Screening for Congenital Myasthenic Syndromes in Adults With Seronegative Myasthenia Gravis Using Next-Generation...

Area of Science:

• Neurology
• Genetics
• Rare Diseases

Background:

• Myasthenia gravis (MG) is a neuromuscular junction disorder often caused by autoantibodies.
• Approximately 10% of MG cases are seronegative (SNMG).
• Hereditary conditions like congenital myasthenic syndromes (CMS) can mimic SNMG, necessitating different treatments.

Purpose of the Study:

• To determine the proportion of congenital myasthenic syndromes (CMS) among patients diagnosed with seronegative myasthenia gravis (SNMG).
• To identify clinical and demographic factors associated with a molecular diagnosis in SNMG patients.

Main Methods:

• Whole-exome sequencing (WES) was performed on 50 adult SNMG patients across 3 Austrian centers.
• Patients underwent comprehensive serologic testing to exclude common MG autoantibodies before genetic screening.
• Clinical and demographic data were analyzed for associations with molecular diagnosis.

Main Results:

• Seven out of 50 (14%) SNMG patients received a genetic diagnosis of CMS via WES, with variants in CHRNE and RAPSN.
• Uncertain genetic findings were noted in 4 additional cases.
• Patients with CMS tended to have an earlier age of onset, but no factors were consistently associated with a molecular diagnosis after correction.
• A response to immunotherapies was observed in some CMS patients, highlighting potential misdiagnosis.

Conclusions:

• A considerable proportion of SNMG diagnoses are attributable to underlying hereditary conditions, specifically CMS.
• A positive response to immunotherapies does not exclude a CMS diagnosis.
• Genetic testing for seronegative myasthenic syndromes is essential for accurate diagnosis and appropriate therapeutic management.