Darier disease is associated with heart failure: a cross-sectional case-control and population based study

Abstract

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. Rare monogenic diseases provide opportunities to study human physiology and pathology from unique perspectives. Besides the importance of diagnosing and successfully treating patients with a rare disorder, major scientific breakthroughs resulting from investigation of rare diseases have often provided insight into more common disorders 1-3. Herein, we examined increased risk of heart disease as a comorbidity of the rare skin disorder Darier disease (DD).

Emerging Evidence for Poxvirus-Mediated Unfolded Protein Response: Lumpy Skin Disease Virus Maintains Self-replication by Activating PERK and IRE1

“…ER stress has been associated with a variety of skin disease conditions in several studies. Chronic dermal ER stress, caused by Darier's disease and Ekpoma virus (EKV), triggers PERK-CHOP, which then activates the ER-mediated mitochondrial apoptosis pathway, allowing skin cells to die (46)(47)(48)(49)(50). Keratinization disorders and Keratosis linearis with Ichthyosis Congenita and Sclerosing Keratoderma syndrome (KLICK syndrome) are caused by ER stress that activates UPR signaling and promotes these disorders (51,52).…”

Molecular Pathogenesis and Complications Associated with Keratosis Follicularis: A Clinical Review

“…This observation also strengthens the clinical evidence of the important role of SERCA2 in heart failure pathophysiology. 36 For example, even though patients with DD present with a normal clinical heart phenotype, they have a 59% higher chance of being diagnosed with heart failure compared to those without DD. 36 Interestingly, the loss of the ATPA2A allele by itself does not affect cardiac performance, however, the development of heart conditions may be worsened in patients with ATPA2A mutation.…”

“…36 For example, even though patients with DD present with a normal clinical heart phenotype, they have a 59% higher chance of being diagnosed with heart failure compared to those without DD. 36 Interestingly, the loss of the ATPA2A allele by itself does not affect cardiac performance, however, the development of heart conditions may be worsened in patients with ATPA2A mutation. 37 It can be concluded that DD is a multisystem rare autosomal dominant disorder that occurs typically in the first or second decade of life, and goes beyond involving the skin.…”

Acral Hemorrhagic Darier’s Disease with Spontaneous Regression over time: A Case Report

“…1 The cause is a gene that encodes the sarco/endoplasmic reticulom Ca2+ ATP ase type 2, which causes calcium dyshomeostasis and endoplasmic reticulum stress including intercellular adhesion. 2,3,4 Its incidence is 1 to 9 per 100,000 individuals. The disease usually begins before the third decade of life with a peak in puberty (11-15 years old) 5,6 ;due to sweating ,sebum exertion or change in bacterial flora.…”

“…8 Classis DD is characterized by malodor keratotic, warty crusted papules and plaques, which are usually located in seborrheic areas, variable nail changes, whitish oral macules and papules(oral cobblestoning),and palmoplanta puctate pits that typically worsen in summer. 2,4 Treatments for DD include:1-topical treatments such as:(retinoids, 5-fu, diclofenac, tacrolimus, tacalcitol, and steroids),2-oral treatments such as:(retinoids, cyclosporine, doxycycline, magnesium chloride, and naltrexone ),3-physical approach such as:[dermabrasion, electrosurgical excision, surgical excision, lasers (Co2,pulse dye, Erbium),and radiotherapy]. 9 Acral hemorrhagic DD is a rare subtype with hemorrhagic macules and vesicles in extremities.…”