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40 years!
Last updated:
12/21/2023
Years published: 2017, 2021
NORD gratefully acknowledges Kim Nye, President, Brenda Porter, MD, PhD, Scientific Advisor, Deepti Dubey, PhD, Scientific Officer, and Tanya Brown, PhD, Research Program Manager, TESS Research Foundation, for the preparation of this report.
Summary
SLC13A5 citrate transporter disorder is a recently identified autosomal recessive disorder. Patients with SLC13A5 citrate transporter disorder are initially identified by the multiple types of seizures that begin within the first week of life. This rare disease is due to changes (mutations) in SLC13A5 gene (solute carrier family 13, member 5). As we learn more about SLC13A5 citrate transporter disorder, the number of affected children described in the literature is increasing (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016; Schossig et al. 2017; Weeke et al. 2017; Yang et al. 2020; Matricardi et al. 2020). Additionally, as of June 2021, there is an ongoing natural history study collecting information to further characterize SLC13A5 citrate transporter disorder.
Patients with SLC13A5 citrate transporter disorder express a wide variety of mostly neurologic symptoms (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 are often refractory to medications and most patients remain on anti-seizure medications throughout life (Yang et al. 2020; Matricardi et al. 2020). Additional symptoms include limited ability to speak, slow motor development including problems standing or walking independently, as well as abnormalities in tooth enamel. Problems with tone are also reported with chronic low tone but also periodic episodes of body stiffening and post stiffening weakness (Klotz et al. 2016; Thevenon et al. 2014; Matricardi et al. 2020; Yang et al. 2020).
This disorder is caused by mutations in both copies of the SLC13A5 gene. The SLC13A5 gene codes for a sodium dependent citrate transporter (NaCT) that brings citrate, a key substrate involved in energy production, into the cell (Inoue et al. 2002; Birkenfeld et al. 2011). To date, all tested mutations lead to reduced amounts or mislocalization of the citrate transporter in the cells (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016). Consistent with this finding, SLC13A5 citrate transporter disorder patients have elevated citrate levels in the cerebrospinal fluid, blood and urine (Bainbridge et al. 2017).
There are several symptoms that are common in the majority of children diagnosed with SLC13A5 citrate transporter disorder:
Siblings with the same genetic mutation show differences in the severity of symptoms. Variations include the type and frequency of seizures as well as the time course of developmental milestones (Anselm et al. 2016; Matricardi et al. 2020; Yang et al. 2020).
SLC13A5 citrate transporter disorder is caused by mutations in SLC13A5 gene. There are multiple SLC13A5 mutations that cause SLC13A5 citrate transporter disorder. Currently identified mutations result in reduced citrate transporter (NaCT) activity (Hardies et al. 2015; Klotz et al. 2016; Knauf et al. 2002; Selch et al. 2018). Since citrate is a key metabolite and is known to play an important role in the energy production in cells, disrupting citrate import into cells may prevent cells from functioning properly. SLC13A5 is most highly expressed in the liver, brain and reproductive organs and most extensively studied in liver cells (Inoue, Zhuang, and Ganapathy 2002; Gopal et al. 2007). However, the role of SLC13A5 in the human brain is not well understood, and researchers hope to better understand the molecular mechanism underlying the symptoms of this devastating disease.
SLC13A5 citrate transporter disorder is inherited in an autosomal recessive pattern, meaning that the disorder occurs when a child inherits a harmful mutation in the SLC13A5 gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents is 25 percent. The risk is the same for males and females.
SLC13A5 citrate transporter disorder is a rare genetic disorder that affects both males and females equally. So far reports on about 120 patients have been reported in various databases and publications (Thevenon et al. 2014; Bainbridge et al. 2017; Klotz et al. 2016; Matricardi et al. 2020; Yang et al. 2020; Hardies et al. 2015; “TESS Research Foundation” 2021). Patients are from families with various ethnic backgrounds from the USA, European and South American countries (Thevenon et al. 2014; “TESS Research Foundation” 2021; Bainbridge et al. 2017).
Currently, SLC13A5 citrate transporter disorder is diagnosed by DNA sequencing of the SLC13A5 gene. If both 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.
Efforts are underway to find other methods of diagnosis with quick turn-around-time such as high throughput metabolomic profiling of a patient’s urine, blood plasma or CSF (cerebro-spinal fluid) (Bainbridge et al. 2017).
Treatment
The first line of treatment in SLC13A5 citrate transporter disorder is anti-seizure medications. Although anti-seizure medications have been successful in controlling seizures in some affected children, patients have variable success with the available drugs.
In 2021, a gene therapy treatment in development for SLC13A5 citrate transporter disorder (Taysha Gene Therapies) received rare pediatric disease and orphan drug designation from the U.S. Food and Drug Administration (FDA). This gene therapy treatment is in the preclinical stage for patients with SLC13A5 citrate transporter disorder.
Research is underway to find better treatment options for SLC13A5 citrate transporter disorder 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 citrate transporter disorder and to screen for drug repurposing candidates.
Multiple seizure drugs have been tried with mixed benefit (efficacy) to manage symptoms of SLC13A5 citrate transporter disorder (Hardies et al. 2015; Klotz et al. 2016; Matricardi et al. 2020; Yang et al. 2020). Some investigational therapies like triheptanoin and ketogenic diet were hypothesized to help patients with SLC13A5 citrate transporter disorder. However, some patients improved and others worsened while on the ketogenic diet (Thevenon et al. 2014; Anselm et al. 2016; Klotz et al. 2016) (Thevenon et al., 2014; Anselm et al, 2016; Klotz et al, 2016). There is currently 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 website.
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: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Akgün-Doğan Ö, Simsek-Kiper PO, Taşkıran E, et al. Kohlschütter-Tönz. Syndrome with a novel ROGD1 variant in 3 individuals: a rare clinical entity [published online ahead of print, 2021 Apr 19]. J Child Neurol. 2021;8830738211004736. doi:10.1177/08830738211004736 https://doi.org/10.1177/08830738211004736.
Matricardi S, De Liso P, Freri E, et al. Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in slc13a5 gene. Epilepsia. 2020;61(11):2474-2485. doi:10.1111/epi.16699.
Yang Q-Z, Spelbrink EM, Nye KL, Hsu ER, Porter BE. Epilepsy and EEG phenotype of SLC13A5 citrate transporter disorder. Child Neurology Open. 2020;7. doi:10.1177/2329048×20931361.
Selch, S., Chafai, A., Sticht, H. et al. Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism. Sci Rep. 2018; 8: 11330. https://doi.org/10.1038/s41598-018-29547-8.
Bainbridge MN, Cooney E, Miller M, Kennedy A, Wulff J, Donti T, Jhangian SN, et al. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. Molecular Genetics and Metabolism 2017; 121 (4): 314–9. https://doi.org/10.1016/j.ymgme.2017.06.009.
Schossig A, Bloch-Zupan A, Lussi A, et alSLC13A5 is the second gene associated with Kohlschütter–Tönz syndrome. Journal of Medical Genetics 2017;54:54-62.
Weeke LC, Brilstra E, Braun KP, et al. Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations. European Journal of Paediatric Neurology. 2017;21(2):396-403. doi:10.1016/j.ejpn.2016.11.002.
Anselm I, MacCuaig M, Prabhu SB, and Berry GT.
Disease heterogeneity in Na+/citrate cotransporter deficiency. JIMD Reports 2016; 31:
107–11. https://doi.org/10.1007/8904_2016_546.
Gürsoy S, Erçal D. Diagnostic approach to genetic causes of early-onset epileptic encephalopathy. Journal of Child Neurology. 2016;31(4):523-532. doi:10.1177/0883073815599262.
Klotz J, Porter BE, Colas C, et al. Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Mol Med. 2016; 22: 310–321. https://doi.org/10.2119/molmed.2016.00077.
Klotz J, Porter BE, Colas C, et al. Mutations in the Na+/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. Mol Med. 2016; 22:310–321. https://doi.org/10.2119/molmed.2016.00077.
Hardies, K, de Kovel CGF, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, Azmi A, et al. 2015. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain 2015; 138 (11):3238–3250. https://doi.org/10.1093/brain/awv263.
Birkenfeld AL, Lee H-Y, Guebre-Egziabher F, Alves TC, Jurczak MJ,
Jornayvaz FR, Zhang D, et al. Deletion of the mammalian INDY homologue mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metabolism 2011;14 (2):184–95. https://doi.org/10.1016/j.cmet.2011.06.009.
Gopal E, Miyauchi S, Martin PM, Ananth S, Srinivas SR , Smith SB, Prasad PD and Ganapathy V.Expression and functional features of NaCT, a sodium-coupled citrate transporter, in human and rat livers and cell lines. American Journal of Physiology-Gastrointestinal and Liver Physiology 2007; 292 (1):G402–8. https://doi.org/10.1152/ajpgi.00371.2006.
Katsuhisa Inoue, You-Jun Fei, Wei Huang, Lina Zhuang, Zhong Chen, Vadivel Ganapathy; Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates. Biochem J. 2002; 367(2):313–319. doi: https://doi.org/10.1042/bj20021132.
Knauf F, Rogina B, Jiang Z, Aronson PS, Helfand SL. Functional characterization and immunolocalization of the transporter encoded by the life-extending gene indy. Proceedings of the National Academy of Sciences. 2002;99(22):14315-14319. doi:10.1073/pnas.222531899.
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