Abstract
Mutations in the SLC13A5 gene that codes for the Na(+)/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In the present study we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and treatment strategies. There are currently no effective treatments, but some anti-epileptic drugs targeting the GABA system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical anti-seizure medication decreases seizures in 4 patients. In contrast to previous reports, the ketogenic diet and fasting produce worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improve transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, our study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na(+)/citrate transporters.
Highlights
The onset of seizures in the first weeks of life has been associated with a large number of metabolic and genetic causes [1] including recently identified heterozygous mutations in the SLC13A5 gene that codes for the Na+/citrate transporter, NaCT [2,3]
This study identifies new autosomal recessive mutations in SLC13A5 in children with early onset epilepsy from six families (Table 1)
All of the patients in this study presented with epilepsy early, with eight of the nine patients presenting in the first week of life, and all had motor and language delays (Table 2)
Summary
The onset of seizures in the first weeks of life has been associated with a large number of metabolic and genetic causes [1] including recently identified heterozygous mutations in the SLC13A5 gene that codes for the Na+/citrate transporter, NaCT [2,3]. Few children with SLC13A5 disorder have been reported in the literature, and the full extent of their neurologic and epileptic phenotypes is only beginning to emerge. It appears that most children present with epilepsy very early within the first few weeks of life and have lifelong seizures. This disorder is characterized by limited and slow motor progress, with children described as unable to sit or walk independently. Language is limited with a few patients speaking in single words and others being nonverbal.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
