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Folates et pathologies du neurodéveloppement : autisme et anomalies de fermeture du tube neural

Abstract : Folates are essentials vitamins in children neurodevelopment with an implication in two pathologies : autism and neural tube defects (NTD). Folates deficiency and some polymorphisms of genes involved in one carbon metabolism (OCM) are associated with NTD. Contrary, periconceptional folate supplementation is associated with decreased NTD frequency.In autism, higher frequency of antibodies against Folate Receptor Alpha (FR alpha) is rapported and associated with folates cerebral deficiency. Folinic acid treatment could improve autistic symptoms by correcting cerebral folate deficiency (cerebral transport mediated by RFC, an other receptor which not blocked by antibodies anti-FR alpha). First part is a randomized controlled trial versus placebo realized in CHU of Nancy in order to evaluate efficiency of folinic acid treatment during 12 weeks on autistic symptoms. 19 children have been included in the study. A significative improvement of autistic symptoms is observed by ADOS score in folinic acid group (p= 0.02) and particularly for mutual social interactions (p=0.012). FRalpha antibodies are present in 58 % of the group. We didn’t observed correlation between antibodies titers and folinic acid response. No serious adverse effects have been observed during the study. Second part is hight throughput next generation sequencing of DNA from patients with NTD using SureSelect Focused Exome Plus (Agilent®). Sequencing has been completed with DNA methylation analysis (Infinium HumanMethylation Beadchip (Illumina®)). 23 patients were included in the study. Six variants have been associated with NTD: from genes of B12 metabolism LRP2, rs137983840, p=0.005; MMAA, rs148142853, p= 0.005 and TCN2, rs35838082, p=0.044), folate cellular metabolism (FPGS, rs41306702, p=0.0012; choline metabolism, BHMT, rs763726268, p= 0.011) and Sonic Hedgehog pathway(SHH) (GLI3, rs35364414, p=0.012). A significative difference of methylation is identified in the vicinity of CFAP46 gene (hemimethylation versus no methylation in pseudo-controls) in one patient exhibited variants of BHMT, LRP2etMMAA. These results highlight implication of folates in these two pathologies of neurodevelopment, wich are autism and NTD. Anti-FRalpha should be routinely evaluated in case of autism in order to propose folinic acid treatment if they are positives. In the NTD study, we identified new variants from gene from one carbon metabolism probably implicated. A new candidate gene is identified (GLI3) and a methylation signature in association with B12 metabolism and OCM gene variants
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Émeline Renard. Folates et pathologies du neurodéveloppement : autisme et anomalies de fermeture du tube neural. Biologie du développement. Université de Lorraine, 2018. Français. ⟨NNT : 2018LORR0279⟩. ⟨tel-02129845⟩



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