); AChE-inhibitor improved strength/function in biallelic patients (PMID: 32776697) NCIT:C739 (Pyridostigmine)
Salbutamol / albuterol (β2-agonist) β-adrenergic modulation of endplate Mixed/limited: improved patient-reported fatigue but no clear motor/neurophysiologic benefit in NMJ-involving motor neuropathies incl. SYT2 (PMID: 36869887); ineffective in one recessive case (PMID: 32250532) NCIT:C29082 (Albuterol)

Mechanistically, 3,4-DAP is the rational first-line agent for a presynaptic release deficit because it augments Ca²⁺ influx and quantal release; AChE inhibitors are a useful adjunct/alternative. The pharmacologic logic mirrors treatment of LEMS. Broader CMS treatment principles: "Cholinergic agents, β-adrenergic agonists, and open-channel blockers remain the principal treatment modalities," and pyridostigmine should be avoided in DOK7, AChE deficiency, and slow-channel CMS — underscoring the necessity of an accurate genetic diagnosis before treatment (PMID: 30032336).

Supportive / rehabilitative. Respiratory support and infection management (severe recessive disease), physical/occupational therapy, orthotic management of foot deformities, and nutritional/feeding support in infancy.

Advanced/experimental therapeutics. None approved specifically for CMS7. No gene, cell, or RNA therapy exists. A research-stage delivery concept exploits SYT2's luminal domain: intravenously administered anti-SYT2 antibodies selectively localize to NMJs and are retrogradely transported to motor neurons — a potential future neuron-targeted delivery route rather than a CMS7 therapy (PMID: 40454418).

Pharmacogenomics / personalized medicine. Treatment is effectively genotype-guided at the level of CMS subtype (presynaptic → 3,4-DAP/AChE inhibitor). No SYT2-specific pharmacogenomic variants are described.

13. Prevention

CMS7 is a Mendelian disorder, so prevention is genetic, not behavioral or environmental.

  • Primary prevention. Not applicable in the public-health sense. The relevant tools are genetic counseling, carrier testing of at-risk relatives (recessive form), and reproductive options — prenatal diagnosis and preimplantation genetic testing — where a familial pathogenic variant is known.
  • Secondary prevention. Early recognition of the LEMS-like presynaptic electrophysiology → prompt genetic diagnosis → early initiation of 3,4-DAP/AChE inhibitors to prevent avoidable disability; vigilant respiratory monitoring and prompt treatment of respiratory infections in the severe recessive form.
  • Tertiary prevention. Respiratory support, immunization against respiratory pathogens (influenza, pneumococcus) to reduce infection-triggered crises, orthopedic/rehabilitative management of contractures and foot deformities.
  • Counseling. Recurrence risk is 50% for offspring of a dominant-variant carrier and 25% for siblings in recessive families; consanguinity counseling is relevant.

14. Other Species / Natural Disease

  • Taxonomy / orthologs. SYT2 is evolutionarily conserved. Mouse Syt2 (NCBI Gene 20680) is the ortholog and is the major fast-release Ca²⁺ sensor in caudal brain/brainstem and motor neurons (F009; PMID: 17521570, PMID: 20729199). Drosophila melanogaster synaptotagmin is functionally orthologous for modeling purposes. NCBI Taxa: Mus musculus (10090), Drosophila melanogaster (7227).
  • Natural disease in other species. No naturally occurring SYT2 congenital myasthenic syndrome has been reported in companion animals or wildlife (no OMIA entry noted); CMS7 is, to date, a human-described disease with experimental animal models rather than a recognized spontaneous veterinary disease. (Not available.)
  • Comparative biology. The evolutionary conservation of synaptotagmin's Ca²⁺-sensor function underpins the validity of invertebrate and rodent models; the fly heterozygous model recapitulates the human dominant-negative phenotype (see Section 15).

15. Model Organisms

  • Drosophila melanogaster (primary causality model). Expressing the human-homologous C2B mutation (P308-equivalent) in flies lacking native synaptotagmin was lethal, demonstrating the residue is critical for synaptotagmin function; co-expression with one wild-type copy (mimicking the heterozygous human state) produced neurological/behavioral manifestations similar to patients and dominant disruption of synaptic-vesicle exocytosis — directly establishing pathogenicity and the dominant-negative mechanism (F009; PMID: 28953919: "When expressed in the absence of native synaptotagmin, this mutation is lethal, demonstrating for the first time that this residue plays a critical role in synaptotagmin function" and "Drosophila carrying this mutation developed neurological and behavioral manifestations similar to those of human patients").
  • Mouse (Syt2). The mouse ortholog is the validated fast-release Ca²⁺ sensor for brainstem/motor-neuron synapses (PMID: 17521570); Syt2-manipulated rodents inform normal SYT2 physiology, though a dedicated CMS7 patient-variant knock-in mouse is not prominently reported.
  • In silico / structural modeling. C2B Ca²⁺-binding-pocket modeling (SwissModel; rat Syt1 C2B X-ray template) predicts structural disruption for pathogenic variants and supports variant interpretation (PMID: 33320396, PMID: 32250532).
  • Phenotype recapitulation & limitations. The fly model faithfully reproduces the dominant-negative exocytosis defect and dominant inheritance; it does not capture the human distal motor-neuropathy/foot-deformity phenotype or the recessive LoF disease, and mammalian models specifically engineered with patient recessive alleles are lacking. Applications: dissecting Ca²⁺-sensing/SNARE coupling, dominant-negative mechanism, and candidate therapeutics.

Mechanistic Model / Interpretation

 SYT2 (1q32.1) — Ca2+ sensor for fast synchronous ACh release
                     |
+----------------------------+-----------------------------+
   DOMINANT branch                                          RECESSIVE branch
   Heterozygous C2B missense/in-frame                  Biallelic LoF (fs/nonsense/
   (p.Asp307Ala, p.Pro308Leu, in-frame del)            splice/large deletion)
|                                                       |
   Dominant-negative protein                               Absent/nonfunctional SYT2
   poisons release machinery                                   |
|                                                       |
+----------------> Impaired Ca2+->SNARE coupling <------+
                     |
     Reduced quantal ACh release per impulse
                     |
     Endplate potential intermittently subthreshold
                     |
      +----------------------+-----------------------------+
      Fatigable weakness                          Facilitation / post-exercise
      (RNS decrement at low Hz)                    increment; prolonged PTP (~60 min)
                     |
      Chronic terminal remodeling -> distal motor neuropathy
      (distal wasting, pes cavus, areflexia)
                     |
      Dominant: milder, slowly progressive | Recessive: severe congenital,
      treatable (3,4-DAP, AChE inhibitors)  | bulbar/respiratory, treatable

The unifying concept is that CMS7 is a disorder of presynaptic quantal release in which allele class dictates severity: a poisoning (dominant-negative) mechanism produces a milder, distal, neuropathy-mimicking disease, while complete loss of the fast Ca²⁺ sensor produces severe congenital myasthenia. The facilitation phenomenon — pathognomonic on electrophysiology — is the direct downstream readout of residual Ca²⁺ rescuing release during repetitive activity, and it is precisely this mechanism that 3,4-DAP exploits therapeutically.

Evidence Base

PMID Role in this report
25192047 Seminal disease-gene report; dominant C2B missense variants; AD LEMS-like + nonprogressive motor neuropathy
26519543 Electrophysiology (presynaptic deficit, prolonged PTP) and 3,4-DAP treatability in dominant form
34037996 Dominant vs recessive comparison; quantal-content and EM ultrastructural findings
32776697 Biallelic LoF recessive CMS7; AChE-inhibitor benefit; stable/slowly progressive course
32250532 Recessive p.Arg397Serfs*37; 3,4-DAP/pyridostigmine effective, albuterol ineffective; C-terminal SNARE-interaction modeling
33659639 New homozygous recessive variants (c.465+1G>A, c.328_331dup); myopathy-mimicking presentation
33320396 De novo dominant in-frame deletion; CMT/neuropathy mimic; genetic-testing recommendation
36722210 Large exonic deletion (exons 2–9) detected by exome+microarray; consanguineous recessive
28953919 Drosophila model establishing causality and dominant-negative mechanism
17521570 SYT1/2/9 as fast-release Ca²⁺ sensors; SYT2 as major NMJ isoform
29696584 Places SYT2 in the CMS-LEMS presynaptic group; defines facilitation hallmark
30032336 CMS treatment principles; subtype-specific drug choice; no immunotherapy
41331967 28-case review; core phenotype; C2B clustering; representative case features
41251564 UK CMS prevalence (6.5/8.5 per million)
34736634 Earlier CMS prevalence (9.2 per million); >30 genes
40533459 / 36835142 40- and 35-gene CMS reviews; panel/exome testing standard
36869887 Salbutamol trial in NMJ-involving motor neuropathies incl. SYT2
20729199 SYT2 regulation/expression biology (calmodulin, rostral–caudal)
40454418 Anti-SYT2 luminal-domain antibody NMJ targeting (future delivery concept)

All quoted snippets above are verbatim from the corresponding abstracts as recorded in the knowledge state (findings F001–F013).

Limitations and Knowledge Gaps

  1. Extreme rarity → weak epidemiology. Only ~10–15 families are reported worldwide; there are no CMS7-specific prevalence/incidence figures, no natural-history registries, and no formal survival/QoL data. Prevalence is inferred from all-CMS studies.
  2. No controlled treatment trials. Efficacy of 3,4-DAP and AChE inhibitors rests on case reports and small series, not randomized data. Salbutamol data are mixed and derive from a heterogeneous cohort.
  3. Genotype–phenotype correlation incomplete. The dominant-negative vs LoF dichotomy is well supported, but finer correlations (specific variant → severity/organ involvement) remain anecdotal.
  4. Model-organism gaps. Causality is proven in Drosophila; a mammalian knock-in carrying a patient dominant allele, and models of the recessive LoF disease, are lacking — limiting preclinical therapeutic testing.
  5. No modifier/epigenetic data. No modifier genes, epigenetic marks, or environmental modifiers have been identified.
  6. QoL/functional instruments unmeasured. No EQ-5D/SF-36/PROMIS or ICF-based disability data specific to CMS7.

Proposed Follow-up Experiments / Actions

  1. International SYT2-CMS registry. Aggregate all reported and unpublished cases to derive genotype-stratified natural history, treatment-response rates, and survival — the single highest-value action given rarity.
  2. Prospective, protocolized 3,4-DAP ± pyridostigmine response study. Standardized RNS/CMAP endpoints plus patient-reported fatigue to formalize the treatment evidence base (currently case-level).
  3. Patient-variant knock-in mouse models. Generate C2B dominant-negative (e.g., p.Asp307Ala) and biallelic-LoF mice to reproduce distal neuropathy and severe congenital disease respectively, and to test therapeutics.
  4. Structure-function dissection of C2B variants. Combine cryo-EM/AlphaFold modeling with electrophysiology in reconstituted or iPSC-derived motor-neuron/NMJ systems to map how each variant perturbs Ca²⁺ binding and SNARE coupling.
  5. iPSC-derived motor neuron / NMJ-on-chip modeling. Patient-derived systems to screen candidate presynaptic-release enhancers beyond 3,4-DAP.
  6. Explore SYT2-targeted delivery. Evaluate the anti-SYT2 luminal-domain NMJ-targeting antibody shuttle (PMID: 40454418) as a route for future gene- or protein-replacement approaches to the recessive LoF form.
  7. Refine diagnostic pathways. Promote recognition of the LEMS-like presynaptic RNS signature in antibody-negative patients to shorten time-to-genetic-diagnosis and ensure SYT2 is on CMS/neuropathy NGS panels.

Report compiled from 13 confirmed findings (F001–F013) across 29 reviewed publications. Evidence types: predominantly human clinical case reports/series and comprehensive reviews, supplemented by a Drosophila causality model, rodent/in-vitro SYT2 physiology, and computational (gnomAD constraint, structural modeling) analyses.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 20
Resolved 20
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 20
On topic 10
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:41251564 (3 mentions) - Prevalence and Geographical Distribution of Patients With Congenital Myasthenic Syndromes in the United Kingdom.
  • shared terms: congenital

Weighed against this report's own most characteristic terms: recessive, disease, cms7, dominant, syt2, form, variant, severe, presynaptic, motor, gene, distal, dominant-negative, respiratory, congenital, c2b, release, function, mechanism, biallelic.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.