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In 1995, we mapped a gene for Lafora's progressive myoclonus epilepsy in chromosome 6q23-25. In 1997 and 1998, we reduced the size of the locus to 300 kb, and an international collaboration identified mutations in the protein tyrosine phosphatase gene. Here, we examine for heterogeneity through the admixture test in 22 families and estimate the proportion of linked families to be 75 to 85%. Extremely low posterior probabilities of linkage (Wi), exclusionary LOD scores, and haplotypes identify 4 families unlikely to be linked to chromosome 6q24.

We performed dynamic [ 18 F]fluoroteoxyglucose ([ 18 F]FDG) positron emission tomographic (PET) analyses in 8 patients. Rate constants of influx (K 1 * ), efflux (k 2 * ), phosphorylation (k 3 * ), and dephosphorylation (k 4 * ) were derived for the regions of interest (ROIs), which included (1) the hypometabolic epileptogenic regions and (2) the homologous regions in the contralateral hemispheres. In addition, the four constants were determined from at least one clearly defined (control) ROI from the same plane and its homologous contralateral ROI. Influx (K l * ) in the epileptogenic region was reduced in comparison with the contralateral ROI. Reductions in influx (K1 * ), which averaged 18 ± 13% (mean ± SD), [ 18 F]FDG phosphorylation (k 3 * ) (25± 20%), and brain glucose utilization rates (26 ± 10%) were observed in the epileptogenic region. Reductions in efflux were not statistically significant (k 2 * = 13 ± 28%) but were comparable in magnitude to the average reduction in K 1 * . No ipsilateral versus contralateral differences were seen for any rate constants measured outside the epileptogenic region. Influx correlated highly with phosphorylation in the epileptogenic region. Our data suggest that the hypometabolic epileptogenic focus seen in [ 18 F]FDG-PET studies is also a region of reduced blood-brain barrier glucose transporter activity and that reductions in phosphorylation are proportional to reductions in [ 18 ]FDG influx.

We recently analyzed under homogeneity a large pedigree from Belize with classic juvenile myoclonic epilepsy (JME). After a genome-wide search with 146 microsatellites, we obtained significant linkage between chromosome 6p markers, D6S257 and D6S272, and both convulsive and EEG traits of JME. Recombinations in two affected members defined a 40 cM JME region flanked by D6S313 and D6S258. In the present communication, we explored if the same chromosome 6p11 microsatellites also have a role in JME mixed with pyknoleptic absences. We allowed for heterogeneity during linkage analyses. We tested for heterogeneity by the admixture test and looked for more recombinations. D6S272, D6S466, D6S294, and D6S257 were significantly linked (Z{sub max} > 3.5) to the clinical and EEG traits of 22 families, assuming autosomal dominant inheritance with 70% penetrance. Pairwise Z{sub max} were 4.230 for D6S294 ({theta}{sub m=f} at 0.133) and 4.442 for D6S466 ({theta}{sub m=f} at 0.111). Admixture test (H{sub 2} vs. H{sub 1}) was significant (P = 0.0234 for D6S294 and 0.0128 for D6S272) supporting the hypotheses of linkage with heterogeneity. Estimated proportion of linked families, {alpha}, was 0.50 (95% confidence interval 0.05-0.99) for D6S294 and D6S272. Multipoint analyses and recombinations in three new families narrowed the JME locusmore » to a 7 cM interval flanked by D6S272 and D6S257. 44 refs., 3 figs., 4 tabs.« less

Summary: The chromosomal loci for seven epilepsy genes have been identified in chromosomes lq, 6p, 8q, 16p, 20q, 21q, and 22q. In 1987, the first epilepsy locus was mapped in a common benign idiopathic generalized epilepsy syndrome, juvenile myoclonic epilepsy (JME). Properdin factor or Bf, human leukocyte antigen (HLA), and DNA markers in the HLA-DQ region were genetically linked to JME and the locus, named EJM1, was assigned to the short arm of chromosome 6. Our latest studies, as well as those by White-house et al., show that not all families with JME have their genetic locus in chromosome 6p, and that childhood absence epilepsy does not map to the same EJM1 locus. Recent results, therefore, favor genetic heterogeneity for JME and for the common idiopathic generalized epilepsies. Heterogeneity also exists in benign familial neonatal convulsions, a rare form of idiopathic generalized epilepsy. Two loci are now recognized; one in chromosome 20q (EBN1) and another in chromosome 8q. Heterogeneity also exists for the broad group of debilitating and often fatal progressive myoclonus epilepsies (PME). The gene locus (EPMI) for both the Baltic and Mediterranean types of PME or Unverricht-Lundborg disease is the same and is located in the long arm of chromosome 21. Lafora type of PME does not map to the same EPMI locus in chromosome 21. PME can be caused by the juvenile type of Gaucher's disease, which maps to chromosome lq, by the juvenile type of neuronal ceroid lipofuscinoses (CLN3), which maps to chromosome 16p, and by the “cherry-red-spot-myoclonus” syndrome of Guazzi or sialidosis type I, which has been localized to chromosome 10. A point mutation in the mitochondrial tRNALys coding gene can also cause PME in children and adults (MERFF).