BackgroundWe report on a novel mutation (S270T) in the M2 domain of theGLRA1(α subunit of the glycine receptor) gene causing autosomal dominant hyperekplexia in a neonate, the mother and maternal uncle. All affected members showed the typical clinical features of the disorder. This novelS270T(T1188A) mutation is located in the boundary of the transmembrane M2 domain of theGLRA1protein, close to other previously reported mutations. Mutations in this ‘hot spot’ domain ofGLRA1are frequent in autosomal dominant hyperekplexia but are not usually seen in the autosomal recessive form of the disease in which both the M1 and the carboxy terminal domains have been implicated.MethodsGenomic DNA was extracted by standard procedures from peripheral blood leukocytes and exon 6 of theGLRA1gene was amplified using primers and PCR conditions. A complete sequence analysis of the fragment was performed. DNA sequences were analyzed both by direct observation of the electropherogram and by comparison with the published sequence.ResultsThe proband had metabolic acidosis, which was probably related to continuous contractions of somatic muscles and intractable hypertonia. Data seem to show a direct relationship between the mechanism of inheritance of the disorder and the location of the molecular defect. The patients showed almost all the clinical signs of hyperekplexia: exaggerated startle response, muscle hypertonia in response to unexpected tactile and/or auditory stimuli, hyperexcitability, and sudden falls.