MicroRNAs regulate protein synthesis by binding non-translated regions of mRNAs and suppressing translation and/or increasing mRNA degradation. MicroRNAs play an important role in the nervous system including controlling synaptic plasticity. Their expression is altered in disease states including stroke, head injury and epilepsy. To better understand microRNA expression changes that might contribute to the development of epilepsy, microRNA arrays were performed on rat hippocampus 4 hours, 48 hours and 3 weeks following an episode of pilocarpine induced status epilepticus. Eighty microRNAs increased at one or more of the time points. No microRNAs decreased at 4 hours, and only a few decreased at 3 weeks, but 188 decreased 48 hours after status epilepticus. The large number of microRNAs with altered expression following status epilepticus suggests that microRNA regulation of translation has the potential to contribute to changes in protein expression during epileptogenesis. We carried out a second set of array’s comparing microRNA expression at 48 hours in synaptoneurosome and nuclear fractions of the hippocampus. In control rat hippocampi multiple microRNAs were enriched in the synaptoneurosomal fraction as compared to the nuclear fraction. In contrast, 48 hours after status epilepticus only one microRNA was enriched in the synaptoneurosome fraction. The loss of microRNAs enriched in the synaptoneurosomal fraction implies a dramatic change in translational regulation in synapses 48 hours after status epilepticus.

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.

Background and Objectives The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate–galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. Methods This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. Results Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in‐frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. Discussion Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.

Mutations in the SLC13A5 gene, a sodium citrate cotransporter, cause a rare autosomal recessive epilepsy (EIEE25) that begins during the neonatal period and is associated with motor and cognitive impairment. Patient’s seizure burden, semiology, and electroencephalography (EEG) findings have not been well characterized. Data on 23 patients, 3 months to 29 years of age are reported. Seizures began during the neonatal period in 22 patients. Although seizures are quite severe in many patients later in life, seizure freedom was attainable in a minority of patients. Multiple patients’ chronic seizure management included a few common medications, phenobarbital and valproic acid in particular. Patients EEGs had a relatively well-preserved background for age, even in the face of frequent seizures, little slowing and multiple normal EEGs and do not support an epileptic encephalopathy. Other causes for the motor and cognitive delay beyond epilepsy warrant further study.