Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment.

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This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families.

Several studies have demonstrated the effectiveness of ketogenic diet (KD) on refractory epilepsies, especially in children. In this category of patients, a strong collaboration between the healthcare providers and the full engagement of parents is required. The regimen is significantly effective for different types of epilepsy that are resistant to medical treatment. It can also be used as a first-line treatment, given its well tolerance. Treatment has been rolled out for children but research into its use in adults is promising. There is no international or national protocol, the implementation of this diet follows a rigor being specific to every ketogenic center. The understanding of the underlying mechanisms is not well elucidated, it would make it possible to optimize the clinical use of the ketogenic diet, but also to develop novel antiepileptic treatments. This article aims to review the different variants of KD and their prescription terms in children with intractable epilepsy. Keywords: drug-resistant epilepsy, ketogenic diet, children, Modified Atkins Diet.

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