What is the mode of inheritance in congenital myasthenia syndrome?

Mode of Inheritance in Congenital Myasthenic Syndrome

Congenital myasthenic syndromes (CMS) are primarily inherited in an autosomal recessive pattern, with rare cases showing autosomal dominant inheritance. 1, 2, 3

Genetic Basis of CMS

Congenital myasthenic syndromes represent a heterogeneous group of inherited disorders caused by mutations in genes affecting the structure and function of the neuromuscular junction. The genetic landscape of CMS has expanded significantly in recent years:

• Over 30 genes have been identified as causative for CMS 3
• CHRNE gene mutations (encoding the epsilon subunit of the acetylcholine receptor) are the most common cause 4
• Most mutations result in defective neuromuscular transmission, either directly or through secondary mechanisms 2

Inheritance Patterns

• Autosomal recessive: The predominant inheritance pattern in CMS

  • Requires two mutated copies of the gene (one from each parent)
  • Parents are typically asymptomatic carriers with heterozygous mutations 4
  • Example: A documented case showed heterozygous parents with no symptoms, while their children with homozygous CHRNE duplication variants manifested the disease 4

• Autosomal dominant: Less common pattern

  • Requires only one mutated copy of the gene
  • Seen in specific subtypes of CMS

Clinical Implications of Inheritance Pattern

Understanding the inheritance pattern has important implications for:

1. Family planning:

   • In autosomal recessive inheritance, each child of carrier parents has a 25% chance of developing CMS
   • Siblings of affected individuals have a 25% chance of being affected and a 50% chance of being asymptomatic carriers

2. Genetic counseling:

   • Identification of the specific genetic mutation allows for targeted genetic counseling
   • Prenatal testing may be available for families with known mutations

3. Treatment approach:

   • Different genetic subtypes may respond differently to treatments
   • β2-adrenergic receptor agonists (salbutamol, ephedrine) have shown benefit in certain subtypes 3
   • Pyridostigmine is effective in many cases 4

Expanding Genetic Landscape

The genetic heterogeneity of CMS continues to grow with advances in next-generation sequencing:

• Mutations in presynaptic, synaptic, and postsynaptic proteins have been identified
• Some CMS-causing genes encode ubiquitously expressed molecules that produce specific defects at the neuromuscular junction
• Novel phenotypes continue to be described, such as myasthenia with distal weakness due to AGRN mutations 1

Diagnostic Considerations

When suspecting CMS, genetic testing should be pursued to:

• Confirm the diagnosis
• Identify the specific subtype
• Guide appropriate treatment selection
• Enable genetic counseling for family members

Important caveat: The expanding genetic spectrum means that some patients with clinical CMS may have mutations in genes not yet associated with the condition, highlighting the importance of comprehensive genetic evaluation.