FAMILIAL HYPEREKPLEXIA - A STARTLE DISEAS E

The major form of familial hyperekplexia, a rare autosomal dominant di sorder, is characterized by an abnormal startle reaction elicited by a uditory and somatosensory stimuli, with transitory stiffness during th e neontam period, followed later by falling attacks accompanied by mom entary generalized muscular stiffness. Affected neonates occasionally have fatal hypertonia. The minor form is characterized only by an inco nstant excessive startle response. We encountered a family in which th ree females presented with a partial or complete major form of the dis ease. All our patients were hyperreflexic, insecure gait was present i n two subjects, without concomitant spontaneous nocturnal myoclonus. T he 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 r eticular formation), where bulbospinal motor efferents originate. More over, nonspecific changes such as large somatosensory evoked potential s and long-loop reflexes (''C-responses'') may indicate increased cort ical neuronal excitability. Polygraphic studies in these patients were normal. The locus of the major form of the disorder is located on chr omosome 5q33-q35. Sequence analysis of the alpha 1 subunit of the inhi bitory 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 p resented patients. Sporadic cases may represent new mutations or lack of penetrance in some family members. Only one of our three patients n eeded clonazepam. The diagnosis of this disorder rules out epilepsy, o r psychogenic pathological startle reaction. Electrophysiological crit eria are useful, however perinatal hypertonia or a tonic generalized s pasm accompanied with falls following an abnormal startle reaction and genetic studies remain the diagnostic milestones of familial hyperekp lexia.