Search

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.

SummaryChildhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%–15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected–pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3–4-Hz spike– and multispike–slow wave complexes were considered to be affected. Significant P values of .00000–.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval.

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 thank the families whose members have carried the burden of LD; without their cooperation this study would not have been possible. We also gratefully acknowledge the cooperation and assistance of Joan Spellman, Bernadette Sakamoto, and Susan G. Pietsch-Escueta, who helped recruit families and coordinate family studies. Our study was approved by the Human Subjects Protection Committee at the UCLA School of Medicine and the West Los Angeles DVA Medical Center. Each participating patient or, in the case of minors or deceased relatives, the responsible adult, signed an informed-consent form. Our project was supported by NIH-NINDS program project 5PO1-NS21908 (to A.V.D.-E.), by special contributions from Mrs. A. Malenfant and the Quebec Lafora's Disease Organization, and by Mrs. Vera Faludi of Sweden.

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

A delayed match-to-sample (DMS) task of abstract, visual memory was performed during the uptake period of 18F-fluorodeoxyglucose. The increase in glucose uptake of cortical and subcortical regions ("activation") during the DMS task was compared with that during a control, immediate match-to-sample task using positron emission tomography. Both discriminant analysis and paired t tests supported the observation that the dorsolateral prefrontal area underwent the greatest activation, while a factor analysis revealed the functional correlation matrices of the tasks. Activations in the ventral premotor cortex and supramarginal and angular gyri were highly correlated with the change in the dorsolateral prefrontal cortex. The basal forebrain/ventral pole region showed a smaller but independently significant change. The findings support the role of the dorsal prefrontal region in the nonspatial working memory of humans.

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).

• A 27-year-old man developed delayed cerebral radiation necrosis following proton beam therapy to an arteriovenous malformation. Neuroimaging with technetium 99m diethylenetriamine penta-acetic acid and positron emission tomographic scanning with fludeoxyglucose F 18 aided in his evaluation. Significant improvement of his neurologic deficits resulted from corticosteroid therapy. Clinical resolution was corroborated by serial computed tomographic scans demonstrating regression of the abnormality (a mass lesion). Various facets of radiation injury are discussed, including pathogenesis, risk factors, diagnosis, and therapy.

It is generally believed that patients with primary generalized epilepsy have normal cognition and neuroimaging studies.We have previously shown that patients with juvenile myoclonic epilepsy (JME) have impaired visual working memory. In this study we examined relative regional changes in18 FDG uptake during a visual working memory paradigm in patients with JME. At rest, there were regional decreases in relative glucose uptake compared to controls. Unlike control subjects, increased activity in the dorsolateral prefrontal cortex was not found during the working memory task. Other regions with increased uptake in controls, such as premotor cortex and basal frontal cortex, also showed no increases, whereas medial temporal structures appeared to play a role in JME but not in control subjects' task performance. The data suggest that JME, a type of primary generalized epilepsy, may suffer from cortical disorganization that affects both the epileptogenic potential and frontal lobe cognitive functioning.NEUROLOGY 1996;47: 1203-1212

Sumary Twenty-two patients whose electroclinical ictal characeristics suggested frontal lobe seizure foci were studied. Computed tomography (CT) scans showed abnormalities in only 32% of patients whereas magnetic resonance imaging was informative in 45%. 18FDG-Positron emission tomography (PET) scanning revealed decreased metabolism in 64% of the group. The areas of hypometabolism were focal, regional, or hemispheric. Focal frontal hypometabolism was significantly correlated with the electroclinical (semiologic) ictal localization. Therefore, FDG-PET scanning is a sensitive and specific technique for investigating patients with seizures of probable frontal lobe origins. RESUME 22 patients presentant des pheitomenes electro-cliniques evocateurs de l'origine focale frontale des crises ont eteetudies. La tomodensitometrie a mis en evidence des anomalies chez suelement 32% des patients, contre 45% pour la RMN. Le PET-SCAN au FDG 18 a mis en evidence une diminution du metabolisme chez 64% des patients. Les zones d'hypometabolisme etaient focales, regionales ou hemispheriques. l'hypometabolisme frontal focal a pu etre significativement coirele avec la localisation electroclinique (semeiologique) des crises. Les auteurs demontrent ainsi que le PET-SCAN au FDG 18 est une technique d'evaluation sensible et specique pour les patients presentant des crises partielles d'origine frontale probable. RESUMEN Se han estudiado 22 pacientes con characteristicas ictales electroclinicas que surgerian la existencia de ataques focales de lobulo frontal. La Tomografia Computarizada mostro anomalias solamente en el 32% de los enfermos mientras que la Resonancia Magnetica ofrecio informacion en el 45%. Los scanner con FDG-PET revelaron una reduccion del metabolismo en el 64% de los casos. Las areas de hipometabolismo eran focales, regionales o hemisfericas. El hipometabolismo focal frontal se correlaciono significativamente con la localizacion electroclinica (semiologica) ictal. Por lo tanto, el FDG-PET es una tecnica sensible y especifica para la investigacion de pacientes con ataques de probable origen en el lobulo frontal. ZUSAMMENFASSUNG 22 Patienten, deren iktales-EEG auf einen Fokus im Frontallappen schliesen lies, wurden untersucht. Das CAT zeigte Auffalligkeiten bei 32%, das NMR bei 45% der Patienten. Das 78 FDG-PET entdeckte bei 64% der Patienten einen verminderten Metabolismus. Die Legalisation des Hypometabolismus war fokal, regional oder hemispharisch Der frontale Hypometabolismus war signifikant mit den iktalen elektroklinischen Befunden korreliert. Deshalb stellt das FDG-PET eine sensible, spezifische Technik dar, um Patienten mit Anfallen, moglicherweise firon-taler Genese, zu untersuchen.