Hyperekplexia phenotype due to compound heterozygosity for GLRA1 gene mutations

Hyperekplexia (MIM 149400), or startle disease, is a neurological disorder characterized by generalized stiffness during the neonatal period, excessiv e startle reflexes, and generalized stiffness related to the startle respon se. Linkage analysis mapped a major gene for this disorder to chromosome 5q 33-35. Subsequently, mutations in the GLRA1 gene, encoding the arl subunit of the glycine receptor, were found in hyperekplexia families with an autos omal dominant or recessive inheritance pattern. In the present study, we de scribe the genetic analysis of the GLRA1 gene of a family consisting of 2 c hildren with hyperekplexia, 2 nonaffected children, and their healthy nonco nsanguineous parents. Although the pedigree suggested the presence of a rec essive mutation, haplotype construction showed that the 2 affected children shared the same haplotype combination in which the maternal haplotype diff ered from the paternal haplotype, suggesting the presence of compound heter ozygosity. Mutation analysis revealed different missense mutations on the t wo haplotypes, changing an arginine to a histidine at amino acid positions 252 and 392, respectively. It is interesting that the hyperekplexia phenoty pe was only seen in individuals compound heterozygous for the two mutations , whereas: family members carrying either one of the two mutations had no c linical signs.