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- Palmer, Elizabeth E., et al.
(författare)
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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- 2023
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Ingår i: Molecular Psychiatry. - : SPRINGERNATURE. - 1359-4184 .- 1476-5578. ; 28:2, s. 668-697
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Tidskriftsartikel (refereegranskat)abstract
- Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
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- Miller, Jennifer L., et al.
(författare)
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Multi-morbidity burden, psychological distress, and quality of life in implantable cardioverter defibrillator recipients: Results from a nationwide study
- 2019
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Ingår i: Journal of Psychosomatic Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0022-3999 .- 1879-1360. ; 120, s. 39-45
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalence of multi-morbidity in implantable cardioverter defibrillator (ICD) recipients is approximately 25%. Multi-morbidity is associated with poor health and psychological outcomes in this population and may affect ICD recipients quality-of-life (QOL). The purpose of this study was to determine the prevalence of psychological distress (anxiety, depressive symptoms, and Type-D personality) in ICD recipients with varying levels of comorbidities, and to examine the association between multi-morbidity burden and QOL in this population. Methods: All adults listed in the Swedish ICD and Pacemaker Registry in 2012 with an ICD implanted for at least one year were invited to participate in this study. Binary logistic regression was used to predict QOL using the EQ-5D mean index dichotomized based on median QOL scores. Multi-morbidity burden scores were based on quartile groupings. Results: A total of 2658 ICD recipients participated in the study (with a mean age of 65, 20.6% female, mean implant duration of 4.7 years, with 35.4% implanted for primary prevention of sudden cardiac arrest). Greater multi-morbidity burden, female sex, not working outside the home, history of ICD shock, negative ICD experience, higher levels of ICD-related concerns, and the presence of anxiety, depression, or Type D personality were associated with worse QOL in ICD recipients. Predictors differed by multi-morbidity burden level. Conclusions: Multi-morbidity burden and psychological distress is an essential factor related to QOL. This issue should be discussed with potential ICD recipients prior to implant. Further exploration of increased recognition and treatment of psychological distress in ICD recipients is warranted.
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