BackgroundQuality of life (QOL) is an important factor in evaluating the effectiveness of treatment in children with cerebral palsy (CP). The aim of this study was to evaluate the effects of autologous bone marrow mononuclear cells (BM MNCs) on the QOL of children with CP.MethodsFrom December 2015 to December 2016, 30 children with CP aged from 2 to 15 years received two intrathecal infusions of BM MNCs, one at baseline and the other 3 months later, at Vinmec International Hospital. The motor function and muscle tone of the patients were evaluated using the Gross Motor Function Measure (GMFM)-88 and Modified Ashworth Score, respectively. Their QOL was assessed at baseline and 6 months after the first BM MNC transplant using the Vietnamese version of the Cerebral Palsy Quality of Life Questionnaire for children (CP QOL-Child)–the parental proxy report, which comprises seven domains. Nineteen mothers (mean age: 32.9±4.9 years) and 11 fathers (mean age: 36.1±6.8 years) were invited to complete the CP QOL-Child assessment before and after the transplantations, Paired t-tests and multivariate regression analyses were used to evaluate the changes in QOL and GMFM scores and to identify the key factors correlated with the QOL score.ResultsSignificant changes were observed in the children’s gross motor function and muscle spasticity, as evidenced by the GMFM-88 total score, scores for each of its domains, the GMFM-66 percentile and the muscle tone (P < 0.001). Six months after the transplantations, the QOL scores of children with CP were markedly increased (P < 0.001) for all the domains, except for the domain of access to services. In the multivariate regression analysis, significant associations were found between higher age of children and higher QOL except for feeling about functioning and pain and impact of disability domains. Gross Motor Function Classification System (GMFCS) level was negatively correlated with the score of pain and impact of disability domain, while the GMFM-88 scores were positively correlated with the QOL in terms of feelings about functioning and family health domain (P < 0.05).ConclusionThe QOL of the children with CP was noticeably improved 6 months after BM MNC transplantation and was accompanied by improvements in gross motor function and muscle tone.Trial registrationClinicalTrials.gov Identifier: NCT02574923. Registered on October 14, 2015.

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Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5′ untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.

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Patients with Rett syndrome (RTT) have severe mental and physical disabilities. The majority of RTT patients carry a heterozygous mutation in methyl-CpG binding protein 2 (MECP2), an X-linked gene encoding an epigenetic factor crucial for normal nerve cell function. No curative therapy for RTT syndrome exists, and cellular mechanisms are incompletely understood. Here, we developed a CRISPR/Cas9-mediated system that targets and corrects the disease relevant regions of the MECP2 exon 4 coding sequence. We achieved homologous recombination (HR) efficiencies of 20% to 30% in human cell lines and iPSCs. Furthermore, we successfully introduced a MECP2 R270X mutation into the MECP2 gene in human induced pluripotent stem cells (iPSCs). Consequently, using CRISPR/Cas9, we were able to repair such mutations with high efficiency in human mutant iPSCs. In summary, we provide a new strategy for MECP2 gene targeting that can be potentially translated into gene therapy or for iPSCs-based disease modeling of RTT syndrome.