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1.
Sci Rep ; 14(1): 7109, 2024 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-38531956

RESUMEN

Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.


Asunto(s)
Enfermedad de Darier , Demencia , Epilepsia , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/epidemiología , Piel , Demencia/epidemiología
3.
Acta Derm Venereol ; 103: adv10436, 2023 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-38014829

RESUMEN

Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey  disease was performed to assess the risks of type 1  diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no  excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.


Asunto(s)
Diabetes Mellitus Tipo 2 , Pénfigo Familiar Benigno , Masculino , Humanos , Femenino , Pénfigo Familiar Benigno/diagnóstico , Pénfigo Familiar Benigno/epidemiología , Pénfigo Familiar Benigno/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Linaje , Estudios de Cohortes , ATPasas Transportadoras de Calcio/genética , ATPasas Transportadoras de Calcio/metabolismo , Mutación
4.
J Invest Dermatol ; 143(10): 2039-2051.e10, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37061123

RESUMEN

Impaired skin wound healing is a significant global health issue, especially among the elderly. Wound healing is a well-orchestrated process involving the sequential phases of inflammation, proliferation, and tissue remodeling. Although wound healing is a highly dynamic and energy-requiring process, the role of metabolism remains largely unexplored. By combining transcriptomics and metabolomics of human skin biopsy samples, we mapped the core bioenergetic and metabolic changes in normal acute as well as chronic wounds in elderly subjects. We found upregulation of glycolysis, the tricarboxylic acid cycle, glutaminolysis, and ß-oxidation in the later stages of acute wound healing and in chronic wounds. To ascertain the role of these metabolic pathways on wound healing, we targeted each pathway in a wound healing assay as well as in a human skin explant model using metabolic inhibitors and stimulants. Enhancement or inhibition of glycolysis and, to a lesser extent, glutaminolysis had a far greater impact on wound healing than similar manipulations of oxidative phosphorylation and fatty acid ß-oxidation. These findings increase the understanding of wound metabolism and identify glycolysis and glutaminolysis as potential targets for therapeutic intervention.


Asunto(s)
Piel , Cicatrización de Heridas , Humanos , Anciano , Cicatrización de Heridas/fisiología , Piel/patología , Redes y Vías Metabólicas , Glucólisis , Metabolómica
5.
Acta Derm Venereol ; 101(6): adv00476, 2021 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-33928397

RESUMEN

Darier disease and Hailey-Hailey disease are severe, monogenetic dermatological disorders with mutations affecting all cells, making them liable to exhibit extra-dermal symptoms. The aim of this study is to assess broad cognitive function in individuals with these diseases, using an experimental, case-control set-up comparing cognition in patients with that in healthy controls matched for age, sex and level of education. Cognition was assessed with the Cambridge Neuropsycho-logical Test Automated Battery. Patients with Darier disease (n = 29) performed significantly poorer on 5 of the 10 key cognitive measurements, while patients with Hailey-Hailey disease (n = 25) did not perform differently from controls. The main conclusion is that patients with Darier disease exhibit significant impairment in cognitive function, which reinforces the view that Darier disease should be regarded as a disorder affecting multiple organs, and should therefore be given medical consideration, and possibly treat-ment, as such.


Asunto(s)
Disfunción Cognitiva , Enfermedad de Darier , Pénfigo Familiar Benigno , Estudios de Casos y Controles , Enfermedad de Darier/diagnóstico , Enfermedad de Darier/genética , Humanos , Mutación , Pénfigo Familiar Benigno/diagnóstico , Pénfigo Familiar Benigno/genética
6.
Acta Derm Venereol ; 101(4): adv00430, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33606037

RESUMEN

Darier disease is a severe, rare autosomal dominant inherited skin condition caused by mutations in the ATP2A2 gene encoding sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 in the endoplasmic reticulum. Since sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 is expressed in most tissues, and intracellular calcium homeostasis is of fundamental importance, it is conceivable that other organs besides the skin may be involved in Darier disease. This review focusses on the association of Darier disease with other organ dysfunctions and diseases, emphasizing their common molecular pathology. In conclusion, Darier disease should be considered a systemic condition that requires systemic and disease mechanism targeted treatments.


Asunto(s)
Enfermedad de Darier , Enfermedad de Darier/diagnóstico , Enfermedad de Darier/genética , Humanos , Mutación , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Piel/metabolismo
7.
Sci Rep ; 10(1): 6886, 2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32327688

RESUMEN

Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in heart disease is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum Ca2+ ATPase isoform 2 (SERCA2), which causes calcium dyshomeostasis and ER stress. We hypothesized that DD patients would have an increased risk for common heart disease. We performed a cross-sectional case-control clinical study on 25 DD patients and 25 matched controls; and a population-based cohort study on 935 subjects with DD and matched comparison subjects. Main outcomes and measures were N-terminal pro-brain natriuretic peptide, ECG and heart diagnosis (myocardial infarction, heart failure and arrythmia). DD subjects showed normal clinical heart phenotype including heart failure markers and ECG. The risk for heart failure was 1.59 (1,16-2,19) times elevated in DD subjects, while no major differences were found in myocardial infarcation or arrhythmias. Risk for heart failure when corrected for cardivascular risk factors or alcohol misuse was 1.53 (1.11-2.11) and 1.58 (1,15-2,18) respectively. Notably, heart failure occurred several years earlier in DD patients as compared to controls. We conclude that DD patients show a disease specific increased risk of heart failure which should be taken into account in patient management. The observation also strenghtens the clinical evidence on the important role of SERCA2 in heart failure pathophysiology.


Asunto(s)
Enfermedad de Darier/complicaciones , Insuficiencia Cardíaca/complicaciones , Adulto , Anciano , Biomarcadores/metabolismo , Estudios de Casos y Controles , Estudios Transversales , Enfermedad de Darier/diagnóstico por imagen , Enfermedad de Darier/enzimología , Enfermedad de Darier/fisiopatología , Electrocardiografía , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/fisiopatología , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Mutación/genética , Factores de Riesgo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo
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