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ObjectiveTo test whether mutations in -aminobutyric acid type A receptor (GABA(A)-R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). MethodsWe performed exome sequencing to compare the frequency of variants in 18 GABA(A)-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. ResultsOf 18 screened GABA(A)-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, p(corr)=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 2 subunit. InterpretationThe 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. Ann Neurol 2015;77:972-986

The purpose of this study was to assess the neurodevelopmental outcome in a larger cohort of higher order multiple births (HOM). To accomplish this, we analysed the perinatal records of 90 HOM from 28 pregnancies (69 triplets, 16 quadruplets and 5 quintuplets) born at the University Hospital Kiel during the period from 1980 to 1994. Sixty-eight out of 79 surviving children (87.2%) were re-examined at a median age of 7.8 years (range: 3 to 14.5 years). Re-examination included assessment of the neurological, psychomotor (Denver developmental scale, Columbia mental maturity scale), and behavioural (childhood behaviour checklist) status. Perinatal mortality was 12%. In 62% of subjects, neurological and cognitive status at follow-up were completely normal; 32% revealed minor and 6% major neurodevelopmental deficits. Comparison between VLBW and LBW HOM disclosed significantly more neurological deficits, lower IQs and more behaviour problems in children with VLBW. Especially social problems, attention deficit, anxiety and depression symptoms were more frequent in the VLBW HOM than in the LBW HOM group. VLBW HOM parents felt significantly more stressed and VLBW HOM mothers reported reduced coping skills. These findings suggest that the overall cognitive and neurological outcome of HOM surviving the neonatal period is good, but that minor neurocognitive deficits are frequent. LBW HOM have less neurological and behaviour problems than VLBW HOM.