Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

Katia Hardies, Carolien G F De Kovel, Sarah Weckhuysen, Bob Asselbergh, Thomas Geuens, Tine Deconinck, Abdelkrim Azmi, Patrick May, Eva Brilstra, Felicitas Becker, Nina Barisic, Dana Craiu, Kees P J Braun, Dennis Lal, Holger Thiele, Julian Schubert, Yvonne Weber, Ruben Van 'T Slot, Peter Nürnberg, Rudi BallingVincent Timmerman, Holger Lerche, Stuart Maudsley, Ingo Helbig, Arvid Suls, Bobby P C Koeleman, Peter De Jonghe, Zaid Afawi, Stéphanie Baulac, Hande Caglayan, Rosa Guerrero Lopez, Renzo Guerrini, Helle Hjalgrim, Johanna Jähn, Karl Martin Klein, Eric LeGuern, Johannes Lemke, Carla Marini, Hiltrud Muhle, Felix Rosenow, Jose Serratosa, Katalin Štěrbová, Rikke S. Moller, Pasquale Striano, Federico Zara

Research output: Contribution to journalArticle

Abstract

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.

Original languageEnglish
Pages (from-to)3238-3250
Number of pages13
JournalBrain
Volume138
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Keywords

  • anaplerosis
  • epileptic encephalopathy
  • NaCT
  • recessive disorder
  • SLC13A5
  • teeth hypoplasia

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

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    Hardies, K., De Kovel, C. G. F., Weckhuysen, S., Asselbergh, B., Geuens, T., Deconinck, T., Azmi, A., May, P., Brilstra, E., Becker, F., Barisic, N., Craiu, D., Braun, K. P. J., Lal, D., Thiele, H., Schubert, J., Weber, Y., Van 'T Slot, R., Nürnberg, P., ... Zara, F. (2015). Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain, 138(11), 3238-3250. https://doi.org/10.1093/brain/awv263