Proton Magnetic Resonance Spectroscopy in Patients with Migration Disorders

Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to detect cerebral metabolites including N-acetylaspartate (NAA)，creatine (Cr) and choline (Ch). Hence，clinical applications of this method for neuropediatric diseases can be expected. However，regarding neuronal migration disorders，there have been only a few reported studies. We therefore examined the lH-MRS in six patients with migration disorders，ages ranged from 8months to 28years 10months with a mean of 10years 10months. Investigation was performed using Magnetom H15 (Siemens) with a repetition time of 1500 msec and an echo time of 270msec. The ratio of NAA/Cr，Ch/Cr were examined. The volume of interest with the size of 2 × 2 × 2 ～ 3 × 3 × 5cm3 was chosen in the area including lesions，and a contralateral area without lesions was also investigated. Results were as follows. 1) The ratio of NAA/Cr was low in the area with lesions in all 6cases; 1.41，1.95，2.27 and 1.71 in cases with heterotopic gray matter，0.99 in one case with polymicrogyria，an d 1.30 in one case with hemimegalencephaly，contrasted with a contralataral area without lesions: 1.89， 2.89，2.87，2.55，3.26，2.03，respectively. 2) The ratio of Ch/Cr showed no consistent difference between the area including lesions and contralataral area without lesions. Our findings of a decreased NAA/Cr ratio can be inferred to reflect the decreased numbers of neuronal cell population，or reduced metabolism in the lesions

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the “de novo paradigm” of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs

MLL2

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty‐five MLL2 mutations and two KDM6A mutations were novel. Non‐protein truncating‐type MLL2 mutations were mainly located around functional domains, while truncating‐type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating‐type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations. © 2013 Wiley Periodicals, Inc