X-LINKED NONPROGRESSIVE CONGENITAL CEREBELLAR HYPOPLASIA - CLINICAL DESCRIPTION AND MAPPING TO CHROMOSOME XQ

We examined a large family in which an X-linked recessive congenital a taxia manifested in 7 males from three generations. The affected boys first exhibited a marked delay of early developmental motor milestones . A neurological syndrome became evident by 5 to 7 years of age and in cluded cerebellar ataxia, dysarthria, and external ophthalmoplegia; th ere were no symptoms of mental retardation, spastic paraparesis, or se nsory loss. Neuroimaging studies revealed hypoplasia of cerebellar hem ispheres and vermis. The disease showed no progression beyond early ch ildhood. The unique heredity and clinical features clearly distinguish this new entity from a variety of previously described familial ataxi as. Pairwise linkage analysis and haplotype reconstruction allowed us to map the gene responsible for this disorder to a 38-cM interval on c hromosome Xp11.21-q24 flanked by the loci DXS998 and DXS1001. Upon mul tipoint linkage analysis, the disease gene was determined to be locate d most likely in the proximal part of chromosome Xq, with the maximal lod score of 4.66 at the locus DXS1059 (Xq23). This is the first examp le of the genetic mapping of a pure congenital cerebellar hypoplasia s yndrome.