Universität zu Köln

Hardies, Katia, de Kovel, Carolien G. F., Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Asselbergh, Bob ORCID: 0000-0003-2784-2470, Geuens, Thomas ORCID: 0000-0002-1764-6233, Deconinck, Tine, Azmi, Abdelkrim, May, Patrick ORCID: 0000-0001-8698-3770, Brilstra, Eva, Becker, Felicitas, Barisic, Nina, Craiu, Dana, Braun, Kees P. J., Lal, Dennis, Thiele, Holger, Schubert, Julian, Weber, Yvonne, van't Slot, Ruben, Nuernberg, Peter, Balling, Rudi ORCID: 0000-0003-2902-5650, Timmerman, Vincent ORCID: 0000-0002-2162-0933, Lerche, Holger, Maudsley, Stuart, Helbig, Ingo ORCID: 0000-0001-8486-0558, Suls, Arvid ORCID: 0000-0003-0328-198X, Koeleman, Bobby P. C. and De Jonghe, Peter (2015). Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain, 138. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hardies, Katia UNSPECIFIED UNSPECIFIED UNSPECIFIED de Kovel, Carolien G. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weckhuysen, Sarah UNSPECIFIED orcid.org/0000-0003-2878-1147 UNSPECIFIED Asselbergh, Bob UNSPECIFIED orcid.org/0000-0003-2784-2470 UNSPECIFIED Geuens, Thomas UNSPECIFIED orcid.org/0000-0002-1764-6233 UNSPECIFIED Deconinck, Tine UNSPECIFIED UNSPECIFIED UNSPECIFIED Azmi, Abdelkrim UNSPECIFIED UNSPECIFIED UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Brilstra, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Felicitas UNSPECIFIED UNSPECIFIED UNSPECIFIED Barisic, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Craiu, Dana UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Kees P. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Schubert, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED van't Slot, Ruben UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Balling, Rudi UNSPECIFIED orcid.org/0000-0003-2902-5650 UNSPECIFIED Timmerman, Vincent UNSPECIFIED orcid.org/0000-0002-2162-0933 UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Maudsley, Stuart UNSPECIFIED UNSPECIFIED UNSPECIFIED Helbig, Ingo UNSPECIFIED orcid.org/0000-0001-8486-0558 UNSPECIFIED Suls, Arvid UNSPECIFIED orcid.org/0000-0003-0328-198X UNSPECIFIED Koeleman, Bobby P. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED De Jonghe, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-387897
DOI:	10.1093/brain/awv263
Journal or Publication Title:	Brain
Volume:	138
Date:	2015
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SODIUM-COUPLED DICARBOXYLATE; DE-NOVO MUTATIONS; NEURONAL CELLS; KETOGENIC DIET; LIFE-SPAN; ENCEPHALOPATHIES; GENES; ASTROCYTES; IDENTIFICATION; ORGANIZATION Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38789