title: Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia.
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.
authors.affiliation: 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.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.affiliation: 3 Departments of Medical Genetics and Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: 5 VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geuens
authors.affiliation: 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.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: 7 Translational Neurobiology Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Azmi
authors.affiliation: 8 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg 9 Institute for Systems Biology, Seattle, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.affiliation: 3 Departments of Medical Genetics and Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Brilstra
authors.affiliation: 10 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: 11 Division for Child Neurology, Department of Pediatrics, Clinical Medical Centre Zagreb, University of Zagreb Medical School, Zagreb, Croatia.
authors.forename: Nina
authors.initials: N
authors.lastname: Barisic
authors.affiliation: 12 Pediatric Neurology Clinic Al Obregia Hospital, Bucharest, Romania 13 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Craiu
authors.affiliation: 3 Departments of Medical Genetics and Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kees P J
authors.initials: KP
authors.lastname: Braun
authors.affiliation: 14 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: 14 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: 10 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schubert
authors.affiliation: 10 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Weber
authors.affiliation: 3 Departments of Medical Genetics and Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van 't Slot
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 8 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg.
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.affiliation: 10 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: 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.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.affiliation: 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.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: 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.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: 3 Departments of Medical Genetics and Child Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
mesh_terms: D000293:Adolescent; D000848:Anodontia / Q000235:genetics*; D001927:Brain Diseases / Q000235:genetics; D002648:Child; D019343:Citric Acid / Q000378:metabolism*; D002658:Developmental Disabilities / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: C470492:SLC13A5 protein, human; D027981:Symporters; D019343:Citric Acid
keywords: NaCT; SLC13A5; anaplerosis; epileptic encephalopathy; recessive disorder; teeth hypoplasia