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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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| 4. |
- Harter Griep, R, et al.
(författare)
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Beyond simple approaches to studying the association between work characteristics and absenteeism : Combining the DCS and ERI models
- 2010
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Ingår i: Work & Stress. - : Informa UK Limited. - 0267-8373 .- 1464-5335. ; 24:2, s. 179-195
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Tidskriftsartikel (refereegranskat)abstract
- The Demand-Control-Support (DCS) and the Effort-Reward Imbalance (ERI) models assess different psychosocial factors. This study investigates whether a combination of these models increases their ability to predict sickness absence, as compared to results based on each model separately. A cross-sectional study with nursing personnel (N = 1307) in Brazil was performed. Regression analyses were conducted in three stages: analysis of each scale of the models and sickness absences; assessment of the independent association of each model with sickness absences; assessment of the associations of three combinations of models/scales with sickness absences: DC and social support (SS), ERI and overcommitment, and DC and ERI. As regards comparisons between the stress models, ERI was shown to be independently associated with short (up to 9 days) and long (10 days or more) spells of absenteeism. The same result held true for low social support. The combinations DC-ERI and DC-SS were better predictors for short spells than each model/scale separately, whereas for long spells, the combination DC-SS was the best predictor. ERI seems to be a good instrument for predicting absenteeism if used alone, whereas DC performed better when combined with ERI or SS. An improved risk estimation of sickness absences by combining information from the two models was observed.
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