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Objective Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome‐wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4‐PAX6 locus in two independent US and Canadian case–control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array. Methods We fine‐mapped the ELP4‐PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome‐12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance. Results Homozygosity at the T allele of SNP rs662702 in the 3′ untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20–47.22), P = 2.6 × 10−4 and is seen in 3.9% of cases but only 0.3% of controls. Interpretation The minor T allele of SNP rs662702 disrupts regulation by microRNA‐328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.

Objective The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. Methods An observational study of 108 probands with RE (age range: 3.6–22 years) and their 159 siblings (age range: 1–29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case–control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. Results Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45–37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15–49.44), and male sex (OR: 3.62, 95% CI: 1.11–11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42–13.0) and not with the presence of interictal EEG focal sharp waves. Significance The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions.

Contains fulltext : 88466.pdf (Publisher’s version ) (Closed access) Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

An 11-month-old female infant attended accident and emergency with haematemesis. There was no preceding gastroenteritis, liver stigmata or trauma. Examination revealed bilateral, two centimetre supratonsillar lacerations and scattered petechiae over the forehead and nasal bridge. The ear-nose-throat ENT team found white slough tissue indicating wound healing. Concerns were raised regarding delay in presentation, minimal explanation and previous partner's domestic …

Forty six infants with the ultrasonic diagnosis of cavitating periventricular leukomalacia (CPVL) have been reviewed. Follow up examination results allow correlation between the ultrasound appearances and subsequent neurodevelopmental and neurological deficits. The highest incidence of this condition was found in infants at and below 27 weeks gestation, and occurred in 15% of very premature infants surviving 14 days or more. Cavities developed 15 days after the onset of periventricular echodensity (median time). Ventricular dilatation occurred in 24% of the infants who developed cavities. Follow up information was available in 27 infants and 18 of these (67%) had significant neurodevelopmental handicap. The location of echolucent cavities were described as involving anterior, middle or posterior cerebral zones or any combination of these. Cerebral palsy was closely related to the presence of cavities, but there was little association between cavities and developmental delay. Four factors were found to predict cerebral palsy: cavities within the occipital zone, the involvement of multiple regions of the brain, lesions greater than 1 cm in diameter and cavities associated with subcortical leukomalacia. Lesions confined to the anterior or middle zones were unlikely to be associated with significant handicap. The presence of cavities per se was not associated with a higher incidence of severe developmental delay.