Evidence for genetic heterogeneity supports clinical differences in congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) define a diverse group of disorders, all of which compromise neuromuscular transmission. Symptoms can be present at birth or appear during childhood, and can range in severity. Both autosomal dominant and recessive forms exist, and a number of clinical subtypes have been described. The cause of many cases of CMS has been traced to mutations in the genes for the acetylcholine receptor (AChR) subunits, previously mapped to chromosomes 2 and 17. Recently, an additional form of CMS known as familial infantile myasthenia (FIM) was linked to chromosome 17p. The gene for FIM has not yet been identified. We examined the DNA from 5 families of Iranian Jewish origin (6 affected individuals) who have been diagnosed with a phenotypically unique form of CMS. Four of the families are consanguinous, and all families originate from the same geographical region, thus it is highly likely that they would carry the same ancestral CMS mutation. We examined these families for linkage to the regions on chromosomes 2 and 17 containing the AChR subunit genes, and to the region on 17p to which FIM was localized. Our data excludes linkage to these regions, suggesting that the clinical differences seen among patients with CMS correlate with locus heterogeneity, and that a defect in a different gene is responsible for the CMS in these patients.