Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Fit for Life Steps: Results of a Community Walking Intervention In the Rural Mississippi Delta

Background: A collaborative communityâuniversityâU.S. Department of Agriculture(USDA)/Agricultural Research Service (ARS) partnership developed and implemented a 6-month walking intervention whereby volunteer coaches were trained to lead community walking groups in a rural Mississippi Delta Community. Objective: Assess the feasibility of implementing community-based participatory research (CBPR), increase physical activity, and improve anthropometric and biological measures. Methods: This quasi-experimental design examined body mass index, percent body fat, waist circumference, blood pressure, blood glucose, lipid profile, self-reported walking, stages of change, social support, self-efficacy, and decisional balance at enrollment, 3 months, and 6 months. Participants were primarily African-American (99%) women (97%). Changes were evaluated using repeated measures analysis of variance (ANOVA) and Friedman\u27s test. Results: Community members actively participated in assessing the problem, identifying the intervention, intervention planning, data collection, and evaluation. Of the 83 enrolled participants, 66 (80%) completed the intervention. Participants exhibited significant improvements in waist circumference (â1.4 inches), systolic blood pressure (â4.3 mmHg), and high-density lipoprotein (HDL) cholesterol (+7.9 mg/dL); (P \u3c .001). Self-reported walking per day was 44.8 (SD+52.2) minutes at enrollment, 76.6 (SD+166.6) minutes at 3-months, and 65.9 (SD+89.7) minutes at 6 months (P = .154). A positive stage of change shift occurred in 57% of participants; however, no significant positive changes occurred in the other psychosocial variables. Conclusion: The process of developing and implementing this CBPR walking intervention was considered successful as evidenced by the community\u27s active contribution and participation in each phase of this research, the undertaking and application of basic research components, significant improvements in several anthropometric and biological values, and sustainability of the collaborative partnership