Understanding Congenital Myasthenic Syndrome: A Genetic Neuromuscular Disorder

General
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Congenital Myasthenic Syndrome (CMS): A Quick Clinical Overview

Congenital Myasthenic Syndrome (CMS) is a group of inherited neuromuscular disorders caused by genetic defects affecting the neuromuscular junction (NMJ)—the site where motor nerves signal skeletal muscles to contract.
Unlike autoimmune myasthenia gravis, CMS is not antibody-mediated and does not respond to immunosuppression.

Pathophysiology: What Goes Wrong?

At the NMJ, acetylcholine (ACh) is released from motor neurons to trigger muscle contraction. In CMS, mutations disrupt one or more steps of neuromuscular transmission:

  • ACh synthesis or packaging
  • ACh release from nerve terminals
  • ACh receptor function or clustering
  • ACh breakdown and recycling

This results in inefficient neuromuscular signaling, leading to fatigable muscle weakness.

Clinical Features

Symptoms usually begin in infancy or early childhood, though adult onset can occur.

Common features include:

  • Fatigable limb weakness
  • Ptosis and ophthalmoparesis
  • Bulbar symptoms (difficulty chewing, swallowing, speaking)
  • Delayed motor milestones
  • Respiratory muscle weakness (especially in infants)

Symptoms are typically non-fluctuating over days to weeks, unlike autoimmune MG.

Genetic Basis

CMS is caused by mutations in genes essential for NMJ structure and function, including:

  • CHRNE – ACh receptor subunit
  • RAPSN – ACh receptor clustering
  • COLQ – acetylcholinesterase anchoring
  • CHAT – ACh synthesis
  • DOK7 – NMJ formation and maintenance

:backhand_index_pointing_right: Genotype directly influences treatment response, making genetic diagnosis crucial.

Diagnosis

  • Repetitive nerve stimulation (decremental response)
  • Single-fiber EMG (high sensitivity)
  • Genetic testing (confirmatory and therapeutic guidance)
  • Exclusion of autoimmune antibodies (AChR, MuSK)

Management

Treatment is symptom- and genotype-specific:

  • Acetylcholinesterase inhibitors (e.g., pyridostigmine)
  • 3,4-Diaminopyridine for presynaptic defects
  • Beta-2 agonists (salbutamol) or ephedrine—especially effective in DOK7-CMS
  • Avoid drugs that impair neuromuscular transmission (e.g., aminoglycosides)

:red_exclamation_mark: Immunosuppressive therapy is ineffective and unnecessary.

Key Takeaways

  • CMS is genetic, not autoimmune
  • Early genetic diagnosis guides therapy
  • Misdiagnosis can lead to ineffective or harmful treatment
  • Personalized management significantly improves outcomes

MBH/AB

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It’s a very painful condition for both parents and the child.