THE GENE FOR PROGRESSIVE MYOCLONUS EPILEPSY OF THE LAFORA TYPE MAPS TO CHROMOSOME 6Q

Progressive myoclonus epilepsy of the Lafora type (Lafora's disease) i s an autosomal recessive disease characterized by epilepsy, myoclonus, dementia, and periodic acid-Schiff-positive intracellular inclusion b odies. The inclusion deposits consist of branched polysaccharides (pol yglucosans) but the responsible biochemical defect has not been identi fied. Onset is during late childhood or adolescence and the disease le ads to a fatal outcome within a decade of first symptoms. We studied n ine families in which Lafora's disease had been proven by biopsy in at least one member. In order to locate the responsible gene, we screene d the human genome with microsatellite markers spaced an average of 13 cM. We used linkage analysis in all nine families and homozygosity ma pping in four consanguineous families to define the Lafora's disease g ene region. Two point linkage analysis resulted in a total peak lod sc ore of 10.54 for marker D6S311. Six additional chromosome 6q23-25 micr osatellites yielded lod scores ranging from 5.92 to 9.60 at theta(m=f) = 0. An extended pedigree with five affected members independently pr oved linkage with peak lod scores over 3.8 at theta(m=f) = 0 for D6S29 2, D6S403, and D6S311. The multipoint one-led-unit support interval co vered a 2.5 cM region surrounding D6S403. Homozygosity mapping defined a 17 cM region in chromosome 6q23-25 flanked by D6S292 and D6S420 tha t contains the Lafora's disease gene.