|Bainbridge, M. N. et al. Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle. Mol Genet Metab 121, 314–319 (2017).|
- Uses mass spectrometry to analyze human patient samples.
- Compares metabolite levels in the CSF, plasma, and urine in SLC13A5 Epilepsy patients to control patients. They find significant dysregulation in multiple TCA cycle intermediates (some increased, some decreased).
- Citrate is about 3 times higher than control patient levels in CSF.
|Hardies, K. et al. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. Brain 138, 3238–3250 (2015).||Clinical data|
- Identifies new mutations in Slc13a5.
- Characterizes different types of mutations (Type I and Type II).
- Type I mutants do not get transported to plasma membrane.
- Type II mutants get transported to the plasma membrane.
- Both Type I and Type II mutants have loss of citrate transport.
|Henke, C. et al. Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus. Neurobiology of Disease 143, 105018 (2020).||Slc13a5 KO mouse||
- Describes the phenotype of the slc13a5 KO mouse (global KO).
- KO mice had lower body weight and normal baseline EEG activity.
- KO mice experienced seizures starting at 7 weeks of age and showed a higher propensity of epileptic episodes in an acute epilepsy model.
- Protein analysis shows altered pathways (including GABA trafficking and metabolism).
|Klotz, J., Porter, B. E., Colas, C., Schlessinger, A. & Pajor, A. M. Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay. Mol Med 22, 310–321 (2016).||Cell culture|
- Describes the clinical features of patients and determines the effect of mutations in slc13a5 on NaCT protein function.
- After a normal pregnancy, patients experience seizures within the first week of life. Most patients also have teeth hypoplasia, are generally social and happy, and have limited communication.
- Each mutation tested led to a loss of citrate transport.
- Some mutations led to decreased protein expression and some had a complete loss of expression.
|Matricardi, S. et al. Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene. Epilepsia 61, 2474–2485 (2020).||Clinical data||
- Provides an overview of SLC13A5 Epilepsy by analyzing information from 14 patients ages 3-24 years old.
- Seizures decrease in frequency with age but unclear whether the number of seizures decrease or whether seizure control with medication is achieved.
- Most patients develop severe motor and cognitive impairment, as well as tooth hypoplasia.
|Sauer, D. B. et al. Structure and inhibition mechanism of the human citrate transporter NaCT. Nature 591, 157–161 (2021).||Human NaCT||
- Describes the cryo-EM structure of human NaCT in complex with citrate or a small-molecule inhibitor.
- Classifies NaCT mutations into 4 categories with proposed effects (Extended Data Table 2).
|Thevenon, J. et al. Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life. The American Journal of Human Genetics 95, 113–120 (2014).||Clinical data|
In silico protein analysis
- First paper to describe association of neonatal epilepsy associated with Slc13a5 mutations.
- Identified mutations are predicted to impact sodium binding.