The development of the human cerebral cortex is an orchestrated process involving the birth of neural progenitors in the peri-ventricular germinal zones, cell proliferation characterized by both symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in 6 highly ordered, functionally-specialized layers1,2. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development (MCD)3-6. Mapping of disease loci in putative Mendelian forms of MCD has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WDR62 as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with WDR62 mutations had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mouse and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. WDR62 expression in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the utility of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

We believe that AHEI is a benign disorder, despite its dramatic appearance. We want to point out that mucosal and trunk involvement may also occur in AHEI.

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg2+-dependent 3’ end ribonucleases with mostly unknown substrate specificity1. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration with ambiguous genitalia2 (MIM%614969). We studied 12 human families with PCH7, uncovering biallelic, loss of function mutations in TOE1 (NC_000001.11), which encodes an unconventional deadenylase3,4. Toe1-morphant zebrafish displayed mid- and hind-brain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found TOE1 associated with incompletely processed small nuclear (sn)RNAs of the spliceosome, which is responsible for pre-mRNA splicing. These pre-snRNAs contained 3’ genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3’ end-extended pre-snRNAs, and immuno-isolated TOE1 complex was sufficient for 3’ end maturation of snRNAs. Our findings reveal the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in processing of snRNA 3’ ends.

SUMMARY Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified 5 independent homozygous deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule severing enzyme katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of katanin, and other microtubule associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

We would like to emphasize that SA is mono-articular, frequently localized in the knee, hip and ankle in 85% of patients, joint fluid culture was positive in 55% of patients, bacteria was isolated from one or more cultures of blood, joint fluid, pus or bone in 70% of patients and the most common isolated micro-organism was S. aureus. In addition, it must be pointed out that children younger than 2 years of age with fever, a positive trauma history and/or abnormal joint findings should be carefully examined for SA because the rate of SA was lower (7.5%) than expected in this age group. We also found that the mortality of SA was not influenced by age, joint involvement and bacterial agents, and there was no significant difference in symptoms on admission, the history of trauma and antibiotic use, sex, age, fever, joint involvement,anemia, leukocytosis and micro-organisms isolated from joint fluid and blood between patients with SA

Analysis revealed that FC with a good prognosis had a high rate of recurrence and a higher risk of epilepsy than in the general population. The prevalence of FC in the province of Kayseri was closer to that in developed rather than developing countries.

The aim of this study was to investigate the relationship between autism spectrum disorders development and exposure to mono-(2-ethylhexyl)-phthalate (MEHP), di-(2-ethylhexyl)-phthalate (DEHP), and bisphenol A (BPA), 1 of the endocrine disruptors, among phthalates. The study included 48 children with autism spectrum disorder (27 boys, 21 girls) and 41 healthy subjects (24 boys, 17 girls) as controls. Serum MEHP, DEHP, and BPA levels were measured by using high-performance liquid chromatography. Children with autism spectrum disorder had significantly increased serum MEHP, DEHP, and BPA concentrations (0.47 ± 0.14 µg/ml, 2.70 ± 0.90 µg/ml, 1.25 ± 0.30 ng/ml) compared to healthy control subjects (0.29 ± 0.05 µg/ml, 1.62 ± 0.56 µg/ml, 0.88 ± 0.18 ng/ml) respectively (P = .000). The fact that higher serum MEHP, DEHP, and BPA were found levels in the autism spectrum disorder group compared to healthy controls suggests that endocrine disruptors may have a role in the pathogenesis of autism spectrum disorders.

Spinal MRI is a reliable imaging method for the diagnosis of GBS as it was positive in 38 of 40 patients. The severity on MRI does not correlate with severity of the clinical condition. MRI can be used as a supplementary diagnostic modality to clinical and laboratory findings of GBS.