Our study is the largest report of patients harboring MORC2 variants. We revealed a clinical and mutational spectrum of Japanese patients with MORC2 variants. More attention should be paid to cognitive impairment, and the responsible mechanism requires further research for elucidation.

The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.

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OBJECTIVEChildren who have experienced neonatal hypoxic-ischemic encephalopathy often develop cerebral palsy. Although many treatments have been performed, few effective therapies are available. In this study, the authors tested in rats with hypoxia-ischemia (HI) injuries the hypothesis that the systemic infusion of mesenchymal stem cells (MSCs) would result in functional improvement by facilitating neural compensation in the contralesional cortex.METHODSPostnatal day (P) 7 (P7) rats that had undergone unilateral hemisphere hypoxia-ischemia (modified Rice-Vannucci model) were randomly assigned to MSC-infused or vehicle-infused groups. MSCs (1.0 × 106/200 μL) or vehicle were intravenously infused on P10. Brain volume was measured using in vivo MRI on P8 and P35. On P35, the rats were sacrificed after their behavior was evaluated using a beam walk test, and their brains were then prepared for histological analyses.RESULTSThe MSC-treated group had fewer slips on the beam walk test compared to those in the vehicle group (p = 0.041). MRI was used to measure the volumes of the whole brain, contralesional brain (hemisphere), and residual brain regions of interest, and the results indicated increased brain volume after the intravenous MSC infusions. The histological analyses revealed increased thicknesses of the contralesional cortex and corpus callosum in the MSC group compared with those in the vehicle group (p = 0.021, p = 0.019), which confirmed the volume increases. In the contralesional cortex, the MSC-treated group exhibited significant increases in the numbers of NeuN-positive cells (p = 0.004) and synaptic puncta (p = 0.000) compared with the numbers observed in the vehicle group.CONCLUSIONSThe intravenous infusion of MSCs resulted in improvements in functional outcome, increased brain volume, and enhanced synaptogenesis in HI rats.