A novel locus for generalized epilepsy with febrile seizures plus in French families.

International audienceBACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS(+)) is a familial autosomal dominant entity characterized by the association of febrile and afebrile seizures. Mutations in 3 genes--the sodium channel alpha1 subunit gene (SCN1A), the sodium channel beta1 subunit gene (SCN1B), and the gamma2 GABA receptor subunit gene (GABRG2)--and linkage to 2 other loci on 2p24 and 21q22 have been identified in families with GEFS(+), indicating genetic heterogeneity. OBJECTIVES: To localize by means of linkage analysis a new gene for GEFS(+) in a large family with 11 affected members and to test the new locus in 4 additional families with GEFS(+). DESIGN: Family-based linkage analysis. SETTING: University hospital. PATIENTS: Five French families with GEFS(+) and at least 7 available affected members with autosomal dominant transmission. All the patients had febrile seizures and/or afebrile generalized tonic-clonic seizures or absence epilepsy. MAIN OUTCOME MEASURES: We analyzed 380 microsatellite markers and conducted linkage analysis. RESULTS: In the largest family, a 10-cM-density genomewide scan revealed linkage to a 13-Mb (megabase) interval on chromosome 8p23-p21 with a maximum pairwise logarithm of odds (LOD) score of 3.00 (at Theta = 0) for markers D8S351 and D8S550 and a multipoint LOD score of 3.23. A second family with GEFS(+) was also possibly linked to chromosome 8p23-p21 and the region was narrowed to a 7.3-Mb candidate interval, flanked by markers D8S1706 and D8S549. We have not, so far, identified mutations in the coding exons of 6 candidate genes (MTMR9, MTMR7, CTSB, SGCZ, SG223, and ATP6V1B2) located in the genetic interval. CONCLUSIONS: We report a sixth locus for GEFS(+) on chromosome 8p23-p21. Because no ion channel genes are located in this interval, identification of the responsible gene will probably uncover a new mechanism of pathogenesis for GEFS(+)

Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism

11 páginas, 8 figuras, 1 tabla.Lafora disease is a fatal autosomal recessive form of progressive myoclonus epilepsy. Patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in adolescence. The two genes known to be involved in Lafora disease are EPM2A and NHLRC1 (EPM2B). The EPM2A gene encodes laforin, a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. Here, we report three Lafora families with two novel pathogenic mutations (C46Y and L261P) and two recurrent mutations (P69A and D146N) in NHLRC1. Investigation of their functional consequences in cultured mammalian cells revealed that malin(C46Y), malin(P69A), malin(D146N), and malin(L261P) mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis. Abnormal accumulation of intracellular glycogen was observed with all malin mutants, reminiscent of the polyglucosan inclusions (Lafora bodies) present in patients with Lafora disease.Peer reviewe

Malignant catatonia due to anti-NMDA-receptor encephalitis in a 17-year-old girl: case report

Anti-NMDA-Receptor encephalitis is a severe form of encephalitis that was recently identified in the context of acute neuropsychiatric presentation. Here, we describe the case of a 17-year-old girl referred for an acute mania with psychotic features and a clinical picture deteriorated to a catatonic state. Positive diagnosis of anti-NMDA-receptor encephalitis suggested specific treatment. She improved after plasma exchange and immunosuppressive therapy. Post-cognitive sequelae (memory impairment) disappeared within 2-year follow-up and intensive cognitive rehabilitation

Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism

Mutations and Deletions in PCDH19 Account for Various Familial or Isolated Epilepsies in Females

Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene. Fifteen novel point mutations were identified in 15 female patients (6 sporadic and 9 familial cases). In addition, qPCR revealed two whole gene deletions and one partial deletion in 3 sporadic female patients. Clinical features were highly variable but included almost constantly a high sensitivity to fever and clusters of brief seizures. Interestingly, cognitive functions were normal in several family members of 2 families: the familial condition in family 1 was suggestive of Generalized Epilepsy with Febrile Seizures Plus (GEFS+) whereas all three affected females had partial cryptogenic epilepsy. These results show that mutations in PCDH19 are a relatively frequent cause of epilepsy in females and should be considered even in absence of family history and/or mental retardation. © 2010 Wiley-Liss, Inc

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable

ETUDE DE L'EXPRESSION DU GENE IMPLIQUE DANS LA MALADIE DE HUNTINGTON ET DES CONSEQUENCES DE LA MALADIE SUR LE FONCTIONNEMENT DES GANGLIONS DE LA BASE

LORSQUE NOUS AVONS DEBUTE CE TRAVAIL, LE GENE (IT15) ET LA MUTATION IMPLIQUES DANS LA MALADIE DE HUNTINGTON ETAIENT IDENTIFIES DEPUIS PEU. NOTRE PREMIER OBJECTIF A ETE D'ETUDIER L'EXPRESSION DU GENE IT15 SUR CERVEAU HUMAIN POST-MORTEM DANS LES CONDITIONS NORMALES ET DANS LE MALADIE DE HUNTINGTON. L'UTILISATION D'ANTICORPS SPECIFIQUES NOUS A PERMIS D'ETUDIER SEPAREMENT A L'ECHELON CELLULAIRE L'EXPRESSION DE LA HUNTINGTINE NORMALE ET MUTEE ET DE METTRE EN EVIDENCE DANS LE CERVEAU DES PATIENTS ATTEINTS PAR LA MALADIE, DES PROCESSUS COMPLEXES DE DELOCALISATION, D'AGREGATION ET DE DEGRADATION DE LA HUNTINGTINE DONT L'IMPORTANCE SEMBLE TRES VARIABLE SELON LES REGIONS CEREBRALES. CES PHENOMENES SONT-ILS CAUSE OU CONSEQUENCES DU DYSFONCTIONNEMENT NEURONAL ACCOMPAGNANT LE PROCESSUS NEURODEGENERATIF OBSERVE DANS LA MALADIE ? CECI RESTE A DETERMINER MAIS CONSTITUE UNE VOIE DE RECHERCHE INTERESSANTE POUR L'ELABORATION DE NOUVELLES STRATEGIES THERAPEUTIQUES. NOTRE SECOND OBJECTIF A ETE D'ETUDIER QUELLES SONT LES CONSEQUENCES LA MALADIE DE HUNTINGTON SUR LE FONCTIONNEMENT NORMAL DES GANGLIONS DE LA BASE. POUR CELA, NOUS AVONS ETUDIE EN HYBRIDATION IN SITU UN MARQUEUR DE L'ACTIVITE NEURONALE : L'EXPRESSION DES ARN MESSAGERS DE LA SOUS-UNITE I DE LA CYTOCHROME OXYDASE. NOS RESULTATS NE CONCORDENT PAS AVEC CEUX QUE PREVOYAIT LE MODELE DE FONCTIONNEMENT DE GANGLIONS DE LA BASE ELABORE DANS LES ANNEES 90. NOTAMMENT, NOUS METTONS EN EVIDENCE UNE ATTEINTE IMPORTANTE, AU MOINS A UN NIVEAU FONCTIONNEL, DU GLOBUS PALLIDUS EXTERNE ET INTERNE SUGGERANT QUE LES MOUVEMENTS CHOREIQUES OBSERVES DANS LA MALADIE SONT SOUS-TENDUS PAR DES MECANISMES PHYSIOPATHOLOGIQUES PLUS COMPLEXES QUE CEUX INITIALEMENT IMAGINES. ENFIN, NOUS AVONS ETUDIE UN MODELE MURIN TRANSGENIQUE DE LA MALADIE DE HUNTINGTON ET AVONS CONTRIBUE A CARACTERISER L'ATTEINTE NEURONALE OBSERVEE DANS CE MODELE. UNE IMPORTANTE ATTEINTE DES NEURONES GABAERGIQUES DU CORTEX CEREBRAL, ET DES STRUCTURES DE SORTIE DES GANGLIONS DE LA BASE (GLOBUS PALLIDUS, NOYAU ENTOPEDONCULAIRE ET SUBSTANTIA NIGRA PARS RETICULATA) EST OBSERVEE ALORS QU'AUCUNE ANOMALIE N'EST OBSERVEE DANS LE STRIATUM DANS CE MODELE. NOUS ESPERONS QUE CE TRAVAIL CONTRIBUERA A UNE MEILLEURE CONNAISSANCE DES MECANISMES PHYSIOPATHOLOGIQUES QUI SOUS-TENDENT LA MALADIE DE HUNTINGTON.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Implication du récepteur nicotinique à l acétylcholine dans l épilepsie frontale nocturne et les parasomnies (étude clinique et génétique de 22 familles)

L épilepsie frontale nocturne autosomique dominante (EFNAD) est une épilepsie rare, non lésionnelle, d origine génétique caractérisée par des crises partielles d origine frontale, survenant avec prédilection durant le sommeil et qui débutent généralement dans l enfance ou l adolescence. Il a été rapporté une prévalence importante des parasomnies du sommeil lent dans ces familles sans que la raison en soit connue. A ce jour, 8 mutations dans 3 gènes codant pour les sous-unités neuronales a4, b2 et a2 des récepteurs nicotiniques à l acétylcholine (nAChR) ont été identifiées dans ce syndrome. Notre travail a consisté à identifier de nouvelles familles atteintes d EFNAD, à étudier le spectre et la fréquence des mutations dans l ensemble des sous-unités neuronales du nAChR dans ces familles, et enfin d examiner la ségrégation des éventuels variants trouvés avec les parasomnies dans ces familles ce qui pourrait suggérer des bases génétiques communes aux 2 pathologies.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF