UNSTABLE MINISATELLITE EXPANSION CAUSING RECESSIVELY INHERITED MYOCLONUS EPILEPSY, EPM1

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low freq uency in many populations but is more common in Finland and the Medite rranean region(1,2). It is characterized by stimulus-sensitive myoclon us and tonic-clonic seizures with onset at age 6-15 years, typical ele ctroencephalographic abnormalities and a variable rate of progression between and within families(3-5). Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critica l region to a small interval(7-9), positional cloning identified the g ene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST 6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutati ons uncharacterized(10). In this study, we report a novel type of dise ase-causing mutation, an unstable 15- to 18-mer minisatellite repeat e xpansion in the putative promoter region of the CST6 gene. The mutatio n accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length o f the repeat array differs between chromosomes and families, but chang es in repeat number seem to be comparatively rare events.