2. Academic Validation
  3. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

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

  • Brain. 2015 Nov;138(Pt 11):3238-50. doi: 10.1093/brain/awv263.
Katia Hardies 1,  Carolien G F de Kovel 2,  Sarah Weckhuysen 3,  Bob Asselbergh 4,  Thomas Geuens 5,  Tine Deconinck 1,  Abdelkrim Azmi 6,  Patrick May 7,  Eva Brilstra 2,  Felicitas Becker 8,  Nina Barisic 9,  Dana Craiu 10,  Kees P J Braun 2,  Dennis Lal 11,  Holger Thiele 11,  Julian Schubert 8,  Yvonne Weber 8,  Ruben van 't Slot 2,  Peter Nürnberg 12,  Rudi Balling 13,  Vincent Timmerman 5,  Holger Lerche 8,  Stuart Maudsley 14,  Ingo Helbig 15,  Arvid Suls 1,  Bobby P C Koeleman 2,  Peter De Jonghe,  autosomal recessive working group of the EuroEPINOMICS RES Consortium
Affiliations

Affiliations

  • 1 1 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 2 3 Departments of Medical Genetics and Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 3 1 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 4 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Centre de reference épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, Paris, France.
  • 4 5 VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
  • 5 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 6 Peripheral Neuropathy Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
  • 6 7 Translational Neurobiology Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
  • 7 8 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg 9 Institute for Systems Biology, Seattle, USA.
  • 8 10 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany.
  • 9 11 Division for Child Neurology, Department of Pediatrics, Clinical Medical Centre Zagreb, University of Zagreb Medical School, Zagreb, Croatia.
  • 10 12 Pediatric Neurology Clinic Al Obregia Hospital, Bucharest, Romania 13 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
  • 11 14 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 12 14 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany 15 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany 16 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • 13 8 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg.
  • 14 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 7 Translational Neurobiology Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
  • 15 17 Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany 18 Division of Neurology, The Children's Hospital of Philadelphia, Philadephia, USA.
PMID: 26384929 DOI: 10.1093/brain/awv263
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.

Keywords

NaCT; SLC13A5; anaplerosis; epileptic encephalopathy; recessive disorder; teeth hypoplasia.

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