Congenital Myasthenic Syndrome 6: Comprehensive Disease-Characteristics Report

Scope and nomenclature note. In current disease-specific literature, congenital myasthenic syndrome 6 (CMS6) means CHAT-associated congenital myasthenic syndrome with episodic apnea (CMS-EA). It should not be confused with COLQ-related endplate acetylcholinesterase deficiency, which has a different mechanism and treatment profile. The evidence base is exceptionally small—approximately 50 patients had been reported by 2024—and consists predominantly of families, case reports, and small case series rather than controlled trials. The findings below therefore describe reported cases, not population-level certainties. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 1-2)

The following table provides a knowledge-base-ready summary.

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.

1. Disease information

CMS6 is an inherited presynaptic neuromuscular-junction disorder caused by biallelic pathogenic variants in CHAT, the gene encoding choline O-acetyltransferase (ChAT). Deficient acetylcholine resynthesis impairs sustained neuromuscular transmission. The classical phenotype comprises neonatal or infantile fatigable weakness with recurrent, potentially fatal apneic crises, although a non-apneic, childhood-onset phenotype is now well established. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 1-2)

Names and identifiers

• Preferred names: congenital myasthenic syndrome 6; congenital myasthenic syndrome with episodic apnea; CMS-EA; CHAT-associated congenital myasthenic syndrome; presynaptic CMS due to choline acetyltransferase deficiency.
• OMIM: commonly catalogued as CMS with episodic apnea, 254210; CHAT gene entry 118490. These identifiers should be checked against the live OMIM release before database ingestion.
• MeSH: D020294, Myasthenic Syndromes, Congenital, a broader class explicitly used in ClinicalTrials.gov indexing. (NCT01203592 chunk 1)
• MONDO: the retrieved Open Targets record maps the broader disease to MONDO:0018940, congenital myasthenic syndrome. An exact CMS6 MONDO record was not resolved by the available search and should not be inferred from similarly numbered CMS subtypes. (OpenTargets Search: congenital myasthenic syndrome-CHAT)
• ICD-10/ICD-11: no retrieved evidence established a unique subtype code; coding generally falls under congenital/other specified myasthenic syndromes or neuromuscular-junction disorders. A local coding authority should verify the current national modification.
• Orphanet: an exact subtype identifier was not securely established in the retrieved evidence.

The evidence is principally aggregated disease-level literature plus individual-patient case series, not an EHR-derived cohort. The 2024 study used WES/WGS and detailed phenotyping of five individuals from four families. (murtazina2024mildphenotypeof pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

CMS6 is a monogenic, autosomal-recessive disorder caused by germline biallelic CHAT variants. Most reported variants are missense, although truncating and splice-altering alleles may occur. It is not caused by autoantibodies, infection, toxin exposure, diet, or lifestyle. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 1-2)

Genetic risk

The principal risk is inheritance of two pathogenic or likely pathogenic CHAT alleles. Siblings of an affected person have, under standard autosomal-recessive assumptions, a 25% recurrence probability when both parents are heterozygous carriers. Consanguinity can increase the probability of homozygosity, but no CMS6-specific estimate was retrieved. Sex does not determine inheritance.

No validated modifier gene, protective allele, polygenic risk score, penetrance estimate, or CMS6-specific carrier frequency was found. Clinical variability—including mild and severe disease associated with the recurrent c.1061C>T, p.(Thr354Met) allele—indicates that genotype alone does not fully predict severity. (murtazina2024mildphenotypeof pages 5-6)

Environmental and physiologic modifiers

Infection, fever, and other physiologic stress can precipitate acute respiratory or bulbar crises; cold may exacerbate weakness, and prolonged exercise can unmask a neuromuscular decrement. These are phenotypic triggers, not causes. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)

No established diet, exercise regimen, toxin avoidance measure, medication, or genetic factor prevents disease occurrence. Practical protection is instead directed toward preventing crises: prompt infection treatment, avoidance of unmonitored respiratory depressants or neuromuscular blockers, an emergency respiratory plan, and adherence to effective symptomatic therapy.

3. Phenotypes

Reported frequencies below derive from a literature aggregation of approximately 42 patients and have variable denominators; ascertainment was biased toward severe CMS-EA. (murtazina2024mildphenotypeof pages 5-6)

• Apneic crises/respiratory disease: apneic crises 36/42 (86%); ventilation 26/41 (63%); respiratory insufficiency 20/42 (48%); explicitly coded apnea 12/42 (28%); tracheostomy 9/36 (25%). Onset is usually neonatal or infantile; episodes fluctuate and can be infection-, fever-, or stress-provoked. Suggested HPO: Apnea, Episodic respiratory distress, Respiratory insufficiency, Neonatal respiratory distress. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)
• Ocular disease: ptosis 36/41 (88%); strabismus or ophthalmoparesis 9/39 (23%). Severity is variable and fluctuating. Suggested HPO: HP:0000508 Ptosis, Ophthalmoparesis, HP:0000486 Strabismus. (murtazina2024mildphenotypeof pages 5-6)
• Muscle weakness/fatigability: fatigable leg weakness 27/28 (96%), proximal weakness 26/39 (67%), and general weakness 17/38 (45%). The cardinal functional effect is reduced walking, running, stair-climbing, or sustained activity. Suggested HPO: HP:0001324 Muscle weakness, HP:0003701 Proximal muscle weakness, HP:0003546 Exercise intolerance, Fatigability. (murtazina2024mildphenotypeof pages 5-6)
• Bulbar involvement: 12/42 (28%), including swallowing or speech difficulty. Suggested HPO: HP:0002015 Dysphagia, HP:0001260 Dysarthria, Bulbar weakness. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)
• Development/CNS: psychomotor delay was reported in 21/37 (57%); severe cases may include impaired consciousness, tonic–clonic seizures, or intellectual disability. These findings may reflect CHAT expression in central cholinergic neurons, hypoxic injury during crises, or both; causality is not fully resolved. Suggested HPO: HP:0001263 Global developmental delay, HP:0001250 Seizure, Loss of consciousness. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)
• Mobility: wheelchair dependence occurred in 7/28 (25%) in historical reports. Suggested HPO: Loss of ambulation or Wheelchair dependence. (murtazina2024mildphenotypeof pages 5-6)

Mild phenotype—2024 development

The 2024 case series described five patients whose onset was at 1–2.5 years and whose sole or initial manifestation was exercise-induced leg fatigability. All five lacked apnea, respiratory insufficiency, ptosis, and ophthalmoparesis and showed a fluctuating but non-progressive course over several years. The authors’ abstract states: “we propose the existence of a mild phenotype characterized by the absence of apneic episodes.” (murtazina2024mildphenotypeof pages 1-2)

No CMS6-specific EQ-5D, SF-36, PROMIS, or utility-weight study was found. Quality-of-life impairment should therefore be represented through respiratory risk, activity limitation, schooling/work effects, treatment burden, and possible ventilatory or wheelchair dependence rather than an unsupported numerical score.

4. Genetic and molecular information

Causal gene: CHAT, chromosome 10q11.23; protein: choline O-acetyltransferase. Open Targets identifies CHAT as ENSG00000070748 and associates it with the broader congenital myasthenic syndrome category. (OpenTargets Search: congenital myasthenic syndrome-CHAT)

The 2024 series identified four novel missense SNVs. c.404C>G, p.(Pro135Arg) was classified as likely pathogenic because another missense substitution at the same residue had been reported; three other novel missense variants remained VUS pending stronger functional evidence. The recurrent c.1061C>T, p.(Thr354Met) variant had previously been associated with infantile onset and apneic crises, yet also occurred in milder families, underscoring incomplete genotype–phenotype predictability. (murtazina2024mildphenotypeof pages 5-6)

Variants are constitutional/germline, not somatic cancer mutations. The expected functional category is loss or reduction of ChAT expression, stability, catalytic activity, or substrate kinetics, producing inadequate acetylcholine resynthesis under sustained demand. Population allele frequencies were not available in the retrieved text and must be obtained variant-by-variant from the current gnomAD release. Likewise, ClinVar classifications should be recorded per accession and review status rather than generalized from publication assertions.

No reproducible modifier genes, disease-specific methylation signature, chromatin abnormality, aneuploidy, translocation, or recurrent pathogenic copy-number alteration has been established. A chromosomal microarray cannot exclude CMS6, although exon-level CNV analysis remains appropriate when sequencing finds only one pathogenic allele.

5. Environmental information

There is no environmental, occupational, lifestyle, toxic, or infectious etiology. Infection and fever are clinically important crisis triggers, cold may aggravate fatigability, and exertion reveals limited presynaptic acetylcholine reserve. Smoking, alcohol, diet, pollution, and radiation have no demonstrated causal role. Pathogens are therefore not disease agents, and the disorder is neither communicable nor zoonotic. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)

6. Mechanism and pathophysiology

Causal chain

1. Upstream genetic lesion: biallelic CHAT loss-of-function or hypomorphic variants.
2. Protein defect: reduced ChAT quantity or catalytic function.
3. Biochemical defect: inadequate conversion of choline plus acetyl-CoA to acetylcholine in the motor-nerve terminal.
4. Cellular defect: acetylcholine stores and replenishment become insufficient during repeated motor-neuron firing.
5. Synaptic defect: quantal transmission falls below the postsynaptic safety margin, often only after sustained stimulation.
6. Tissue/organ manifestations: fatigable ocular, bulbar, limb, and respiratory-muscle weakness.
7. Clinical crisis: fever, infection, stress, or sustained activity raises demand and may trigger abrupt apnea, hypoxemia, loss of consciousness, seizures, or death. (ohno2023clinicalandpathologic pages 4-6, pugliese2023presynapticcongenitalmyasthenic pages 7-9)

The 2023 comprehensive review describes the normal step directly: “Choline acetyltransferase (ChAT, CHAT) in the nerve terminal generates ACh from up taken choline and acetyl-CoA.” (ohno2023clinicalandpathologic pages 4-6)

This is primarily a neurotransmitter-biosynthesis and synaptic-transmission disorder, not an inflammatory myopathy, autoimmune disease, primary mitochondrial disorder, degenerative motor-neuron disease, or structural ACh-receptor channelopathy. Secondary muscle atrophy, developmental delay, or hypoxic injury may occur downstream.

Suggested annotations include GO acetylcholine biosynthetic process, neuromuscular synaptic transmission, chemical synaptic transmission, synaptic vesicle cycle, and regulation of neurotransmitter levels; GO cellular components presynaptic active zone, axon terminal, synaptic vesicle, and neuromuscular junction; CL motor neuron and skeletal muscle fiber.

No validated CMS6-specific transcriptomic, proteomic, metabolomic, lipidomic, epigenomic, single-cell, spatial-transcriptomic, or integrated multi-omics signature is available. ChAT activity and electrophysiologic transmission are mechanistically relevant but are not validated circulating biomarkers.

7. Anatomical structures affected

The primary lesion is at cholinergic motor-neuron presynaptic terminals of the neuromuscular junction. Functionally affected tissues include skeletal muscle innervated by somatic motor neurons—especially the diaphragm and other respiratory muscles, extraocular and levator muscles, bulbar/pharyngeal musculature, proximal limb muscles, and distal leg muscles. Laterality is generally bilateral rather than focal. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)

Suggested UBERON concepts: neuromuscular junction, skeletal muscle organ, diaphragm, extraocular muscle, pharyngeal muscle, and limb muscle. Suggested GO cellular components are presynaptic membrane, axon terminus, synaptic vesicle, and cytosol, where ChAT catalysis occurs.

8. Temporal development

The classical severe form begins at birth or in early infancy, sometimes abruptly with apnea. The milder form may become evident in early childhood after sustained walking or exercise. Disease is chronic and lifelong, but manifestations fluctuate. Severe neonatal disease may cause fatal crises, whereas the five 2024 mild cases remained non-progressive for several years. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6, murtazina2024mildphenotypeof pages 1-2)

There is no accepted staging system. Clinically useful states are: baseline compensated weakness; exertional deterioration; bulbar/respiratory exacerbation; and acute apneic crisis requiring ventilation. Early diagnosis is a critical intervention window because respiratory support and genotype-appropriate medication may prevent hypoxic injury or death. True spontaneous molecular remission is not expected, although symptom-free intervals and treatment-induced functional improvement occur.

9. Inheritance and population

Inheritance is autosomal recessive, with variable expressivity. Penetrance for individuals with two definitively pathogenic alleles is presumed high but has not been quantified. Anticipation is not expected. No CHAT-specific germline-mosaicism rate, founder allele, sex ratio, ethnic enrichment, or carrier-frequency estimate was established by the retrieved evidence. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 1-2)

CHAT-CMS represents approximately 4–5% of all CMS cases, but only about 50 CMS-EA patients had been reported by 2024. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 1-2)

Subtype-specific incidence and prevalence are unknown. For context—not as a CMS6 estimate—the pediatric prevalence of all CMS was 9.2 per million in the UK, with regional estimates of 2.8–14.8 per million; published estimates were 1.8 per million in Brazil, 22.2 per million in Slovenia, and 1.8 per million in Spain. Investigators considered these underestimates because patients remain undiagnosed. (ohno2023clinicalandpathologic pages 4-6)

10. Diagnostics

Clinical and electrophysiologic diagnosis

Suspect CMS6 in neonatal/infantile episodic apnea, especially with ptosis, ophthalmoparesis, bulbar weakness, hypotonia, or fatigability; also consider it in children with isolated exertional leg weakness. Standard 3-Hz repetitive nerve stimulation may be falsely normal. Prolonged 10-Hz stimulation for five minutes was positive in 9/10 reported patients. In the 2024 mild cohort, 3-Hz peroneal stimulation after 15 minutes of exercise produced a 22–37% CMAP decrement, which improved after 3–4 minutes’ rest. (murtazina2024mildphenotypeof pages 5-6)

Single-fiber EMG can demonstrate increased jitter/blocking but may be difficult in children. Routine CK, imaging, muscle biopsy, and histopathology are not diagnostic and may be normal or nonspecific. Pulmonary-function testing, pulse oximetry, sleep/ventilation assessment, swallowing assessment, and ECG/cardiovascular review before sympathomimetic therapy are clinically useful.

Genetic testing

A CMS/NMJ panel containing CHAT is efficient when the phenotype is recognizable. WES or WGS is appropriate when panel testing is negative, the presentation is atypical, or CNV/noncoding analysis is needed. The 2024 series used WES at mean ×76.1 coverage and WGS at approximately ×30 coverage. Pathogenicity assessment should incorporate phase, segregation, population frequency, computational evidence, RNA studies for splice variants, and functional ChAT assays where feasible. (murtazina2024mildphenotypeof pages 1-2)

CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line for isolated CMS6. RNA sequencing may resolve splice variants but is not an established routine assay. Prenatal and preimplantation testing become possible after familial variants are established.

Differential diagnosis

Major alternatives include other presynaptic CMS—especially SLC5A7 and SLC18A3 disorders—RAPSN-associated CMS, congenital AChR deficiency, DOK7-CMS, COLQ-CMS, congenital myopathies, spinal muscular atrophy, mitochondrial disease, infantile epilepsy or central apnea, botulism, and autoimmune myasthenia gravis. AChR/MuSK seronegativity supports congenital rather than autoimmune myasthenia but is not by itself diagnostic. The albuterol study required a typical history, AChR/MuSK seronegativity, and decremental EMG. (NCT01203592 chunk 1)

11. Outcome and prognosis

No reliable 5- or 10-year survival rate, life-expectancy estimate, or CMS6-specific mortality rate exists. Historical severe cases include death during infantile apneic crises; ventilation, tracheostomy, developmental disability, impaired mobility, and hypoxic complications drive morbidity. Conversely, mild non-apneic disease can remain stable for years with preserved routine neurologic function. (pugliese2023presynapticcongenitalmyasthenic pages 7-9, murtazina2024mildphenotypeof pages 5-6)

Likely adverse prognostic features are neonatal onset, recurrent apnea, need for early ventilation, severe bulbar weakness, delayed diagnosis, and poor drug response. Favorable features include isolated exertional fatigability, no respiratory events, and treatment responsiveness. These are clinical observations, not validated prediction-model variables or biomarkers.

12. Treatment

Genotype-guided pharmacotherapy

Pyridostigmine, an acetylcholinesterase inhibitor, is generally first-line for CHAT-CMS because prolonging acetylcholine action can partly compensate for reduced synthesis. Historical response was reported in 27/37 patients (73%). If response is incomplete, amifampridine/3,4-diaminopyridine, which prolongs the presynaptic action potential and increases calcium-dependent acetylcholine release, may be added; 5/7 reported patients (71%) responded. (ohno2023clinicalandpathologic pages 4-6, murtazina2024mildphenotypeof pages 5-6)

In the 2024 mild series, two children improved clearly on 3,4-diaminopyridine, while one experienced severe adverse effects and later had slight benefit from salbutamol plus pyridostigmine. Treatment must therefore be initiated and titrated by a neuromuscular specialist, with cardiac and seizure-risk consideration for amifampridine and cardiovascular monitoring for β-agonists. (murtazina2024mildphenotypeof pages 1-2)

Important subtype distinction: acetylcholinesterase inhibitors are contraindicated or harmful in many COLQ-CMS patients, but this rule does not apply automatically to CHAT/CMS6. The recent CMS review explicitly reserves that contraindication for COLQ- and LAMB2-related disease. (ohno2023clinicalandpathologic pages 4-6)

Acute and supportive management

Apneic crisis requires immediate airway support, bag-mask ventilation or mechanical ventilation as indicated, oxygenation and CO₂ monitoring, treatment of infection/fever, and avoidance of diagnostic delay. Families should have a written emergency plan and resuscitation training when recurrent apnea is a risk. Supportive care may include noninvasive ventilation, tracheostomy in refractory disease, feeding/swallowing support, physical and occupational therapy, and school/activity accommodations.

Suggested MAXO annotations include genetic testing, electromyography, acetylcholinesterase inhibitor therapy, potassium-channel blocker therapy, adrenergic agonist therapy, noninvasive positive-pressure ventilation, mechanical ventilation, tracheostomy, physical therapy, occupational therapy, and genetic counseling.

Trials and emerging therapy

No controlled trial specific to CHAT-CMS6 was identified. NCT01203592, an open-label Phase 1 albuterol study, enrolled 21 heterogeneous CMS patients; it was not CHAT-specific. NCT00541216 tested ephedrine in a COLQ-deficient kindred and should not be represented as CMS6 evidence. (NCT01203592 chunk 1, NCT00541216 chunk 1)

A 2024 report of AAV9-mediated CHAT gene therapy in ChAT-deficient mice represents an important preclinical development, not an approved or clinically validated treatment. No human gene-, RNA-, or cell-therapy implementation for CMS6 was identified.

13. Prevention

Primary prevention by lifestyle or vaccination is impossible because CMS6 is inherited. Reproductive prevention options after molecular diagnosis include carrier testing of relatives, partner testing, prenatal diagnosis, and preimplantation genetic testing. Population newborn screening is unavailable, but targeted neonatal testing is justified in an at-risk pregnancy or symptomatic neonate.

Secondary prevention comprises early molecular diagnosis, family cascade testing, respiratory monitoring, and early effective therapy. Tertiary prevention includes infection and fever management, crisis planning, vaccination according to routine schedules to reduce preventable respiratory illness, ventilatory/feeding support, rehabilitation, and avoidance of medications or anesthesia practices that may worsen neuromuscular transmission. Vaccines do not prevent the genetic disease itself.

14. Other species and natural disease

A naturally occurring CHAT-associated myasthenic disorder occurs in the Old Danish Pointing Dog (Canis lupus familiaris, NCBI Taxonomy 9615). Affected dogs carry a CHAT valine-to-methionine substitution and develop fore- and hind-limb fatigability after only 5–30 minutes of walking or running; prolonged 3-Hz stimulation induces a decrement. This provides strong comparative evidence for conserved activity-dependent failure of cholinergic transmission. (pugliese2023presynapticcongenitalmyasthenic pages 7-9)

There is no zoonotic transmission. Veterinary breed and VBO identifiers should be obtained from live VBO/OMIA records before ingestion.

15. Model organisms

• Mouse (Mus musculus, Taxon 10090): heterozygous Chat-targeted mice appear normal, whereas homozygous knockout pups die at birth with flaccid paralysis, absent spontaneous and nerve-evoked postsynaptic potentials, excessive nerve-terminal branching, altered synapse distribution, widened endplates, thin muscles, and prematurely enlarged AChR-rich sites. The null model captures severe transmission failure but is more lethal than most human hypomorphic disease. (pugliese2023presynapticcongenitalmyasthenic pages 7-9)
• Zebrafish (Danio rerio, Taxon 7955): bajan carries a Chat intron-2 splice-acceptor mutation; chatatk64 carries p.Ser102Arg. Homozygotes lack normal coiling, have reduced touch responses, and show markedly reduced spontaneous and evoked synaptic currents. These models permit developmental imaging and rapid therapeutic screening. (pugliese2023presynapticcongenitalmyasthenic pages 7-9)
• Drosophila: reduced ChAT activity and impaired synaptic transmission at low temperature provide a mechanistic model for cold-sensitive weakness, although an invertebrate NMJ does not reproduce human respiratory crises directly. (murtazina2024mildphenotypeof pages 5-6)
• Dog: the natural Old Danish Pointing Dog disorder recapitulates exertional fatigability and activity-dependent electrophysiologic decrement, making it translationally relevant. (pugliese2023presynapticcongenitalmyasthenic pages 7-9)

Evidence assessment and current research priorities

The most important 2023–2024 advance is recognition that “episodic apnea” is not obligatory: CHAT disease spans lethal neonatal apnea through isolated childhood exercise intolerance. The 2024 series also showed that exercise-conditioned RNS can reveal abnormalities missed by routine testing. These findings favor phenotype expansion, exertion-provoked electrophysiology, and broad genetic testing rather than exclusion of CHAT because apnea is absent. (murtazina2024mildphenotypeof pages 5-6, murtazina2024mildphenotypeof pages 1-2)

Major gaps are CMS6-specific prevalence, prospective natural history, standardized patient-reported outcomes, variant-level functional assays, validated prognostic markers, controlled comparative treatment trials, and human gene-therapy safety data. Expert reviews consequently emphasize genotype-guided treatment and molecular confirmation because clinical and electrophysiologic findings alone cannot reliably identify the affected CMS molecule. (ohno2023clinicalandpathologic pages 4-6)

Key recent sources

1. Murtazina A, et al. Mild phenotype of CHAT-associated congenital myasthenic syndrome: case series. Frontiers in Pediatrics. Published 18 January 2024. DOI/URL: https://doi.org/10.3389/fped.2024.1280394. (murtazina2024mildphenotypeof pages 5-6, murtazina2024mildphenotypeof pages 1-2)
2. Pugliese A, et al. Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models. Journal of Neuromuscular Diseases. Published September 2023. DOI/URL: https://doi.org/10.3233/JND-221646. (pugliese2023presynapticcongenitalmyasthenic pages 7-9)
3. Ohno K, et al. Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review. International Journal of Molecular Sciences. Published February 2023. DOI/URL: https://doi.org/10.3390/ijms24043730. (ohno2023clinicalandpathologic pages 4-6)
4. ClinicalTrials.gov. NCT01203592: Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes. First posted 16 September 2010; completed August 2013. https://clinicaltrials.gov/study/NCT01203592. (NCT01203592 chunk 1)

Evidence-type labels: Murtazina et al. is human clinical case-series evidence; Pugliese et al. and Ohno et al. are authoritative reviews integrating human, in vitro, and model-organism studies; the NCT records are trial-registry evidence. Exact PMID values were not exposed in the retrieved records and are therefore not supplied rather than risked as unverified identifiers.

References

1. (pugliese2023presynapticcongenitalmyasthenic pages 7-9): Alessia Pugliese, Stephen H. Holland, Carmelo Rodolico, Hanns Lochmüller, and Sally Spendiff. Presynaptic congenital myasthenic syndromes: understanding clinical phenotypes through in vivo models. Journal of Neuromuscular Diseases, 10:731-759, Sep 2023. URL: https://doi.org/10.3233/jnd-221646, doi:10.3233/jnd-221646. This article has 22 citations and is from a peer-reviewed journal.

2. (murtazina2024mildphenotypeof pages 1-2): Aysylu Murtazina, Artem Borovikov, Andrey Marakhonov, Artem Sharkov, Inna Sharkova, Alena Mirzoyan, Sviatlana Kulikova, Ralina Ganieva, Viktoriia Zabnenkova, Oksana Ryzhkova, Sergey Nikitin, Elena Dadali, and Sergey Kutsev. Mild phenotype of chat-associated congenital myasthenic syndrome: case series. Frontiers in Pediatrics, Jan 2024. URL: https://doi.org/10.3389/fped.2024.1280394, doi:10.3389/fped.2024.1280394. This article has 4 citations.

3. (NCT01203592 chunk 1): Andrew Engel. Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes. Mayo Clinic. 2010. ClinicalTrials.gov Identifier: NCT01203592

4. (OpenTargets Search: congenital myasthenic syndrome-CHAT): Open Targets Query (congenital myasthenic syndrome-CHAT, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

5. (ohno2023clinicalandpathologic pages 4-6): K. Ohno, B. Ohkawara, Xinming Shen, D. Selcen, and A. Engel. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—a comprehensive review. International Journal of Molecular Sciences, Feb 2023. URL: https://doi.org/10.3390/ijms24043730, doi:10.3390/ijms24043730. This article has 132 citations.

6. (murtazina2024mildphenotypeof pages 5-6): Aysylu Murtazina, Artem Borovikov, Andrey Marakhonov, Artem Sharkov, Inna Sharkova, Alena Mirzoyan, Sviatlana Kulikova, Ralina Ganieva, Viktoriia Zabnenkova, Oksana Ryzhkova, Sergey Nikitin, Elena Dadali, and Sergey Kutsev. Mild phenotype of chat-associated congenital myasthenic syndrome: case series. Frontiers in Pediatrics, Jan 2024. URL: https://doi.org/10.3389/fped.2024.1280394, doi:10.3389/fped.2024.1280394. This article has 4 citations.

7. (NCT00541216 chunk 1): Ephedrine for the Treatment of Congenital Myasthenia. Hadassah Medical Organization. 2007. ClinicalTrials.gov Identifier: NCT00541216

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