Genetic analysis of congenital myasthenic syndromes (CMS)

Congenital myasthenic syndromes (CMS) are a heterogeneous group of hereditary disorders in which the neuromuscular transmission is compromised. CMS are caused by various genetic defects of the neuromuscular endplate. Clinically and genetically, we analyzed a collective of more than 200 CMS patients from Germany and other European countries. In about 60% of patients, we identified the underlying molecular defect by genetic analysis of seven synapse-specific genes (genes of the AChR subunits, RAPSN, COLQ and CHAT). The majority of mutations affect the AChR-epsilon subunit gene (CHRNE). A specific mutation of CHRNE (1267delG) has been identified in about 50% of patients from Southeastern European and/or Roma origin. Our data support a founder effect for this mutation and moreover provide genetic evidence of the Indian origin of the Roma population. A single missense mutation of the gene RAPSN which encodes the postsynaptic protein rapsyn was detected in about 20% of patients from Middle Europe and was found to be the result of a founder event in the ancient Indo-European population. Clinical symptoms of RAPSN N88K patients typically included crisis-like exacerbations of weakness with respiratory insufficiency. In addition, a distinct phenotype with unusual late-onset in adulthood was observed in N88K patients. In other CMS patients, mutations of the synapse-specific COLQ gene as well as in the presynaptic expressed CHAT gene were identified and characterized. Analysis of geno- and phenotypes revealed important information on clinical findings, therapeutic options, and prognosis of different CMS forms as well as first data on the frequency distribution of single CMS mutations in different populations.