Darier disease : more than skin deep

Sammanfattning: Darier disease (DD) is a severe, inherited dermatological disorder with a characteristic clinical and histopathological appearance. It is caused by mutations in the ATP2A2 gene, encoding a Ca2+ pump in the endoplasmic reticulum, Sarco/Endoplasmic Reticulum Ca2+-ATPase 2 (SERCA2), which has been found to be an essential regulator of cellular Ca2+ homeostasis. SERCA2 is expressed in all cells of the body, not just the skin, and has been implicated in physiological and pathophysiological mechanisms in several organs, thus rendering the occurrence of extra-dermal presentations plausible. DD has so far only been associated with brain-related disorders. The overall aim of this thesis was to investigate comorbidities associated with DD. In study I, II and III, experimental, matched case-control designs were used to evaluate broad cognitive function, heart disease and diabetes in individuals with DD compared with matched healthy controls. Individuals with DD were found to exhibit a widespread, significant impairment in cognitive function assessed with the Cambridge Neuropsychological Test Automated Battery, evaluating general cognitive function. A possible defect in serum lipid handling was also seen, as well as evidence of pancreatic β-cell dysfunction indicating a metabolic state seen during the development of type 2 diabetes. In study II and IV, a population-based cohort design, comparing data on individuals with DD taken from the National Patient Register with matched comparison subjects from the Total Population Register, was used. Individuals with DD displayed a 59% risk increase of heart failure (risk ratio [RR] 1.59, confidence interval [CI] 1.16-2.19) and a 32% risk increase of any heart diagnosis (RR 1.32, CI 1.02-1.70). Female DD patients had a 59% risk increase of any heart diagnosis (RR 1.59, CI 1.13-2.25). The first heart diagnosis also occurred almost seven years earlier in individuals with DD (70.0 vs. 76.9 years). A 74% increased risk of type 1 diabetes diagnosis was also seen (RR 1.74, CI 1.13-2.69). In study V, immune cell markers were evaluated in a small cohort of DD patients. The values of CD19+ B cells were found to be lower than the normal laboratory range on average, which together with the evidence of the importance of SERCA2 in B cell development indicates a possible immune system defect. This finding can help explain the recurring secondary infections often troubling individuals with DD. In conclusion, DD has been found to be associated with impaired cognitive function, heart disease and diabetes, as well as a possible defect in the immune system. The range of comorbidities associated with DD has been expanded to include several organs, resulting in the confident conclusion that DD should be viewed as a systemic disorder. This has several important implications, both for the individual patient and in routine care for this group of patients. Looking forward, it will quite possibly influence the way DD is treated.