Particularites de l’epilepsie au cours des maladies inflammatoires du systeme nerveux central

Introduction : Les crises épileptiques (CE) font partie des manifestations neurologiques des maladies inflammatoires (MI). Elles constituent un tournant évolutif grave de la maladie. Objectifs : Nous avons évalué les particularités sémiologiques, électriques, radiologiques, thérapeutiques et évolutives de l’épilepsie au cours des MI du système nerveux central (SNC). Nous avons également discuté les mécanismes physiopathologiques de l’épilepsie ainsi que les facteurs prédictifs de survenue de CE chez ces patients. Méthodes : C’est une étude rétrospective incluant les patients suivis pour épilepsie dans le cadre d’une MI du SNC. Tous nos patients ont bénéficié d’une imagerie cérébrale. Résultat : Nous avons colligé 32 patients (11 avec sclérose en plaque, 6 avec maladie de Behcet et 15 avec lupus érythémateux disséminé). Le délai des CE au cours des MI était de 3,2 ans. Elles étaient généralisées dans 62,5 % des cas. L’IRM a montré des lésions sous corticales et des lésions du tronc cérébral respectivement dans 71,8 % et 25% des cas. Une thrombose veineuse cérébrale était diagnostiquée chez 3 malades. L’EEG a objectivé des ondes lentes dans 34% des cas, et des anomalies paroxystiques chez 3 patients. Le phénobarbital était le traitement le plus prescrit. Le contrôle des CE était obtenu dans la majorité des cas. Conclusion : La survenue des CE au cours des MI pose un problème de prise en charge. Un diagnostic précoce et un traitement de l’épilepsie permettent de contrôler ces crises afin d’éviter les états de mal épileptiques qui mettent en jeu le pronostic vital des patients. Mots clés: Epilepsie, Facteurs de risque, Maladies inflammatoires  Particularities of epilepsy associated with inflammatory diseases of the central nervous systemIntroduction: The frequency of the central nervous system involvement in autoimmune disorders is very variable. Seizures are among the most common neurological manifestations, and can be occasionally the presenting symptom.Methods: All files of 32 patients with autoimmune disorder diagnosed with epilepsy were evaluated retrospectively (11 with multiple sclerosis, 6 with Behcet disease, and 15 systemic lupus erythematosus). The demographic data, clinical findings including seizures, EEG and neuroimaging findings were reviewed. Results: The sex ratio was 0.45 (10H / 22F). Seizures started 3.2 years after the onset of the inflammatory diseases. They were during either the first or following neurological attacks in 68.7% of cases. 20 patients (62,5%) had only generalized tonic-clonic seizures. Brain magnetic resonance imaging (MRI) was performed to all patients. Sub-cortical and brainstem lesions were identified respectively in 71,8 % and 25%. MRI revealed cerebral sinus thrombosis in three patients. The EEG revealed focal epileptiform discharges in three patients. In 12 patients (34%) slow waves were seen. Antiepileptic drugs were prescribed in all cases (phenobarbital :53%, valproic acid: 31%, Carbamazepine: 15%). A sufficient control of seizures was obtained in most cases. Conclusion: Seizures often complicate systemic autoimmune disorders through a variety of mechanisms. A better understanding of the mechanisms of epileptogenesis in those patients could lead to targeted treatments and better outcomes. Key words: Epilepsy, inflammatory disease, risk factor

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p