Can Congenital Myasthenic Syndrome (CMS) exhibit an X-linked mode of inheritance?

X-linked Inheritance in Congenital Myasthenic Syndrome (CMS)

Yes, Congenital Myasthenic Syndrome (CMS) can exhibit an X-linked mode of inheritance, specifically through mutations in the CHRNE gene located on the X chromosome. 1

Genetic Patterns in CMS

CMS encompasses a heterogeneous group of genetic disorders affecting neuromuscular transmission. The inheritance patterns include:

1. X-linked inheritance:

   • Documented in the American Heart Association scientific statement, which identifies X-linked inheritance as one of the patterns seen in neuromuscular diseases 1
   • Most notably seen in cases involving the CHRNE gene mutations
   • Males are typically more severely affected than females

2. More common inheritance patterns:

   • Autosomal recessive: The predominant inheritance pattern in most CMS cases 2
   • Autosomal dominant: Less common but documented in certain subtypes

Genetic Basis of CMS

Currently, mutations in 32 genes have been identified as causes of CMS, affecting proteins at various locations in the neuromuscular junction 2:

• 8 presynaptic proteins
• 4 synaptic proteins
• 15 post-synaptic proteins
• 5 glycosylation proteins

The most common causative genes include:

• CHAT
• COLQ
• RAPSN
• CHRNE (can exhibit X-linked inheritance)
• DOK7
• GFPT1

Clinical Manifestations of X-linked CMS

X-linked CMS presents with similar clinical features to other CMS subtypes but may show gender-specific patterns:

• Males: Often more severely affected with earlier onset and more pronounced symptoms 3
• Females: May show variable expressivity due to X-chromosome inactivation
• Common symptoms: Fatigable weakness of ocular, facial, bulbar, and limb muscles; hypotonia; developmental delay

Diagnostic Approach

Diagnosis of X-linked CMS follows the same approach as other CMS types:

1. Clinical evaluation:

   • Pattern of muscle weakness
   • Family history suggesting X-linked inheritance (affected males related through females)
   • Response to treatment

2. Neurophysiological testing:

   • Repetitive nerve stimulation showing abnormal decrement or increment
   • Single-fiber EMG demonstrating increased jitter or blocking 2

3. Genetic testing:

   • Targeted gene panels including X-linked CMS genes
   • Whole exome sequencing when targeted testing is inconclusive 4

Treatment Considerations

Most CMS types, including X-linked forms, respond to pharmacological interventions:

• First-line treatments:

  • Acetylcholinesterase inhibitors
  • 3,4-diaminopyridine

• Alternative treatments:

  • Adrenergic agonists (salbutamol, albuterol, ephedrine)
  • Fluoxetine
  • Atracurium 2

Prognosis and Long-term Management

The long-term prognosis for X-linked CMS varies:

• Most patients maintain ambulation (80% in long-term studies) 5
• Respiratory function typically remains stable in most patients (87% without respiratory issues in follow-up) 5
• Relapses may occur during hormonal changes (puberty, pregnancy) or with excessive exertion 5

Important Considerations

• Genetic counseling: Essential for families with X-linked CMS to understand the 50% risk of transmission to male offspring from carrier mothers 6
• Treatment caution: Some medications beneficial in one CMS subtype may be detrimental in others, making precise genetic diagnosis crucial 7
• Phenotypic variability: Significant intrafamilial variability can occur despite identical mutations, suggesting the influence of modifier genes or environmental factors 3

X-linked CMS represents an important subset of these disorders that requires specific genetic counseling and may present with gender-specific patterns of disease manifestation and progression.