NORD gratefully acknowledges Kim Nye, President, Brenda Porter, MD PhD, Scientific Advisor, and Deepti Dubey, PhD, Scientific Officer, TESS Research Foundation, for the preparation of this report.
SLC13A5 deficiency is a rare autosomal recessive disorder. It is a newly diagnosed form of infantile epilepsy and developmental delays with seizures beginning within the first days of life. This rare form of epileptic encephalopathy is due to changes (mutations) in SLC13A5 gene. A handful of reports on children with mutations in SLC13A5 gene (Solute Carrier family 13 member 5) have been published, and we have only begun to understand the neurologic and epileptic characteristics (phenotype) in these children (Thevenon et al, 2014; Hardies et al, 2015; Klotz et al, 2016; Schossig et al, 2017; Weeke et al, 2017).
Affected children present with seizures beginning within a few days of birth which persist throughout life. They show difficulty with speech production, limited and slow motor progress with problems standing or walking independently. Problems with tone are also reported with episodes of body stiffening and weakening. Almost all the affected children have abnormalities in their tooth enamel. Brain MRIs appear normal or have subtle changes in the white matter (Weeke et al, 2017). This disorder is caused by mutations in both copies of the SLC13A5 gene which codes for a sodium dependent citrate transporter. To date all tested mutations result in no or a very reduced amount of the citrate transporter in the cells (Thevenon et al, 2014; Hardies et al, 2015; Klotz et al, 2016; Weeke et al, 2016).
Because this is a rare disorder and very few patients have been diagnosed with this disease, the full extent of symptoms is yet to be described. However, there are several symptoms that are common in the majority of children diagnosed with SLC13A5 deficiency:
• Seizures beginning within first few days of birth
• Persistent seizures of multiple types
• Severe expressive language delay, with better receptive language
• Low muscle tone (hypotonia) and a lack of muscle control or coordination of voluntary movements, such as walking or picking up an object (ataxia)
• Episodes of body stiffening or weakness lasting a few minutes to a few hours
• Poor development of teeth (hypodontia) or weakness of teeth enamel
• Brain MRI that appears normal or has subtle changes in the white matter
• Mildly elevated Citrate levels in blood
The disease phenotype is variable and even siblings with same genetic mutation show differences in the symptoms including type and frequency of seizures, time course of developmental milestones (Anselm et al, 2015).
SLC13A5 deficiency is caused by mutations in SLC13A5 gene located on chromosome 17 in humans. This is a genetically inherited disorder and the mode of inheritance is autosomal recessive, meaning the disease manifests itself only when the child inherits mutant copies of this gene from both parents. If a child inherits one mutant copy and one normal copy, he/she will not show symptoms of the disease but will be a carrier of the disease and is at risk for having a child with the disorder.
SLC13A5 mutations described to date result in no or a reduced amount of citrate transporter activity. Citrate is a key metabolite and is known to play an important role in the energy generation pathways in the cells. In addition, it could also be involved in regulating the concentration of other ions inside and outside of the cells due to its chelating properties (Bhutia et al., 2017). Although SLC13A5 transporter is extensively studied in liver cells, the function of this transporter in the human brain is largely unknown. Studies are ongoing to understand the role of SLC13A5 in the human brain, and researchers hope to better understand the molecular mechanism underlying the neuronal dysfunction and epilepsy in this devastating disease soon.
This is a rare genetic disorder that affects both males and females equally. So far reports of about 50 patients have been published in various databases/ publications. These patients are from families with various ethnic backgrounds from the USA, European and South American countries.
Currently, the way to identify a citrate transporter disorder (SLC13A5 deficiency) as the cause of a child having intractable seizures is to look at the DNA sequence of the SLC13A5 gene. If both the copies of the patient’s SLC13A5 genes are mutated, it is considered to be disease causing. For diagnosis, either whole exome sequencing (WES) can be performed or targeted panel sequencing (SLC13A5 is included in many epilepsy panels) can be performed which is often less expensive and faster to get results.
Efforts are underway to find other methods of diagnosis with quick turn-around-time like high throughput metabolomic profiling of patient’s urine, blood plasma or CSF (cerebro-spinal fluid) (Bainbridge et al., 2017).
The first line of treatment in SLC13A5 deficiency is anti-seizure medications. Although anti-seizure medications have been successful in controlling seizures in some patients, most patients have limited success with the available drugs.
Research is underway to find better treatment options for SLC13A5 deficiency patients. Efforts are being made to create animal models mimicking the disease symptoms. These models will be used to better understand the mechanism of the disease, to discover new therapies targeted at SLC13A5 deficiency, and to screen for drug repurposing candidates.
Multiple seizure drugs have been tried with mixed benefit (efficacy) to manage symptoms of SLC13A5 deficiency (Hardies et al., 2015; Klotz et al., 2016; Weeke et al, 2017). Some investigational therapies like triheptanoin and ketogenic diet were hypothesized to help patients with SLC13A5 deficiency (Thevenon et al., 2014; Anselm et al, 2016; Klotz et al, 2016). There is only one clinical trial registered for SLC13A5 (https://clinicaltrials.gov/ct2/results?cond=SLC13A5) for triheptanoin and anecdotal evidence for informal trials of TCA cycle intermediates and supplements including magnesium and zinc. However, to date no clinical trial outcomes have been reported in the medical literature.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Anselm I, MacCuaig M, Prabhu SB, Berry GT. Disease Heterogeneity in Na(+)/Citrate Cotransporter Deficiency. JIMD Rep. 2017;31:107-111. doi: 10.1007/8904_2016_546. Epub 2016 Mar 10. Erratum in: JIMD Rep. 2017;31:113. PubMed PMID: 26960556; PubMed Central PMCID: PMC5388636.
Bainbridge MN, Cooney E, Miller M, Kennedy AD, Wulff JE, Donti T, Jhangiani SN, Gibbs RA, Elsea SH, Porter BE, Graham BH. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. Mol Genet Metab. 2017 Jun 24. pii: S1096-7192(17)30289-5. doi: 10.1016/j.ymgme.2017.06.009. [Epub ahead of print] PubMed PMID: 28673551.
Bhutia YD, Kopel JJ, Lawrence JJ, Neugebauer V, Ganapathy V. Plasma Membrane Na⁺-Coupled Citrate Transporter (SLC13A5) and Neonatal Epileptic Encephalopathy. Molecules. 2017 Feb 28;22(3). pii: E378. doi: 10.3390/molecules22030378. Review. PubMed PMID: 28264506.
Schossig A, Bloch-Zupan A, Lussi A, Wolf NI, Raskin S, Cohen M, Giuliano F, Jurgens J, Krabichler B, Koolen DA, de Macena Sobreira NL, Maurer E, Muller-Bolla M, Penzien J, Zschocke J, Kapferer-Seebacher I. SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome. J Med Genet. 2017 Jan;54(1):54-62. doi: 10.1136/jmedgenet-2016-103988. Epub 2016 Sep 6. PubMed PMID: 27600704.
Weeke LC, Brilstra E, Braun KP, Zonneveld-Huijssoon E, Salomons GS, Koeleman BP, van Gassen KL, van Straaten HL, Craiu D, de Vries LS. Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations. Eur J Paediatr Neurol. 2017 Mar;21(2):396-403. doi: 10.1016/j.ejpn.2016.11.002. Epub 2016 Nov 19. PubMed PMID: 27913086.
Klotz J, Porter BE, Colas C, Schlessinger A, Pajor AM. Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Mol Med. 2016 May 26;22. doi: 10.2119/molmed.2016.00077. PubMed PMID: 27261973; PubMed Central PMCID: PMC5023510.
Gürsoy S, Erçal D. Diagnostic Approach to Genetic Causes of Early-Onset
Epileptic Encephalopathy. J Child Neurol. 2016 Mar;31(4):523-32. doi:
10.1177/0883073815599262. Epub 2015 Aug 13. Review. PubMed PMID: 26271793.
Hardies K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, Azmi A, May P, Brilstra E, Becker F, Barisic N, Craiu D, Braun KP, Lal D, Thiele H, Schubert J, Weber Y, van ‘t Slot R, Nürnberg P, Balling R, Timmerman V, Lerche H, Maudsley S, Helbig I, Suls A, Koeleman BP, De Jonghe P; autosomal recessive working group of the EuroEPINOMICS RES Consortium. 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. Epub 2015 Sep 17. PubMed PMID: 26384929
Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Jugé C, Roubertie A, Héron D, Mignot C, Raffo E, Isidor B, Wahlen S, Sanlaville D, Villeneuve N, Darmency-Stamboul V, Toutain A, Lefebvre M, Chouchane M, Huet F, Lafon A, de Saint Martin A, Lesca G, El Chehadeh S, Thauvin-Robinet C, Masurel-Paulet A, Odent S, Villard L, Philippe C, Faivre L, Rivière JB. Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. Am J Hum Genet. 2014 Jul 3;95(1):113-20. doi: 10.1016/j.ajhg.2014.06.006. PubMed PMID: 24995870; PubMed Central PMCID: PMC4085634
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100