PME of Unverricht-Lundborg type in the Mediterranean region: linkage and linkage disequilibrium confirm the assignment to the EPM1 locus

Abstract

Seven phenotypically homogeneous Mediterranean myoclonus families were studied using DNA markers from the genetically defined EPM1 region on chromosome 21. No recombinations between the disease phenotype and the markers studied were detected. Within the EPM1 region, the highest lod score value of 5.07 (at theta = 0.00) was reached at locus PFKL. Significant allelic association (P = 0.02) between the disease mutation and PFKL was detected suggesting a founder effect in Mediterranean myoclonus. However, haplotype data using four marker loci residing within 300 kb of each other and of EPM1 suggest the occurrence of more than one mutation. The data are compatible with Mediterranean myoclonus being caused by mutations in the EPM1 gene and strengthen the concept that a large subset of progressive myoclonus epilepsies conforms with Unverricht-Lundborg disease and that this subset is an etiologically homogeneous entity.

Familial Unverricht‐Lundborg Disease: A Clinical, Neurophysiologic, and Genetic Study

“…Based on less informative restriction fragment length polymorphism (RFLP) markers, however, the Finnish haplotype was seen earlier in another Italian family (16). These findings might suggest the existence of one very old EPMl mutation in the Finnish and Italian populations.…”

Autosomal recessive progressive myoclonus epilepsy with ataxia and mental retardation

“…Blood samples were taken in 50 mM EDTA for DNA analysis from all patients and 8 unaffected family members. Linkage to 21q region was studied with markers CBS, PFKL and D21S171 [6], and to 6q with markers D6S1049, D6S1703, D6S1042 and D6S311 [7].…”

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

“…Other cis-acting elements include the composition and number of repeats. EPM1 is similar to many other repeat expansion disorders in that the mutant alleles have common haplotypes in several different populations, presumably due to a founder effect (Lehesjoki et al, 1993b(Lehesjoki et al, , 1994Richards, 2001;Moulard et al, 2002). Recently it was shown in mice that changing the flanking genomic sequences of the SCA7 CAG repeat dramatically altered repeat stability (Libby et al, 2003).…”

“…Comparable studies of Mediterranean EPM1 predicted a similar founder effect in Mediterranean myoclonus and a common Mediterranean EPM1 mutation(s). It was not clear whether this was the same as the Baltic myoclonus mutation (Lehesjoki et al, 1994;Labauge et al, 1997;Parmeggiani et al, 1997).…”