Increased risk of cardiac arrhythmia in Hailey-Hailey disease patients.

BACKGROUND: Hailey-Hailey disease (HHD) is a rare autosomal dominant skin disease caused by mutations in the ATP2C1 gene, which encodes the secretory Ca2+/Mn2+-ATPase (SPCA1) pump in the Golgi apparatus. Although ATP2C1 is ubiquitously expressed in the body, possible extracutaneous manifestations of HHD are unknown. However, dysfunction of the Golgi apparatus not specifically coupled to ATP2C1 has been associated with heart disease. OBJECTIVE: To investigate the association between HHD and common heart disease in a Swedish, population-based cohort. METHODS: We conducted a population-based cohort study based on a linkage of Swedish nationwide registers to investigate the relationship between HHD and heart disease. We have been granted ethical approval from the Swedish Ethical Review Authority to conduct this study. The patients in this manuscript have given written informed consent to the publication of their case details. A total of 342 individuals with an ICD-10 diagnosis of HHD (Q82.8E) were identified and matched with randomly selected comparison individuals without HHD on a 1:100 ratio. Furthermore, in a separate clinical cohort we matched 23 HHD patients for age, sex, and BMI with control subjects to examine electrocardiogram parameters, electrolytes, and cardiovascular biomarkers. RESULTS: Compared with individuals without HHD, individuals with HHD had an excess risk of arrhythmia (RR 1.4, CI 1.0-2.0), whereas no increased risks of myocardial infarction (RR 1.1, CI 0.6-1.7) or heart failure (RR 1.0, CI 0.6-1.6; Table 1) were found. We found no difference in ECG parameters, cardiovascular biomarkers, and electrolytes in the clinical subset. CONCLUSION: This study reveals that HHD is associated with an increased risk of arrhythmia and represents the first data of any extracutaneous comorbidity in HHD. Thus, HHD may be a systemic disease. Our findings also shed light on the importance of the Golgi apparatus' Ca2+/Mn2+ homeostasis in common heart disease.

Risk of relationship separation in men with Peyronie's disease in a matched Swedish cohort.

Peyronie's disease (PD) has detrimental effects on the quality of life, mental health, sexual functioning and several other aspects that increase the risk of relationship problems. However, no study to date has assessed the risk of relationship separation in med with PD. Herein, we utilized data from Swedish national registers to examine the risk of relationship separation in men with PD. We conducted a matched cohort study on men born 1933-1992, followed from 1997 to 2013. PD was defined as a physician-assigned diagnosis according to the International Classification of Diseases, Tenth version. Each man with PD (n = 8020) was matched with 10 comparison men. We defined relationship separation as (1) ever separated, and (2) separation rate. We used log-linear regression to estimate the risk ratio, and rate ratio of relationship separation. We adjusted for matching variables (birth year and country of birth), and an indicator of each follow-up year. We found that men with PD had a 13% increased risk of relationship separation (risk ratio 1.13, 95% confidence interval [CI] 1.08-1.17). The rate of relationship separation events, measured on a yearly basis, was increased by 18% (rate ratio 1.18, CI 1.12-1.24), and remained similar when adjusting for follow-up year and socio-economic status.

Darier disease is associated with neurodegenerative disorders and epilepsy.

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.

Risk of Psychosis Among Individuals Who Have Presented to Hospital With Self-harm: A Prospective Nationwide Register Study in Sweden.

BACKGROUND AND HYPOTHESIS: Recent research showed that young people who presented to hospital with self-harm in Finland had a significantly elevated risk of later psychosis. We investigated the prospective relationship between hospital presentation for self-harm and risk of psychosis in an unprecedentedly large national Swedish cohort. STUDY DESIGN: We used inpatient and outpatient healthcare registers to identify all individuals born between 1981 and 1993 who were alive and living in Sweden on their 12th birthday and who presented to hospital one or more times with self-harm. We compared them with a matched cohort, followed up for up to 20 years, and compared the cumulative incidence of psychotic disorders. Furthermore, we examined whether the strength of the relationship between hospital presentation for self-harm and later psychosis changed over time by examining for cohort effects. STUDY RESULTS: In total, 28 908 (2.0%) individuals presented to hospital with self-harm without prior psychosis diagnosis during the follow-up. For individuals who presented to hospital with self-harm, the cumulative incidence of diagnosed psychosis was 20.7% at 20 years follow-up (hazard radio = 13.9, 95% CI 13.3-14.6, P-value <5 × 10-308). There was no evidence of a dilution of the effect over time: while the incidence of hospital self-harm presentation increased, this did not result in an attenuation over time of the strength of the relationship between hospital self-harm presentation and subsequent psychosis. CONCLUSIONS: Individuals who present to hospital with self-harm in their teens and 20s represent an important risk group for psychosis prediction and prevention.

Hailey-Hailey Disease is Associated with Diabetes: A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis.

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.

Associations of impulsivity, hyperactivity, and inattention with nonsuicidal self-injury and suicidal behavior: longitudinal cohort study following children at risk for neurodevelopmental disorders into mid-adolescence.

BACKGROUND: The knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD). METHODS: The sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately. RESULTS: A total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes. CONCLUSION: Impulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies.

Adverse clinical outcomes among youths with nonsuicidal self-injury and suicide attempts: a longitudinal cohort study.

BACKGROUND: More knowledge about risks of clinical outcomes associated with nonsuicidal self-injury (NSSI) and suicide attempts (SAs) is needed to inform risk assessment and intervention. METHODS: Longitudinal cohort study based on 1,855 youths was clinically assessed for NSSI and SA, and followed up (from December, 2011 to December 2013) for the outcomes; diagnosed self-injury, alcohol/substance use disorder, and psychiatric inpatient care data derived from Swedish registers. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the outcomes were estimated with Cox regressions, and additionally adjusted for the potential effect of sex and the number of clinical assessments. NSSI and SA were treated as time-varying covariates. RESULTS: Youths with NSSI had elevated risks of all outcomes, compared with youths without NSSI or SA; the HR was 2.3, 95% confidence interval [1.6, 3.4] for self-injury, 1.4 [0.9, 2.1] for alcohol/substance use disorder, and 1.3 [1.0, 1.7] for psychiatric inpatient care. Youths with SA displayed higher risks for the outcomes than the NSSI group; the HR was 5.5 [2.4, 12.6] for self-injury, 2.0 [0.9, 4.4] for alcohol/substance use disorder, and 2.6 [1.5, 4.5] for psychiatric inpatient care. Youths with both NSSI and SA showed similar risks as youths with SA; HR 4.1 [2.0, 8.3] for self-injury, 2.0 [1.1, 4.1] for alcohol/substance use disorder, but a higher risk of psychiatric inpatient care; HR 5.0 [3.1, 7.9]. All results remained virtually unchanged in the adjusted analyses. CONCLUSIONS: Youths with NSSI and/or SA had higher risks for subsequent adverse clinical outcomes. These excess risks were more pronounced among youths with SA and youths with both NSSI and SA, and the risk for psychiatric inpatient care was particularly high in youths with both NSSI and SA. Our findings suggest that early interventions for youths with NSSI or SA should not exclusively focus on suicide prevention, but also consider the risk of subsequent alcohol/substance use disorder.

Patients with Darier Disease Exhibit Cognitive Impairment while Patients with Hailey-Hailey Disease Do Not: An Experimental, Matched Case-control Study.

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.

Mental Disorders in Peyronie's Disease: A Swedish Cohort Study of 3.5 Million Men.

PURPOSE: Studies have shown that men with Peyronie's disease often suffer from psychological problems, but the psychiatric burden of this disorder remains largely unknown. We assessed risks of a range of psychiatric outcomes in a population based Swedish cohort comprising 3.5 million men. MATERIALS AND METHODS: We conducted a longitudinal cohort study based on Swedish national registers. A total of 8,105 men diagnosed with Peyronie's disease and 3.5 million comparison subjects from the general Swedish population were selected, and followed up with for diagnosed psychiatric outcomes including substance use disorder, alcohol misuse, anxiety disorder, depression, and self-injurious behaviors. Risks of psychiatric outcomes were estimated with Cox regressions and additionally adjusted for birth year. RESULTS: Men with Peyronie's disease had increased risks of being diagnosed with substance use disorder (HR 1.4, 95% CI 1.1-1.9), no excess risk of alcohol misuse (HR 0.9, CI 0.8-1.1), but elevated risks of anxiety disorder (HR 1.9, CI 1.6-2.2), depression (HR 1.7, CI 1.5-2.0), self-injurious behaviors (HR 2.0, 95% CI 1.7-2.3) as well as any psychiatric outcomes (HR 1.4, 95% CI 1.2-1.5). The risk estimates were slightly decreased when adjusted for birth year. A limitation of the study was that we had no information about Peyronie's disease diagnoses assigned before year 1997. CONCLUSIONS: Men with Peyronie's disease are at increased risk of being diagnosed with adverse psychiatric outcomes. Health care providers should ensure that men with Peyronie's disease have a documented mental health status assessment.

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

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.

Metabolic phenotype in Darier disease: a cross-sectional clinical study.

BACKGROUND: Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in diabetes is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum ATPase 2 (SERCA2) calcium pump, which causes calcium dyshomeostasis and ER stress. We hypothesize that DD patients have a diabetes-like metabolic phenotype and the objective of this study was to examine the association between DD with impaired glucose tolerance and diabetes. METHODS: Cross-sectional clinical study on 25 DD patients and 25 matched controls. Metabolic status was assessed primarily by fasting blood glucose, oral glucose tolerance test, HOMA2-%S (insulin resistence) and HOMA2-%B (beta cell function). RESULTS: DD subjects showed normal oral glucose tolerance test and HOMA2-%S, while fasting blood glucose was lower and c-peptide as well as HOMA2-%B was higher. CONCLUSION: Increased HOMA2-%B values are indicative of increased basal insulin secretion which is a type of beta cell dysfunction associated to diabetes development. These results supports a role of ER stress in diabetes pathophysiology and contribute to the understanding of DD as a multi-organ syndrome.

Comparison of suicide risk and other outcomes among boys and girls who self-harm.

Little is known about sex differences in outcomes of self-harm, and there are inconclusive results concerning the association between sex, self-harm, and suicide attempts. The aim of this study was to explore sex differences in outcomes of self-harm in adolescence. In this cohort study, all individuals (0-17 years) enrolled at the child- and adolescent mental health services (CAMHS) in Stockholm between 2001 and 2015 (N = 110,072) were followed in national registers from their last contact with the CAMHS, until end of 2015. Exposure was self-harm as reason for contact, outcome measures were: alcohol-/substance use disorder, psychiatric hospitalization, non-violent or violent crime, and suicide. Differences in outcomes rates between exposed versus unexposed males, and exposed versus unexposed females, were examined using Cox regressions, expressed as hazard ratios (HR) with 95% confidence intervals (CI). Median follow-up time was 5.8 years (Q1: 2.3 years; Q3: 9.7 years). Self-harm was documented in 2.2% (N = 1241) males and 8.7% (4716) females. Exposed individuals had higher HR for all outcomes as compared with unexposed individuals of their own sex. Exposed females had more pronounced risk for drug use disorder (HR 11.2; 95% CI 9.9-12.7) compared with exposed males (HR 6.5, 95% 5.2-8.0). Both males and females who had engaged in self-harm had elevated risks for future suicide. Adjusting for socio-economic status and age at start of follow-up only marginally affected the associations. Females and males with self-harm had similarly elevated risk for suicide, and self-harm was also an important risk marker for other adverse outcomes within both sexes.

Associations between conduct problems in childhood and adverse outcomes in emerging adulthood: a longitudinal Swedish nationwide twin cohort.

BACKGROUND: We examined whether childhood conduct problems predicted a wide range of adverse outcomes in emerging adulthood and whether the association with internalizing problems remained after adjusting for general comorbidity and externalizing problems. METHODS: Participants were 18,649 twins from the Child and Adolescent Twin Study in Sweden. At age 9/12, parents rated their children on eight conduct problems. Adverse outcomes were retrieved from national registers in emerging adulthood (median follow-up time = 9.2 years), including diagnoses of six psychiatric disorders, prescriptions of antidepressants, suicide attempts, criminality, high school ineligibility, and social welfare recipiency. We estimated risk for the separate outcomes and examined if conduct problems predicted an internalizing factor above and beyond a general comorbidity and an externalizing factor. We used twin analyses to estimate genetic and environmental contributions to these associations. RESULTS: On the average, each additional conduct symptom in childhood was associated with a 32% increased risk of the adverse outcomes in emerging adulthood (mean hazard ratio = 1.32; range = 1.16, 1.56). A latent childhood conduct problems factor predicted the internalizing factor in emerging adulthood (ßboys  = .24, standard error, SE = 0.03; ßgirls  = .17, SE = 0.03), above and beyond its association with the externalizing (ßboys  = 0.21, SE = 0.04; ßgirls  = 0.17, SE = 0.05) and general factors (ßboys  = 0.45, SE = 0.03; ßgirls  = 0.34, SE = 0.04). These associations were differentially influenced by genetic and environmental factors. CONCLUSIONS: It is important to monitor boys and girls with conduct problems not only for future externalizing problems, but also for future internalizing problems. Prevention of specific outcomes, however, might require interventions at different levels.

Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths: A Systematic Review and Meta-analysis of Longitudinal Population Studies.

Importance: Recent research has highlighted that psychotic experiences are far more prevalent than psychotic disorders and associated with the full range of mental disorders. A particularly strong association between psychotic experiences and suicidal behavior has recently been noted. Objective: To provide a quantitative synthesis of the literature examining the longitudinal association between psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide deaths in the general population. Data Sources: We searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO from their inception until September 2017 for longitudinal population studies on psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. Study Selection: Two authors searched for original articles that reported a prospective assessment of psychotic experiences and suicidal ideation, suicide attempts, or suicide death in general population samples, with at least 1 follow-up point. Data Extraction and Synthesis: Two authors conducted independent data extraction. Authors of included studies were contacted for information where necessary. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale. We calculated pooled odds ratios using a random-effects model. A secondary analysis assessed the mediating role of co-occurring psychopathology. Main Outcomes and Measures: Psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. Results: Of a total of 2540 studies retrieved, 10 met inclusion criteria. These 10 studies reported on 84 285 participants from 12 different samples and 23 countries. Follow-up periods ranged from 1 month to 27 years. Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78]). Risk was increased in excess of that explained by co-occurring psychopathology: suicidal ideation (adjusted OR, 1.59 [95% CI, 1.09-2.32]) and suicide attempt (adjusted OR, 2.68 [95% CI, 1.71-4.21]). Conclusions and Relevance: Individuals with psychotic experiences are at increased risk of suicidal ideation, suicide attempts, and suicide death. Psychotic experiences are important clinical markers of risk for future suicidal behavior.

Adolescent self-harm with and without suicidality: cross-sectional and longitudinal analyses of a Swedish regional register.

BACKGROUND: Self-harm is common and there is a need for studies that investigate the relevance of this behavior in clinical samples to inform risk assessment and treatment. The objectives in the current studies were to compare clinical and psychosocial correlates and subsequent adverse outcomes in youth who present to child and adolescent mental health services (CAMHS) with self-harm only (SH), self-harm with suicidality (SH+SU), with those without any indication of SH or SH+SU. METHODS: We conducted a case-control study and a longitudinal cohort study using data from a regional clinical care register, and Swedish national registers. The case-control study included all patients (5-17 years) between 2011 and 2015 (N = 25,161). SH and SH+SU cases were compared with controls (patients without SH) regarding a range of correlates. The longitudinal study included former CAMHS patients (N = 6,120) who were followed for a median time of 2.8 years after termination of CAMHS contact regarding outcomes such as clinical care consumption, social welfare recipiency, and crime conviction. RESULTS: In the case-control study, both the SH and SH+SU groups received more clinical care, had lower global functioning, and higher odds of having mental disorders compared to controls. In most comparisons, the SH+SU group had more problems than the SH group. In the longitudinal study, the same pattern emerged for most outcomes; for example, the adjusted hazard ratio for recurrent care due to self-harm was 23.1 (95% confidence interval [CI], 17.0-31.4) in the SH+SU group compared to 3.9 (95% CI, 2.3-6.7) in the SH group. CONCLUSIONS: Adolescent patients presenting with self-harm have higher risks for adverse outcomes than patients without self-harm. Suicidality in addition to self-harm is associated with more severe outcomes, importantly recurrent episodes of care for self-harm.

Novel mutations in Darier disease and association to self-reported disease severity.

Darier disease is a rare and severe autosomal dominant skin disease characterised by malodorous keratotic papules in seborrheic areas of the skin. Darier disease affects up to 1 in 30 000 people and is caused by mutations in the ATP2A2 gene, which encodes to the sarco/endoplasmic reticulum calcium-ATPase isoform 2 that pumps calcium into the endoplasmic reticulum. Although many ATP2A2 variants have been described, it is not known if genotype correlates with phenotype, which could be important for prognosis and treatment. This is the first study to use whole exome sequencing to screen the ATP2A2 gene in a cohort of 28 clinically diagnosed Darier disease patients. Twenty-one different disease causing variants were identified and 15 of these were novel. Sixteen of the 21 variants were predicted to be pathogenic using in silico prediction programs. There were seven missense, four intronic/splice-sites, three frameshifts, two in-frame deletions, four nonsense and one synonymous mutations. This study also found ten patients who harbour more than one ATP2A2 variant. The phenotype of the patient cohort was assessed by photography and by patient questionnaires. The genotype-phenotype association was examined for all variants in relation to the patient's disease severity score, and no correlation could be established.