Genetics of idiopathic epilepsies.

One of the most exciting areas in epilepsy has been the explosion in our understanding of the genetics of the epilepsies over the last decade. Built on a long history of careful clinical genetic studies of the epilepsies, the relatively recent discovery of epilepsy genes has enabled insights into pathways causing seizure disorders. A variety of mutational mechanisms can cause epilepsy resulting from different, and sometimes surprising, molecular processes such as copy number variation within the genome.

Sturge-Weber syndrome.

Sturge-Weber syndrome (SWS) is a rare sporadic neurocutaneous syndrome defined by the association of a facial capillary malformation in the ophthalmic distribution of the trigeminal nerve, with ipsilateral vascular glaucoma and vascular malformation of the eye, and a leptomeningeal angioma. SWS is suspected at birth in the presence of facial angioma in the trigeminal nerve area. MRI with gadolinium enhancement and pondered T1, T2, FLAIR and diffusion sequences is today the technique of choice to visualize the leptomeningeal angioma or to suspect it by indirect signs, even before the development of neurological signs, from the first months of life.

Experimental designs for small randomised clinical trials: an algorithm for choice.

Background: Small clinical trials are necessary when there are difficulties in recruiting enough patients for conventional frequentist statistical analyses to provide an appropriate answer. These trials are often necessary for the study of rare diseases as well as specific study populations e.g.

Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy.

Early-onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug-resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings.

Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): Clinical recommendations.

Subependymal giant cell astrocytoma (SEGA) is a type of brain tumour that develops in 10-15% of individuals with tuberous sclerosis complex (TSC). SEGAs can be unilateral or bilateral, developing from benign subependymal nodules (hamartomas) located near the foramen of Monro. These are usually slow-growing, glialneuronal tumours that develop within the first 2 decades of life.

A revisited strategy for antiepileptic drug development in children: designing an initial exploratory step.

Background: Randomized controlled trials (RCTs) in refractory paediatric epilepsy usually involve the two main types of epilepsy shared by children and adults, focal epilepsy and Lennox-Gastaut syndrome (LGS). Most other epilepsy syndromes, specifically paediatric, are excluded from drug development. In order to identify among them the candidate(s) for dedicated RCTs with a new drug, the European Medicine Agency (EMA) recently recommended proceeding in two steps: (1) an exploratory (prospective-observational) trial (POT) including a large variety of paediatric epilepsy syndromes and (2) a subsequent RCT in each of those that disclose a signal for possible efficacy.

Do mutations in SCN1B cause Dravet syndrome?

A homozygous SCN1B mutation was previously identified in a patient with early onset epileptic encephalopathy (EOEE) described as Dravet syndrome (DS) despite a more severe phenotype than DS. We investigated whether SCN1B mutations are a common cause of DS. Patients with DS who did not have a SCN1A sequencing mutation or copy number variation were studied.

De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.

Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals.

Autoimmune and inflammatory epilepsies.

The role of immunity and inflammation in epilepsy have long been suggested by the anticonvulsant activity of steroids in some infancy and childhood epilepsies. The role of fever and infection in exacerbating seizures due to possible proinflammatory molecules, the increased frequency of seizures in systemic autoimmune diseases like systemic lupus erythematous, and, recently, the detection of autoantibodies in some unexplained epilepsies reinforced the causal place of immunity and inflammation in epilepsies with unknown etiology. In this article, we summarize epilepsies where clinical and biologic data strongly support the pathogenic role of autoantibodies (e.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive.

Stiripentol: an example of antiepileptic drug development in childhood epilepsies.

The efficacy of stiripentol (STP) in Dravet Syndrome (DS) was discovered first in an exploratory study in pediatric pharmacoresistant epilepsies. This efficacy signal, used as a proof of concept, led to - two independent multicenter randomized, double-blind, placebo-controlled trials in DS patients: STICLO-France and STICLO-Italy. In adjunction to valproate and clobazam, STP demonstrated marked efficacy and these trials became the basis for the registration of STP as an orphan drug for DS.

Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations.

Tuberous sclerosis complex (TSC) is a leading genetic cause of epilepsy. TSC-associated epilepsy generally begins during the first year of life, and is associated with neurodevelopmental and cognitive problems. Management is challenging and seizures tend to persist in a large proportion of patients despite pharmacological and surgical treatment.

Epilepsy. Genetics of early-onset epilepsy with encephalopathy.

Genetically determined epilepsy with encephalopathy can develop early in life, often with prenatal onset, which makes diagnosis difficult. New molecular screening studies have identified causative mutations in patients with early-onset epilepsy with encephalopathy. What can we learn from the results of genetic screening in patients with this disorder?

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance.

Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.

Purpose: To explore the correlations between treatment modalities and selected disease parameters with outcome in febrile infection-related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy with a yet undefined etiology.

Methods: We conducted a retrospective multicenter study on children who had been included in eight studies published between November 2001 and July 2010. Additional data were retrieved from six of the eight participating centers.

Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study.

We aimed to test the efficacy of ketogenic diet (KD) in patients with Dravet syndrome (DS) not satisfactorily controlled by antiepileptic drugs (AEDs). We included prospectively 15 DS patients aged >3 years with partial response to AEDs including stiripentol. All patients had a seizure diary and clinical examination with Conners and Achenbach scales before KD, at 1 month following onset and every 3 months thereafter.

The genetics of Dravet syndrome.

Dravet syndrome (DS), otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an epileptic encephalopathy presenting in the first year of life. DS has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset. The remaining SCN1A mutations comprise splice-site and missense mutations, most of which fall into the pore-forming region of the sodium channel.

Topiramate pharmacokinetics in infants and young children: contribution of population analysis.

Purpose: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3-9 mg/kg/day) and to compare them to adult target ranges.

Methods: The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (C(trough)s) within the adult ranges.

Results: TPM pharmacokinetics was described by a one-compartment model.

Acute encephalopathy with inflammation-mediated status epilepticus.

Fever-induced refractory epileptic encephalopathy in school-aged children (FIRES), and idiopathic hemiconvulsion-hemiplegia syndrome (IHHS) are both triggered by fever, although evidence for a causal microorganism or an autoimmune phenomenon is lacking. FIRES begins in school age with status epilepticus lasting several weeks, involves perisylvian areas including mesial temporal structures, and is followed by pharmacoresistant epilepsy with major cognitive deterioration. IHHS begins in infancy with unilateral clonic status epilepticus and is followed by hemiplegia with pharmacoresistant epilepsy.

Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females.

Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. Heterozygous females are affected while hemizygous males are spared, this unusual mode of inheritance being probably due to a mechanism called cellular interference. To extend the mutational and clinical spectra associated with PCDH19, we screened 150 unrelated patients (113 females) with febrile and afebrile seizures for mutations or rearrangements in the gene.

Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects.

Mutations in the TUBB3 gene, encoding β-tubulin isotype III, were recently shown to be associated with various neurological syndromes which all have in common the ocular motility disorder, congenital fibrosis of the extraocular muscle type 3 (CFEOM3). Surprisingly and in contrast to previously described TUBA1A and TUBB2B phenotypes, no evidence of dysfunctional neuronal migration and cortical organization was reported. In our study, we report the discovery of six novel missense mutations in the TUBB3 gene, including one fetal case and one homozygous variation, in nine patients that all share cortical disorganization, axonal abnormalities associated with pontocerebellar hypoplasia, but with no ocular motility defects, CFEOM3.

Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).

Purpose: Fever induced refractory epileptic encephalopathy in school age children (FIRES) is a devastating condition initiated by prolonged perisylvian refractory status epilepticus (SE) triggered by fever of unknown cause. SE may last more than 1 month, and this condition may evolve into pharmacoresistant epilepsy associated with severe cognitive impairment. We aimed to report the effect of ketogenic diet (KD) in this condition.