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- Helbig, K. L., et al.
(författare)
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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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- Nahhas, M. A., et al.
(författare)
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Epidemiology of overweight and obesity in early childhood in the Gulf Cooperation Council countries: a systematic review and meta analysis protocol
- 2018
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Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction There has been a notable increase in the prevalence of overweight and obesity in school-aged children in many industrialised regions. The worldwide prevalence of childhood overweight and obesity increased from 4.2% in 1990 to 6.7% in 2010. Although many studies have been published, the epidemiological burden of overweight and obesity in the Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates) is unclear. There is a need to bring together and appraise relevant studies in order to estimate the epidemiological burden (including incidence, prevalence, risk factors, trend over time) of overweight and obesity in this region and thus help to inform national and regional policies. Methods and analysis We will conduct a systematic review and meta-analysis on the epidemiology of overweight and obesity in early childhood including incidence, prevalence, risk factors and trends over time in the GCC countries. We will search international electronic databases including MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Google Scholar, AMED, Psych INFO, CAB International and WHO Global Health Library for published, unpublished and in-progress epidemiological studies of interest published from inception to 2017. In addition, we will contact an international panel of experts on the topic. There will be no restriction on the language of publication of studies. We will use the Effective Public Health Practice Project (EPHPP) to appraise the methodological quality of included studies. Meta-analysis will be undertaken using random effects models. Ethics and dissemination Ethical approval is riot required. The outcome of the review will he disseminated through conference presentations and peer-reviewed journal publication.
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