| domain | curated finding | quantitative evidence | suggested ontology terms |
|---|---|---:|---|
| Identity / identifiers | Congenital myasthenic syndrome 6 (CMS6) corresponds to **CHAT-associated congenital myasthenic syndrome with episodic apnea (CMS-EA)**; recent disease-specific literature explicitly states “CMS-EA, also known as CMS type 6.” MONDO for the exact subtype was not confirmed from available evidence; broader congenital myasthenic syndrome is MONDO_0018940. MeSH for the broader class: *Myasthenic Syndromes, Congenital* (D020294). (pqac-00000010, pqac-00000003, pqac-00000000) | ~50 patients reported by 2024 (pqac-00000010) | MONDO: congenital myasthenic syndrome (MONDO_0018940, broader); MeSH: D020294; disease synonym candidates: “CMS-EA”, “CHAT-associated CMS” |
| Gene / inheritance | Cause is biallelic pathogenic variants in **CHAT** encoding choline acetyltransferase; disorder is a **presynaptic** CMS and is **autosomal recessive**. Most known variants are missense. (pqac-00000010, pqac-00000007, pqac-00000000) | CHAT accounts for ~4–5% of all CMS cases (pqac-00000007) | HGNC gene: CHAT; GO: acetylcholine biosynthetic process (suggested), chemical synaptic transmission (suggested) |
| Molecular mechanism | ChAT catalyzes resynthesis of acetylcholine from choline and acetyl-CoA in the nerve terminal; impaired ChAT reduces presynaptic ACh resynthesis, causing failure of sustained neuromuscular transmission, especially under repetitive activity or stress. (pqac-00000005, pqac-00000007, pqac-00000010) | Qualitative; no disease-wide effect size available | GO: acetylcholine biosynthetic process; GO: synaptic vesicle cycle; GO: neuromuscular synaptic transmission; CL: motor neuron; UBERON: neuromuscular junction |
| Major phenotype: apneic crises / respiratory involvement | Classical CMS6 commonly presents in infancy with apnea, respiratory insufficiency, and episodic respiratory crises; crises may be severe or fatal. (pqac-00000007, pqac-00000010) | Literature summary in CHAT cohort: apneic crises 86% (36/42), ventilation 63% (26/41), tracheostomy 25% (9/36), respiratory insufficiency 48% (20/42), apnea 28% (12/42) (pqac-00000009) | HPO: Apnea; Respiratory insufficiency; Recurrent respiratory infections/crises (suggested) |
| Major phenotype: ocular / bulbar | Ocular findings and bulbar weakness are common in typical disease, though absent in the 2024 mild series. (pqac-00000009, pqac-00000010) | Ptosis 88% (36/41), strabismus/ophthalmoparesis 23% (9/39), bulbar weakness 28% (12/42) (pqac-00000009) | HPO: Ptosis; Ophthalmoparesis; Strabismus; Dysphagia; Dysarthria |
| Major phenotype: limb weakness / fatigability | Generalized, proximal, or exercise-induced fatigable weakness is typical; a mild phenotype may present mainly with exercise intolerance and leg fatigability without apnea or ocular signs. (pqac-00000007, pqac-00000010, pqac-00000009) | General muscle weakness 45% (17/38), proximal weakness 67% (26/39), fatigable leg weakness 96% (27/28); in 2024 mild series 5/5 had leg fatigability and 0/5 had apnea or ptosis (pqac-00000009, pqac-00000010) | HPO: Muscle weakness; Proximal muscle weakness; Exercise intolerance; Fatigability |
| Neurodevelopment / CNS features | Some patients, especially severe early-onset cases, may have delayed motor milestones, intellectual disability, loss of consciousness, or seizures; recent mild cases had normal neurologic status aside from fatigability. (pqac-00000007, pqac-00000010) | Psychomotor delay 57% (21/37) in summarized literature; 0/5 in 2024 mild cohort (pqac-00000009) | HPO: Global developmental delay; Seizure; Loss of consciousness |
| Temporal development / course | Typical onset is birth or early infancy for severe disease; mild phenotype can begin at 1–2.5 years. Course is often fluctuating; the 2024 mild series showed no progression over several years. (pqac-00000007, pqac-00000010, pqac-00000009) | Mild cohort onset 1–2.5 years, 5/5 fluctuating without progression (pqac-00000010, pqac-00000009) | HPO: Infantile onset; Childhood onset; Fluctuating weakness |
| Triggers / gene-environment interaction | Infection, fever, and other stressful conditions can provoke sudden respiratory crises in infancy; cold may aggravate weakness; prolonged exertion unmasks fatigability. These are **triggers/modifiers**, not primary causes. (pqac-00000007, pqac-00000009) | Qualitative; no pooled effect estimates available | HPO: Cold-induced myasthenic symptoms (suggested); Exercise-induced weakness |
| Pathogenic variants | 2024 mild series identified four novel missense SNVs and one recurrent severe-associated missense variant; example variants include **c.404C>G p.(Pro135Arg)** (likely pathogenic) and **c.1061C>T p.(Thr354Met)**. Three novel SNVs were VUS at publication. (pqac-00000002, pqac-00000009) | 5 patients from 4 families; 4 novel missense SNVs; 1 recurrent severe-associated missense variant (pqac-00000009) | Sequence Ontology: missense_variant; nonsense_variant (reported in one family context) |
| Diagnostics: electrophysiology | Standard low-frequency RNS may be normal; decrement often appears after prolonged high-frequency stimulation or exercise. In the pediatric mild series, modified 3 Hz peroneal RNS after 15–20 min exercise was informative. (pqac-00000007, pqac-00000009, pqac-00000003) | Standard 3 Hz decrement >10% in only a small percentage; prolonged 10 Hz for 5 min positive in 9/10; modified post-exercise 3 Hz showed 22–37% decrement improving after 3–4 min rest; in literature 44% (14/32) had increased decrement at 3 Hz after 20 s exercise (pqac-00000009) | LOINC/SNOMED not confirmed; HPO: Abnormal repetitive nerve stimulation; MAXO: Electromyography |
| Diagnostics: genetic testing | Accurate diagnosis requires genetic testing because clinical/electrophysiologic features alone do not identify the defective molecule. Exome/genome sequencing captured CHAT variants in recent series; trial inclusion criteria for CMS required seronegativity to AChR and MuSK plus decremental EMG. (pqac-00000000, pqac-00000010, pqac-00000003) | WES mean coverage ×76.1 in 2024 series; WGS average on-target coverage 30× (pqac-00000010) | MAXO: Sequence analysis of gene panel / exome / genome (suggested); MeSH: Myasthenic Syndromes, Congenital |
| Differential diagnosis / distinction | Important distinction: **CMS6 is CHAT-related**, not COLQ-related endplate AChE deficiency. COLQ-CMS is the subtype where AChE inhibitors are usually contraindicated and β-adrenergic agonists often first-line; that treatment rule should not be misapplied to CMS6. (pqac-00000010, pqac-00000005) | Not quantitative | Differential terms: COLQ-related congenital myasthenic syndrome; autoimmune myasthenia gravis |
| Treatment | First-line therapy is usually **acetylcholinesterase inhibitors**; if response is limited/absent, **3,4-diaminopyridine** may be added, and some patients may receive **salbutamol/albuterol** combinations. Evidence is mainly case based. (pqac-00000009, pqac-00000007) | Response to AChE inhibitors ~73% (27/37); response to 3,4-DAP 71% (5/7); in 2024 mild series, 2 children improved clearly on 3,4-DAP, 1 had only slight benefit on salbutamol+pyridostigmine, and 1 had severe adverse effects to 3,4-DAP (pqac-00000009, pqac-00000010) | CHEBI/drugs: pyridostigmine, amifampridine/3,4-diaminopyridine, salbutamol/albuterol; MAXO: Acetylcholinesterase inhibitor therapy; Adrenergic agonist therapy; Ventilatory support |
| Clinical trials / real-world implementation | Broad CMS interventional studies exist for albuterol and ephedrine, but they were not specific to CHAT/CMS6; ephedrine trial targeted COLQ-deficient kindred. Real-world use in CMS is genotype-guided. (pqac-00000003, pqac-00000004, pqac-00000005) | Albuterol study NCT01203592 enrolled 21; ephedrine study NCT00541216 planned 15 and was COLQ-specific (pqac-00000003, pqac-00000004) | ClinicalTrials.gov: NCT01203592; NCT00541216 |
| Prognosis / outcomes | Prognosis is variable. Severe neonatal/infantile disease can be life-threatening, with fatal infancy cases reported; however, a mild non-apneic phenotype appears to have favorable medium-term outcome without progression. (pqac-00000007, pqac-00000009) | Wheelchair dependency 25% (7/28) in summarized literature; 0/5 in 2024 mild cohort (pqac-00000009) | HPO: Respiratory failure; Wheelchair dependence; Favorable prognosis (not an HPO term; narrative only) |
| Epidemiology / population | CMS overall is rare and likely underdiagnosed; pediatric prevalence estimates for all CMS vary by region. Subtype-specific prevalence for CMS6 was not available from retrieved sources. (pqac-00000005, pqac-00000010) | CMS prevalence under age 18: UK average 9.2/million (range 2.8–14.8), Brazil 1.8/million, Slovenia 22.2/million, Spain 1.8/million (pqac-00000005) | MONDO: congenital myasthenic syndrome (broader); note: CMS6-specific prevalence unavailable |
| Anatomy / cell types | Primary site is the **presynaptic motor nerve terminal** at the **neuromuscular junction** of skeletal muscle; clinically affects ocular, bulbar, respiratory, axial, and limb muscles. Central nervous system expression of CHAT may help explain occasional CNS manifestations. (pqac-00000007, pqac-00000010, pqac-00000005) | Qualitative | UBERON: neuromuscular junction; skeletal muscle; diaphragm; extraocular muscle; CL: motor neuron; skeletal muscle fiber |
| Model organisms / natural disease | Models include Chat-targeted mouse knockout (heterozygotes normal; homozygous pups die at birth with flaccid paralysis and absent spontaneous/nerve-evoked postsynaptic potentials), zebrafish **bajan** and **chatatk64** mutants (reduced movement and synaptic responses), and a naturally occurring **Old Danish Pointing Dog** CHAT mutation causing exercise-induced fatigability. A 2024 AAV9 CHAT mouse gene therapy study was identified as emerging preclinical work, but detailed results were not available in retrieved text. (pqac-00000007) | Mouse homozygotes die at birth; zebrafish homozygotes show absent coiling and reduced touch response; affected dogs tolerate only ~5–30 min walking/running before weakness (pqac-00000007) | NCBI Taxon suggestions: Mus musculus, Danio rerio, Canis lupus familiaris; GO: neuromuscular synaptic transmission |
| Data provenance / evidence level | Evidence is derived from **aggregated disease-level resources**, **recent reviews**, **case series/case reports**, and **trial registry entries**, not EHR-only datasets. Many subtype-specific claims remain based on small case numbers. (pqac-00000000, pqac-00000010, pqac-00000003, pqac-00000004) | Highest disease-specific 2024 cohort size in retrieved evidence: n=5; historical total ~50 cases reported (pqac-00000010) | Evidence type labels: human clinical, review, model organism, trial registry |


*Table: This table summarizes high-value, citable knowledge-base facts for Congenital Myasthenic Syndrome 6, resolved as CHAT-associated CMS with episodic apnea. It emphasizes disease identity, genotype-mechanism links, quantitative phenotypes, diagnostics, treatment, and model systems while clearly marking broader-class versus subtype-specific evidence.*