Congenital myasthenic syndromes – variability of symptoms, importance of a final diagnosis

Objectives: To introduce the variability of clinical and special data in patients with congenital myasthenic syndromes (CMS) caused by different gene mutations. Correlations of suggestive symptoms and results with distinct genetic defects will be highlighted.

Methods: We report on 6 of our 18 patients with CMS at the age of 4 to 12 years. The clinical work-up was always followed by special investigations and therapeutic trials.

Results: Clinical symptoms vary from mild ptosis, external ophthalmoplegia,

facial hypomimia, generalized muscle weakness and hypotonia to respiratory insufficiency. Serum AChR-antibodies are negative in all patients; distal or

only proximal repetitive stimulation tests (3/s) revealed pathological decrements independent of clinical severity. The intravenous edrophonium-test was positive in 4/6 cases; pyridostigminbromide therapy showed positive effects in 5/6 patients, worsening of symptoms in one.

Mutations were disclosed in COLQ (1), CHRNE (1), CHRND (1), RAPSN (3). Severe symptoms are often caused by COLQ mutations; defects in a single gene however can lead to different phenotypes. While mutations in CHRNE often cause facial and bulbar symptoms patients with mutations in CHRND may show more generalized muscle weakness and hypotonia, crises with worsening clinical symptoms can occur.

Conclusion: CMS are clinically and genetically heterogeneous. A diagnosis

is necessary for family counselling concerning prognosis and therapy. Careful analysis of data may facilitate genetic investigations. In some patients with negative results indirect haplotype analysis and investigations of a muscle biopsy in specialized centers may be helpful.