The major form of familial hyperekplexia, a rare autosomal dominant disorder, is characterized by an abnormal startle reaction elicited by auditory and somatosensory stimuli, with transitory stiffness during the neontam period, followed later by falling attacks accompanied by momentary generalized muscular stiffness. Affected neonates occasionally have fatal hypertonia. The minor form is characterized only by an inconstant excessive startle response. We encountered a family in which three females presented with a partial or complete major form of the disease. All our patients were hyperreflexic, insecure gait was present in two subjects, without concomitant spontaneous nocturnal myoclonus. The pathophysiological basis of the hyperekplexia remains unclear. The abnormal startle reflex, probably related to the lack of inhibition by higher centers, is relayed in the caudal brainstem (ponto-medullary reticular formation), where bulbospinal motor efferents originate. Moreover, nonspecific changes such as large somatosensory evoked potentials and long-loop reflexes ("C-responses") may indicate increased cortical neuronal excitability. Polygraphic studies in these patients were normal. The locus of the major form of the disorder is located on chromosome 5q33-q35. Sequence analysis of the alpha 1 subunit of the inhibitory glycine receptor (GLRA1) revealed a mutation at the same codon 271 in several families (G1192A and G1192T). We analyzed this gene and found a G1192A mutation changing an ARG to a LEU codon in all three presented patients. Sporadic cases may represent new mutations or lack of penetrance in some family members. Only one of our three patients needed clonazepam. The diagnosis of this disorder rules out epilepsy, or psychogenic pathological startle reaction. Electrophysiological criteria are useful, however perinatal hypertonia or a tonic generalized spasm accompanied with falls following an abnormal startle reaction and genetic studies remain the diagnostic milestones of familial hyperekplexia.