Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

Julien Thévenon 1 Mathieu Milh 2 François Feillet 3, 4 Judith St-Onge 5 Yannis Duffourd 6 Clara Jugé 5 Agathe Roubertie 7 Delphine Heron 8 Cyril Mignot 8 Emmanuel Raffo 9, 10 Bertrand Isidor 11 Sandra Wahlen 8 Damien Sanlaville 12 Nathalie Villeneuve 2 Véronique Darmency-Stamboul 13 Annick Toutain 14 Mathilde Lefebvre 15 Mondher Chouchane 16 Frédéric Huet 17 Arnaud Lafon 18 Anne De saint martin 19 Gaetan Lesca 20 Salima Chehadeh 6, 15 Christel Thauvin-Robinet 6 Alice Masurel-Paulet 15 Sylvie Odent 21 Laurent Villard 20 Christophe Philippe 22 Laurence Faivre 15 Jean-Baptiste Rivière 6
Abstract : Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.
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American Journal of Human Genetics, Elsevier (Cell Press), 2014, 95 (1), pp.113 - 120. 〈10.1016/j.ajhg.2014.06.006〉
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Julien Thévenon, Mathieu Milh, François Feillet, Judith St-Onge, Yannis Duffourd, et al.. Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life. American Journal of Human Genetics, Elsevier (Cell Press), 2014, 95 (1), pp.113 - 120. 〈10.1016/j.ajhg.2014.06.006〉. 〈hal-01668025〉

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