EVIDENCE FOR GENETIC-HETEROGENEITY SUPPORTS CLINICAL DIFFERENCES IN CONGENITAL MYASTHENIC SYNDROMES

Congenital myasthenic syndromes (CMS) define a diverse group of disord ers, all of which compromise neuromuscular transmission. Symptoms can be present at birth or appear during childhood, and can range in sever ity. Both autosomal dominant and recessive forms exist, and a number o f clinical subtypes have been described. The cause of many cases of CM S has been traced to mutations in the genes for the acetylcholine rece ptor (AChR) subunits, previously mapped to chromosomes 2 and 17. Recen tly, 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 orig in (6 affected individuals) who have been diagnosed with a phenotypica lly unique form of CMS. Four of the families are consanguinous, and al l families originate from the same geographical region, thus it is hig hly likely that they would carry the same ancestral CMS mutation. We e xamined these families for linkage to the regions on chromosomes 2 and 17 containing the AChR subunit genes, and to the region on 17p to whi ch FIM was localized. Our data excludes linkage to these regions, sugg esting that the clinical differences seen among patients with CMS corr elate with locus heterogeneity, and that a defect in a different gene is responsible for the CMS in these patients.