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Congenital Myasthenic Syndromes (CMS)

Congenital Myasthenic Syndrome (CMS) is a heterogeneous group of hereditary neuromuscular diseases characterized by muscle weakness and fatigability due to genetic defects of the neuromuscular junction. Unlike Myasthenia Gravis, it is not autoimmune in origin. The prevalence is 2–10 cases per million people, with symptoms typically appearing at birth or during early childhood. The severity varies from mild forms to severe, potentially fatal cases if not properly treated.

CMS is caused by mutations in over 30 genes encoding proteins essential for neuromuscular transmission. The inheritance pattern is predominantly autosomal recessive (95%).

The forms are classified as follows:

  • Pre-synaptic (5%): Genes such as SLC5A7 and SLC18A3.

  • Synaptic (15%): Genes such as COLQ and PLEC.

  • Post-synaptic (80%): Most frequent forms, including CHRNE, DOK7, and RAPSN.

  • Glycosylation defects: Genes such as GFPT1 and DPAGT1.

Each form requires specific and personalized treatment.

The symptoms of CMS vary based on the age of onset and the genetic subtype:

Neonatal Presentation (60% of cases)

  • Neonatal hypotonia: (“Floppy baby” syndrome), respiratory difficulties.

  • Weak cry: Difficulties with sucking and feeding.

  • Congenital ptosis: Drooping eyelids, apneic episodes (common in CHAT/CHT1 and VAChT).

  • Respiratory failure: Failure to thrive (growth retardation).

Infantile Presentation (30% of cases)

  • Delayed motor milestones: Fluctuating muscle weakness.

  • Ptosis and ophthalmoplegia: Myasthenic facies (expressionless face), exercise intolerance.

  • Muscle involvement: Ocular muscles (ptosis, diplopia), bulbar muscles (dysphagia/swallowing difficulty, dysarthria/speech difficulty).

  • Limb weakness: Proximal weakness and exertional dyspnea (shortness of breath).

Late-Onset Presentation (10% of cases)

  • Onset: School age or adulthood; symptoms are often underestimated or misdiagnosed.

  • Progression: Slowly progressive weakness and easy fatigability.

Specific Phenotypes

  • DOK7-CMS: Characterized by proximal weakness, axial involvement (neck/trunk), and muscle atrophy.

  • COLQ-CMS: Progressive course, trunk involvement, scoliosis; notably resistant to acetylcholinesterase inhibitors.

  • RAPSN-CMS: Often presents with arthrogryposis multiplex (joint contractures at birth), severe generalized weakness, and episodic apnea.

  • Clinical Evaluation: Suspicion criteria include congenital weakness, fatigability, fluctuating ptosis, a positive family history, and the absence of anti-AChR/MuSK antibodies.

  • Specialized Electrophysiology: * Repetitive Nerve Stimulation (RNS): Showing a decrement >10%.

    • Single-Fiber Electromyography (SFEMG): Increased jitter.

    • Pharmacological Testing: Assessing response to specific agents.

  • Genetic Diagnostics: CMS panels (>30 genes), exome/genome sequencing (WES/WGS), CNV (Copy Number Variant) analysis, and functional studies.

  • Most Frequent Genes: CHRNE (30%), DOK7 (15%), RAPSN (10%), and COLQ (8%).

  • Muscle Biopsy: Selective indications for forms associated with myopathy, ultrastructural studies of the neuromuscular junction (NMJ), and histochemical analysis.

  • Differential Diagnosis: Autoimmune Myasthenia Gravis, congenital myopathies, muscular dystrophies, and hereditary neuropathies.

Available therapies

Acetylcholinesterase Inhibitors:

  • Pyridostigmine (1–7 mg/kg/day): Effective in forms involving AChR receptors and RAPSN.

  • Warning: Ineffective or harmful in DOK7 and COLQ subtypes.

3,4-Diaminopyridine (3,4-DAP):

  • Dosage: 0.5–1 mg/kg/day.

  • Indications: Indicated for pre-synaptic forms and certain post-synaptic forms.

Salbutamol (Albuterol):

  • Dosage: 2–4 mg/day (children), up to 16 mg/day (adults).

  • Efficacy: Effective in DOK7-CMS and COLQ-CMS (works by increasing the expression of AChR receptors).

Subtype-Specific Protocols

  • CHT1-CMS: Choline acetate, pyridostigmine.

  • DOK7-CMS: Salbutamol (first choice); strictly avoid pyridostigmine.

  • COLQ-CMS: Salbutamol; strictly avoid acetylcholinesterase inhibitors.

  • RAPSN-CMS: Pyridostigmine; 3,4-DAP may be used synergistically.

Multidisciplinary Support

  • Respiratory Support: Non-invasive or invasive ventilation, airway clearance (secretion management).

  • Nutritional Support: Dysphagia assessment, PEG tube placement if necessary.

  • Rehabilitation: Physiotherapy, prevention of contractures, mobility aids.

Research in progress

  • Regenerative Medicine: Stem cells and tissue engineering.
  • Biomarker Identification: Discovery of diagnostic and progression biomarkers to monitor the disease.
  • Clinical Trials: Ongoing studies for new pharmacological formulations and therapeutic combinations.
  • International Registries: Collaborative efforts for the characterization of the natural history of the disease.

Reference laboratory

Contacts and informations

Email/Telefono: malattieneuromuscolari@policlinico.mi.it

Associazioni pazienti:
– UILDM:– Tel. 049 8021001

– Famiglie SMA 

– CMS International Patient Registry

– Muscular Dystrophy Association

Risorse specialistiche:

– Database genetici: ClinVar, OMIM, LOVD

– Protocolli clinici: scale valutazione CMS, guidelines internazionali