Novel mutation in GLRB in a large family with hereditary hyperekplexia.

Hereditary hyperekplexia (HH) is a disorder of the inhibitory glycinergic neurotransmitter system. Mutations in five genes have been reported to cause the disease. However, only single mutation in GLRB, the gene encoding beta-subunit of the glycine receptor, in a singleton patient with HH has been found to date. In this study, 13 patients with HH were identified through neurology and genetic clinics. Formal clinical examinations, linkage analysis, homozygosity mapping, in-mutation screening of GLRB and in silico functional analyses were carried out. A novel mutation in GLRB among nine patients was identified. This c.596 T>G perturbation results in the change of the highly conserved methionine at position 177 to arginine. Besides the classical HH phenotype, seven patients had esotropia and few of them had behavioral problems. This study presents a large family with HH as a result of homozygous mutation in GLRB and expands the clinical spectrum of HH to include eye misalignment disorder. Moreover, the report of these familial cases supports the previous evidence in a single patient of an autosomal recessive inheritance of HH because of defects in GLRB.