Galanin pathogenic mutations in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatmen

Caractérisation de variants génétiques de vulnérabilité à l'épilepsie chez des familles Algériennes

A genetic component to epilepsy has been recognized since Antiquity and is well established through twin and familial aggregation studies, which provide convincing evidence for the heritability of epilepsy. Despite major advances in genetic studies, genetic epilepsies have not yet revealed all their secrets. This prospective study aimed to identify genetic variants of epilepsy, to document the genotype/phenotype correlations and inheritance patterns in multigenerational Algerian families. Genetic analyzes included exome sequencing, CGH-array and Southern blotting.We studied a family with a pair of monozygotic twins affected by temporal lobe epilepsy. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene encoding the galanin neuropeptide. This latter was found to act as a potent anticonvulsant and regulates epileptic seizures in animal models. However, until now its role in human epilepsy was not established. Functional analysis showed evidence that the mutant protein disrupts galanin signalling, and strongly supports GAL as the causal gene for the TLE in this family.We described a family with two siblings affected by temporal lobe epilepsy and psychiatric comorbidities. Exome sequencing identified a single nucleotide polymorphism in the RELN gene (rs55689103) whose mutations have been associated with epilepsy and schizophrenia.We identified two families with progressive myoclonus epilepsy type 1. Genetic studies by Southern blotting showed an expansion of dodecamer CCCCGCCCCGCG in EPM1 gene. In addition, two other families were analysed by CGH-array, but no pathogenic CNV was identified. The study of other multigenerational families would identify new genetic variants of epilepsy.L’existence d’une composante génétique dans l’épilepsie est connue depuis des années grâce aux études épidémiologiques de concordance entre jumeaux et d’agrégation familiale, qui fournissent des preuves convaincantes pour l'héritabilité de l'épilepsie. En dépit des avancées majeures des techniques d’exploration pangénomique, les épilepsies génétiques n’ont pas encore livré tous leurs secrets. Cette étude avait pour objectifs de caractériser des variants génétiques de vulnérabilité à l’épilepsie, d’étudier les modes de transmission et d’analyser les relations génotype/phénotype chez des familles Algériennes.Il s’agit d’une étude prospective menée au service de Neurologie du CHU d’Oran sur une période de 05 ans. Des familles multigénérationnelles comportant chacune au moins deux individus épileptiques ont participé à l’étude. Les analyses génétiques réalisées consistaient en un séquençage exomique de nouvelle génération, la technique de Southern Blot, et la recherche de variations du nombre de copies d’ADN (CNV) par la technique de CGH-array. Parmi les quarante familles ayant participé à l’étude, six ont bénéficié d’études génétiques. Ces études ont permis d’identifier une mutation de novo (p.A39E) dans le gène GAL codant pour le neuropeptide galanine chez des jumeaux monozygotes atteints d’épilepsie du lobe temporal (ELT). Le rôle du peptide Galanine dans la régulation du processus d’épileptogénèse a été démontré il y a plus de deux décennies sur des modèles animaux, mais à ce jour, aucune mutation GAL en rapport avec un phénotype épileptique n’avait été décrite chez l’Homme. Nous avons complété l’étude génétique par des analyses in silico qui ont confirmé l’hypothèse de causalité de la mutation identifiée, et corrélé le génotype au phénotype dans cette famille. Nos résultats pourraient avoir des retombées directes sur le développement de molécules antiépileptiques à base de galanine et de traitements par thérapie génique. Nous avons analysé une deuxième famille au phénotype d’ELT et comorbidités psychiatriques. Le séquençage exomique a mis en évidence un variant (rs55689103) du gène RELN déjà incriminé dans l’épilepsie et la schizophrénie. Nous avons identifié deux autres familles au phénotype d’épilepsie myoclonique progressive de type 1. L’étude génétique par Southern Blot a confirmé l’expansion du dodécamère CCCCGCCCCGCG dans le gène EPM1. Par ailleurs, deux autres familles ont été analysées par CGH-array, mais aucun CNV pathogène n’a été identifié par cette technique. L’étude d’autres familles multigénérationnelles permettrait d'identifier de nouveaux variants génétiques des épilepsies

Fibrodysplasia ossificans progressiva: a case report and literature review

IntroductionFibrodysplasia Ossificans Progressiva (FOP) is an extremely rare genetic disease characterized by heterotopic ossification of muscles and connective tissue occurring in relapses, which can lead to the creation of a real second skeleton. The rarity of this disease is responsible for a delay in diagnosis of several years. FOP is described mainly in young children; cases with a late onset are extremely rare. ObservationWe report a case of late-onset Fibrodysplasia Ossificans Progressiva and we discuss clinical, radiological and genetic aspects, as well as treatment and outcomes

Manifestations neurologiques de la COVID-19 : Revue de littérature: Neurological Manifestations of COVID-19: A systematic review

SARS-CoV-2, the viral agent of COVID-19 primarily affects the respiratory and cardiovascular system. However, neurological damage is not uncommon and can lead to serious complications if it is not diagnosed and taken care too early. The most common neurological manifestations encompasses headache, encephalopathy, stroke and Guillain Barré syndrome. Through this literature review, we discuss the mechanisms of penetration of the SARS-CoV-2 virus into the nervous system, and we report the central and peripheral neurological manifestations of COVID-19 infection. Le virus SARS-CoV-2, responsable de la COVID-19 affecte principalement le système respiratoire et cardiovasculaire. Cependant, l’atteinte neurologique n’est pas rare et peut entraîner des complications graves si elle n’est pas diagnostiquée et prise en charge précocement. Les manifestations neurologiques les plus fréquentes sont les céphalées, l’encéphalopathie, les accidents vasculaires cérébraux et le syndrome de Guillain Barré. A travers cette revue de littérature, nous discutons les mécanismes de dissémination du virus SARS-CoV-2 dans le système nerveux, et nous rapportons les manifestations neurologiques centrales et périphériques liées à l’infection COVID-19

Familial epilepsy in Algeria: Clinical features and inheritance profiles

To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families

Disease-Modifying Therapies, Outcomes, Risk Factors and Severity of COVID-19 in Multiple Sclerosis: A MENACTRIMS Registry Based Study

International audienceMultiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data in our Middle East and North Africa region (MENA) identifying clinical characteristics of MS associated with worse COVID-19 outcomes

Safety and Efficacy of Disease Modifying Therapies After Switching from Natalizumab: A MENACTRIMS Observational Study

International audienc

Galanin pathogenic mutations in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment