Molecular genetic reevaluation of the Dutch hyperekplexia family

M. A. Tijssen, R. Shiang, J. van Deutekom, R. H. Boerman, J. J. Wasmuth, L. A. Sandkuijl, R. R. Frants and G. W. Padberg
Department of Neurology, University Hospital Leiden, The Netherlands.

OBJECTIVES: To confirm linkage of the locus of the major form of hyperekplexia to markers on chromosome 5q, to screen for a point mutation in the gene encoding the alpha 1 subunit of the glycine receptor, and to investigate whether the putative "minor" form of hyperkeplexia consisting of an excessive startle response without stiffness, is based on the same genetic defect as the major form. DESIGN: A survey of various symptoms of hyperekplexia was performed in the Dutch pedigree. Linkage studies were performed for these symptoms. SETTING: Subjects were visited at home, and the genetic study was performed at University Hospital Leiden, (the Netherlands). PATIENTS: A history was taken from 76 subjects in the pedigree, and neurologic examinations were performed on 61 subjects from four generations of the pedigree. MAIN OUTCOME MEASURES: The main outcome measures were lod scores for markers on chromosome 5q for the major and minor forms of hyperekplexia and periodic leg movements during sleep. Mutations in the alpha 1 subunit of the glycine receptor were detected by screening the exons with denaturing gradient gel electrophoresis. RESULTS: Exaggerated startle responses were reported in 44 patients. The major form consisted of stiffness in addition to the excessive startle reaction and occurred in 28 subjects. Sixteen of 44 subjects had startle responses without stiffness, indicating the minor form. Linkage was found between markers CSF1-R, D5S209, and D5S119 and the disease locus for the major form, but not for the minor form. The alpha 1 subunit of the glycine receptor showed a G to A transition mutation in codon 271 for the major form, but not for the minor form. CONCLUSIONS: Linkage and an abnormal glycine receptor were found only in the major form of hyperekplexia. Recognition of a major form is based on additional stiffness. This is therefore the most important diagnostic symptom. The minor form is not a different expression of the same genetic defect and may represent a normal but pronounced startle response.