16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes.

OBJECTIVE: To test whether mutations in γ-aminobutyric acid type A receptor (GABAA -R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). METHODS: We performed exome sequencing to compare the frequency of variants in 18 GABAA -R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function. RESULTS: Of 18 screened GABAA -R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio = 18.07, 95% confidence interval = 2.01-855.07, p = 0.0024, pcorr = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant γ2 subunit. INTERPRETATION: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants.

Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy.

Rolandic epilepsy (RE) and its atypical variants (atypical rolandic epilepsy, ARE) along the spectrum of epilepsy-aphasia disorders are characterized by a strong but largely unknown genetic basis. Two genes with a putative (ELP4) or a proven (SRPX2) function in neuronal migration were postulated to confer susceptibility to parts of the disease spectrum: the ELP4 gene to centrotemporal spikes and SRPX2 to ARE. To reexamine these findings, we investigated a cohort of 280 patients of European ancestry with RE/ARE for the etiological contribution of these genes and their close interaction partners. We performed next-generation sequencing and single-nucleotide polymorphism (SNP)-array based genotyping to screen for sequence and structural variants. In comparison to European controls we could not detect an enrichment of rare deleterious variants of ELP4, SRPX2, or their interaction partners in affected individuals. The previously described functional p.N327S variant in the X chromosomal SRPX2 gene was detected in two affected individuals (0.81%) and also in controls (0.26%), with some preponderance of male patients. We did not detect an association of SNPs in the ELP4 gene with centrotemporal spikes as previously reported. In conclusion our data do not support a major role of ELP4 and SRPX2 in the etiology of RE/ARE.

An adolescent with herpes simplex encephalitis, presenting with mild symptoms and rapid deterioration: A case report.

Headaches in children are a common, but unspecific symptom that can have many underlying causes, ranging from unspecific tension headache through migraine and up to encephalitis and intracranial hypertension. We present the case of a 14-year-old boy who presented to our emergency department with headache, nausea as well as vomiting and developed seizures later on. The initial diagnosis was complicated by a magnetic resonance imaging which did not show any signs of inflammation, but was of limited informative value due to orthodontic appliances. Despite the unremarkable imaging, prophylactic antiviral and antibiotic treatment was started after lumbar puncture. Herpes simplex virus as well as human herpes virus 7 were confirmed in the cerebrospinal fluid. Although both viruses are ubiquitous, severe infections are a rare complication. Immunodeficiency syndromes are predisposing factors for serious complications and genetic analysis of UNC93B and TLR-3 might be helpful for decision-making. No genetic or immunologic predisposition was found in our patient. The patient's condition deteriorated rapidly, so he had to be admitted to the pediatric intensive care unit, where he was intubated and his antiviral treatment with acyclovir was extended by foscarnet. After prolonged mechanical ventilation, he slowly improved. With intensive neurorehabilitation, he could finally return to his daily life activities 3 months after diagnosis. Despite headaches being an unspecific symptom, the possibility of a herpes simplex virus encephalitis should always kept in mind, especially in patients presenting with additional symptoms such as vomiting, altered mental status and/or focal neurological deficits. An initial magnetic resonance imaging might be misleading if orthodontic appliances are in place. Initiation of treatment without delay is crucial for neurologic outcome of herpes simplex virus encephalitis.

Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.

Rolandic epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and atypical RE (ARE). Here we report on whole-exome sequencing of 194 unrelated patients with RE/ARE and 567 ethnically matched population controls. We identified an exome-wide significantly enriched burden for deleterious and loss-of-function variants only for the established RE/ARE gene GRIN2A. The statistical significance of the enrichment disappeared after removing ARE patients. For several disease-related gene-sets, an odds ratio >1 was detected for loss-of-function variants.