Persistent physical symptoms: definition, genesis, and management.

Persistent physical symptoms (synonymous with persistent somatic symptoms) is an umbrella term for distressing somatic complaints that last several months or more, regardless of their cause. These symptoms are associated with substantial disability and represent a major burden for patients, health-care professionals, and society. Persistent physical symptoms can follow infections, injuries, medical diseases, stressful life events, or arise de novo. As symptoms persist, their link to clearly identifiable pathophysiology often weakens, making diagnosis and treatment challenging. Multiple biological and psychosocial risk factors and mechanisms contribute to the persistence of somatic symptoms, including persistent inflammation; epigenetic profiles; immune, metabolic and microbiome dysregulation; early adverse life experiences; depression; illness-related anxiety; dysfunctional symptom expectations; symptom focusing; symptom learning; and avoidance behaviours, with many factors being common across symptoms and diagnoses. Basic care consists of addressing underlying pathophysiology and using person-centred communication techniques with validation, appropriate reassurance, and biopsychosocial explanation. If basic care is insufficient, targeted psychological and pharmacological interventions can be beneficial. A better understanding of the multifactorial persistence of somatic symptoms should lead to more specific, personalised, and mechanism-based treatment, and a reduction in the stigma patients commonly face.

Understanding illness experiences of patients with primary sclerosing cholangitis: a qualitative analysis within the SOMA.LIV study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with a largely unpredictable course. Due to limited treatment options, individuals may for many years suffer from distressing symptoms and the emotional burden of an uncertain future. The need to shift from cure to care of PSC has spurred an interest into patients' health-related quality of life. Qualitative research in this context remains scarce. Hence, this study aimed to enrich the clinical understanding about the lived experience of PSC through a qualitative approach. METHODS: A total of 20 patients with PSC were recruited at a specialist centre for autoimmune liver disease in Germany and engaged in semi-structured telephone-based interviews between March and June 2022. Verbatim transcripts were interpreted using inductive thematic analysis. RESULTS: An overarching concept of 'a wave-like experience' was formulated to illustrate the dual and shifting nature of living with PSC. Reflecting upon this central idea, three major themes were generated to address important aspects of participants' illness experiences: 'Invisible presence' focused on perceptions of suffering from a seemingly hidden illness that periodically reveals itself through specific trigger events. 'Embracing the threat' captured the psycho-emotional response shift to this chronic disease from a predominantly negative to a coping-oriented pattern with regular setbacks. 'Between control and constraints' uncovered restrictions that PSC enforces onto patients' lives and their desire for controllability. CONCLUSIONS: The present study provides an in-depth look at the fluctuating tensions arising from a life with PSC. Insights on perceived invisibility, disease-related triggers of emotional distress and the complexity behind self-management highlight opportunities for enhanced clinical support of this patient group.

Beliefs about emotions predict psychological stress related to somatic symptoms.

BACKGROUND: Previous research has shown that the more people believe their emotions are controllable and useful (BECU), the less they generally report psychological distress. Psychological distress, in turn, impacts health outcomes, and is among the most frequently reported complaints in psychotherapeutic and psychosomatic practice. OBJECTIVE: We aimed to examine how BECU predicts psychological distress related to somatic symptoms in a prospective sample from the general population and to replicate this association in two cross-sectional samples of psychosomatic patients. METHODS: We applied a panel design with an interval of 2 weeks between T1 and T2 in general-population panel-participants (N = 310), assessing BECU and psychological distress related to somatic symptoms via validated self-report measures. Moreover, we cross-sectionally replicated the relationship between BECU and psychological distress in a clinical sample of psychosomatic outpatients diagnosed with somatoform disorders (n = 101) or without somatoform disorders (n = 628). RESULTS: BECU predicted over and above the lagged criterion panel-participants' psychological distress related to somatic symptoms, ß = -.18, p < .001. BECU was also cross-sectionally related to psychological distress in our clinical replication-sample of psychosomatic outpatients diagnosed with somatoform disorders, rS (87) = -.33, p = .002 and in those without, rS (557) = -.21, p < .001. CONCLUSIONS: BECU as a malleable way of thinking about emotions predicted psychological distress related to somatic symptoms in general-population panel-participants and correlated with the same in two clinical replication samples. BECU thus becomes a promising treatment target in psychotherapeutic approaches.

Predictors of somatic symptom burden in healthcare professionals during the COVID-19 pandemic: an 8-week follow-up study.

BACKGROUND: Literature investigating the impact of COVID-19 on healthcare professionals barely addresses predictors of somatic symptom burden during the COVID-19 pandemic. AIMS: As biopsychosocial models propose that not only the disease but also sociodemographic and psychosocial factors contribute to the development and maintenance of symptoms, this study investigates the predictive value of these factors for bothersome somatic symptoms in SARS-CoV-2 negative healthcare professionals. METHODS: German healthcare professionals were assessed with self-rating questionnaires and underwent SARS-CoV-2 IgG antibody tests at baseline and 8 weeks later between April and August 2020. Differences in psychosocial variables between the time points were analyzed and regression analyses were performed to predict somatic symptoms at follow-up. RESULTS: 1185 seronegative healthcare professionals completed both assessments. Previous somatic symptom burden, higher levels of anxiety, being a nurse, younger age, higher psychological symptom burden, lower efficiency, and higher fatigability at baseline predicted somatic symptom burden at follow-up. Comparisons between baseline and follow-up showed a significant improvement in psychological impairment and deterioration of physical exhaustion. CONCLUSIONS: Our study applies a biopsychosocial perspective to bothersome somatic symptoms during the COVID-19 pandemic and contributes to the identification of potential risk factors as a starting point for future interventions that could support the handling of symptoms.

Somatic symptom disorder: a scoping review on the empirical evidence of a new diagnosis.

BACKGROUND: In 2013, the diagnosis of somatic symptom disorder (SSD) was introduced into the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). This review aims to comprehensively synthesize contemporary evidence related to SSD. METHODS: A scoping review was conducted using PubMed, PsycINFO, and Cochrane Library. The main inclusion criteria were SSD and publication in the English language between 01/2009 and 05/2020. Systematic search terms also included subheadings for the DSM-5 text sections; i.e., diagnostic features, prevalence, development and course, risk and prognostic factors, culture, gender, suicide risk, functional consequences, differential diagnosis, and comorbidity. RESULTS: Eight hundred and eighty-two articles were identified, of which 59 full texts were included for analysis. Empirical evidence supports the reliability, validity, and clinical utility of SSD diagnostic criteria, but the further specification of the psychological SSD B-criteria criteria seems necessary. General population studies using self-report questionnaires reported mean frequencies for SSD of 12.9% [95% confidence interval (CI) 12.5-13.3%], while prevalence studies based on criterion standard interviews are lacking. SSD was associated with increased functional impairment, decreased quality of life, and high comorbidity with anxiety and depressive disorders. Relevant research gaps remain regarding developmental aspects, risk and prognostic factors, suicide risk as well as culture- and gender-associated issues. CONCLUSIONS: Strengths of the SSD diagnosis are its good reliability, validity, and clinical utility, which substantially improved on its predecessors. SSD characterizes a specific patient population that is significantly impaired both physically and psychologically. However, substantial research gaps exist, e.g., regarding SSD prevalence assessed with criterion standard diagnostic interviews.

Prevalence of DSM-5 somatic symptom disorder in Chinese patients with breast cancer.

OBJECTIVE: The aims of this study were to explore the frequency of somatic symptom disorder (SSD) and the relationship between SSD and somatic, psychological, and social factors in Chinese patients with breast cancer. METHODS: This multicenter cross-sectional study enrolled 264 patients with breast cancer from three different departments in Beijing. The structured clinical interview for fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (SCID-5) for SSD. Standardized questionnaires and clinical data were used to compare patients with and without SSD. RESULTS: Somatic symptom disorder was diagnosed in 21.6% (57/264) of all enrolled patients. No differences were found between SSD patients and non-SSD patients in terms of sociodemographic characteristics and tumor-specific variables, except radiotherapy. However, patients with SSD reported higher levels of depression, anxiety and cancer-related worry. They also showed a longer duration of symptoms, greater impairment in daily life, more concern over their physical complaints and more doctor visits. In a stepwise binary logistic regression analysis, among others, higher health anxiety (WI-8, Exp(B) = 0.107, p = 0.009) and more doctor visits (OR = -1.841, p < 0.001) showed a significant association with SSD; the model explained 53.7% of the variance. CONCLUSIONS: Similar to other physical diseases, there is a high prevalence of SSD in patients with breast cancer. Somatic symptom disorder patients differ from non-SSD patients by exhibiting higher cancer-related emotional distress and dysfunctional illness perception and behavior. There remain substantial challenges in the diagnosis of SSD in patients with cancer and other medical conditions. CLINICAL TRIAL REGISTRATION: ChiCTR2100051525.

A multicenter study of bodily distress syndrome in Chinese outpatient hospital care: prevalence and associations with psychosocial variables.

BACKGROUND: Bodily distress syndrome (BDS) is a new, empirical-based diagnosis of functional somatic symptoms. This study aimed to explore the prevalence of BDS and its association with psychosocial variables in a Chinese clinical population. METHODS: A multicentre cross-sectional study of 1269 patients was conducted in 9 different Chinese tertiary outpatient hospitals. The BDS was identified by trained interviewers face-to face, based on a brief version of the Schedules for Assessment in Neuropsychiatry (RIFD) and the BDS Checklist-25. Sociodemographic data and further information were characterised from psychometric questionnaires (The Patient Health Questionnaire-15, the Patient Health Questionnaire-9, the General Anxiety Disorder-7, the Whiteley scale-8) . RESULTS: Complete data were available for 697 patients. The prevalence of BDS was 26.8% (95% confidence interval (CI): 23.5-30.1). Among the participants, 5.8% (95% CI: 4.1-7.6) fulfilled the criteria for single-organ BDS, while 20.9% (95%CI: 17.9-24.0) had multi-organ BDS. Comparison of the PHQ-15, PHQ-9, GAD-7, and WI-8 scores revealed higher scores on all dimensions for patients with BDS. In a binary logistic regression analysis, BDS was significantly associated with increased health-related anxiety (WI-8) and depression (PHQ-9). The explained variance was Nagelkerke's R2 = 0.42. CONCLUSIONS: In China, the BDS is a common clinical condition in tertiary outpatient hospital settings with high prevalence, and is associated with health anxiety and depressive symptoms. In this clinical population, the severe multi-organ subtype of BDS was the most frequent.

Excessiveness in Symptom-Related Thoughts, Feelings, and Behaviors: An Investigation of Somatic Symptom Disorders in the General Population.

OBJECTIVE: The diagnostic criteria of somatic symptom disorder (SSD) emphasize that somatic symptoms receive disease value once they are accompanied by excessive thoughts, feelings, or behaviors. The main objective of this study was to examine what constitutes excessiveness in psychological reactions to somatic complaints and how excessive symptom-related behavior influences self-reported health status and health care utilization. METHODS: A national, representative general population survey was performed between January and March 2016 in Germany, including 2395 individuals older than 13 years. Self-report questionnaires (Somatic Symptom Scale-8, Somatic Symptom Disorder-B Criteria Scale) were used to operationalize the SSD criteria. Group differences in the daily amount of time dedicated to physical complaints were analyzed between individuals with and without SSD. Stepwise linear regression analyses were performed to predict general mental and physical health status, and health care utilization. RESULTS: There was a significant effect of group (SSD yes/no) in daily time spent on symptoms, after controlling for age, sex, depression, and anxiety (F(1,2336) = 447.53, p < .001). The SSD group (n = 213) reported an average of 4 hours, whereas individuals without SSD reported 30 minutes. Results of the regression analyses showed that the combination of somatic symptoms and symptom-related psychological features is predictive of worsened self-reported physical and mental health status, and increased health care utilization. CONCLUSIONS: A range of 3 to 4 hours per day spent on dealing with physical complaints seems indicative of excessiveness. If, during a clinical consultation, a patient reports such a large amount of time, a more comprehensive clinical examination of SSD should follow.

Assessment of the structured clinical interview (SCID) for DSM-5 for somatic symptom disorder in general hospital outpatient clinics in China.

BACKGROUND: It is still unknown whether the "Somatic symptom disorders (SSD) and related disorders" module of the Structured Clinical Interview for DSM-5, research version (SCID-5-RV), is valid in China. This study aimed to assess the SCID-5-RV for SSD in general hospital outpatient clinics in China. METHODS: This multicentre cross-sectional study was conducted in the outpatient clinics of nine tertiary hospitals in Beijing, Jincheng, Shanghai, Wuhan, and Chengdu between May 2016 and March 2017. The "SSD and related disorders" module of the SCID-5-RV was translated, reversed-translated, revised, and used by trained clinical researchers to make a diagnosis of SSD. Several standardized questionnaires measuring somatic symptom severity, emotional distress, and quality of life were compared with the SCID-5-RV. RESULTS: A total of 699 patients were recruited, and 236 were diagnosed with SSD. Of these patients, 46 had mild SSD, 78 had moderate SSD, 100 had severe SSD, and 12 were excluded due to incomplete data. The SCID-5-RV for SSD was highly correlated with somatic symptom severity, emotional distress, and quality of life (all P < 0.001) and could distinguish nonsevere forms of SSD from severe ones. CONCLUSIONS: This study suggests that SCID-5-RV for SSD can distinguish SSD from non-SSD patients and severe cases from nonsevere cases. It has good discriminative validity and reflects the DSM-5 diagnostic approach that emphasizes excessive emotional, thinking, and behavioural responses related to symptoms.

Persistence rate of DSM-5 somatic symptom disorder: 4-year follow-up in patients from a psychosomatic outpatient clinic.

BACKGROUND: Somatic Symptom and Related Disorders (SSD) were introduced by DSM-5 in order to improve the classification of somatoform disorders. There is a lack of longitudinal studies on course and predictors of SSD. The present study investigates the natural course of SSD in a four-year follow-up study in patients from a psychosomatic outpatient clinic. MATERIAL AND METHODS: At baseline, n = 360 outpatients completed a semi-structured clinical interview to assess SSD, and additional self-report questionnaires (SSS-8, SSD-12, PHQ-8, GAD-7, SF-12). 112 patients were re-assessed after four years. Persistence rate and predictors for persisting SSD were evaluated. RESULTS: The prevalence rate of SSD at baseline was 51.8%, and 47.3% at follow-up. We found a persisting SSD in 30.4% (n = 34) of the patients, a remission rate of 21.4% (n = 24) and an incidence rate of 16.9% (n = 19). 31.3% (n = 35) of the sample never received a SSD diagnosis. Significant predictors for persistence were a high psychological burden through somatic symptoms (OR: 1.13, 95% CI: 1.01-1.26) and general anxiety (OR: 1.38, 95% CI: 1.01-1.88) at baseline. CONCLUSION: This study indicates that SSD is highly prevalent and persistent in patients from a psychosomatic setting. Our findings indicate that psychological and behavioral factors contribute to the maintenance of SSD and present potential targets for interventions. Future interventions for SSD could potentially be optimized by addressing psychological processes such as catastrophic thinking styles and symptom focusing.

Validation of the Chinese Version of the Somatic Symptom Disorder-B Criteria Scale for Detecting DSM-5 Somatic Symptom Disorders: A Multicenter Study.

OBJECTIVE: This study aimed to validate the Chinese version of the Somatic Symptom Disorder-B Criteria Scale (SSD-12) in an outpatient sample from Chinese general hospitals and to determine the diagnostic performance of the SSD-12 as a screening tool for somatic symptom disorder (SSD). METHODS: The Chinese version of the SSD-12 was completed by 699 outpatients from nine general hospitals during a 16-month period (2016-2018). The SSD section of the Structured Clinical Interview for DSM Disorders, Fifth Edition, Research Version, was used to determine diagnostic accuracy (criterion validity). The construct validity of the SSD-12 was evaluated by examining correlations with the Whiteley Index-7, Patient Health Questionnaire-15, Patient Health Questionnaire-9, General Anxiety Disorder-7, World Health Organization Disability Assessment Schedule, and Medical Outcome Study 12-item Short Form Health Survey (SF-12). RESULTS: The SSD-12 had excellent internal consistency in this sample (Cronbach α = .95). Confirmatory factor analyses replicated a three-factor structure that reflects the cognitive, affective, and behavioral aspects (Comparative Fit Index = 0.963, Tucker-Lewis Index = 0.952, root mean square error of approximation = 0.08, 90% confidence interval = 0.08-0.09), but was also consistent with a general one-factor model of the SSD-12 (Comparative Fit Index = 0.957, Tucker-Lewis Index = 0.948, root mean square error of approximation = 0.09, 90% confidence interval = 0.08-0.10). The optimal cutoff point for the Structured Clinical Interview for DSM Disorders-based diagnosis of SSD was 16 (sensitivity = 0.76, specificity = 0.80). The SSD-12 sum score was significantly associated with somatic symptom burden (Patient Health Questionnaire-15: r = 0.52, p < .001), health anxiety (Whiteley Index-7: r = 0.82, p < .001), depressive symptoms (Patient Health Questionnaire-9: r = 0.63, p < .001), general anxiety (General Anxiety Disorder-7: r = 0.64, p < .001), health-related quality of life (physical component score of SF-12: r = -0.49, p < .001; mental component score of SF-12: r = -0.61, p < .001), and health-related disabilities (World Health Organization Disability Assessment Schedule: r = 0.56, p < .001). CONCLUSIONS: Initial assessment indicates that the Chinese version of the SSD-12 has sufficient reliability and validity to warrant further testing in both research and clinical settings.

Detecting DSM-5 somatic symptom disorder: criterion validity of the Patient Health Questionnaire-15 (PHQ-15) and the Somatic Symptom Scale-8 (SSS-8) in combination with the Somatic Symptom Disorder - B Criteria Scale (SSD-12).

BACKGROUND: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduced somatic symptom and related disorders (SSD) to improve the diagnosis of somatoform disorders. It is unclear whether existing questionnaires are useful to identify patients with SSD. Our study investigates the diagnostic accuracy of the Patient Health Questionnaire-15 (PHQ-15) and the Somatic Symptom Scale-8 (SSS-8) in combination with the Somatic Symptom Disorder - B Criteria Scale (SSD-12). METHODS: For this cross-sectional study, participants were recruited from a psychosomatic outpatient clinic. PHQ-15, SSS-8, and SSD-12 were administered and compared with SSD criteria from a diagnostic interview. Sensitivity and specificity were calculated for optimal individual and combined cutpoints. Receiver operator curves were created and area under the curve (AUC) analyses assessed. RESULTS: Data of n = 372 patients [31.2% male, mean age: 39.3 years (s.d. = 13.6)] were analyzed. A total of 56.2% fulfilled the SSD criteria. Diagnostic accuracy was moderate for each questionnaire (PHQ-15: AUC = 0.70; 95% CI = 0.65-0.76; SSS-8: AUC = 0.71; 95% CI = 0.66-0.77; SSD-12: AUC = 0.74; 95% CI = 0.69-0.80). Combining questionnaires improved diagnostic accuracy (PHQ-15 + SSD-12: AUC = 0.77; 95% CI = 0.72-0.82; SSS-8 + SSD-12: AUC = 0.79; 95% CI = 0.74-0.84). Optimal combined cutpoints were ⩾9 for the PHQ-15 or SSS-8, and ⩾23 for the SSD-12 (sensitivity and specificity = 69% and 70%). CONCLUSIONS: The combination of the PHQ-15 or SSS-8 with the SSD-12 provides an easy-to-use and time- and cost-efficient opportunity to identify persons at risk for SSD. If systematically applied in routine care, effective screening and subsequent treatment might help to improve quality of life and reduce health care excess costs.

Validity of the Somatic Symptom Disorder-B Criteria Scale (SSD-12) in primary care.

Aim: The Somatic Symptom Disorder-B Criteria Scale (SSD-12) assesses the psychological features of DSM-5 somatic symptom disorder. The purpose of the current study was to investigate the psychometric characteristics and validity of the 12-item instrument to demonstrate its suitability in primary care. Method: The study was designed as a cross-sectional survey set in five primary care practices from Munich, Germany (n = 501, 52.0% female, mean age 47 ± 16 years). Item and scale characteristics, as well as measures of reliability and validity, were determined. Results: The SSD-12 has good item characteristics and excellent reliability (Cronbach's α = 0.92). Confirmatory factor analyses provided evidence to support a general factor model of the SSD-12 in primary care (comparative fit index > 0.98, Tucker-Lewis index > 0.98, root mean square error of approximation = 0.090, 90% confidence interval: 0.078-0.102). SSD-12 total sum-score was significantly associated with somatic symptom burden (r = 0.48, P < 0.001), general anxiety (r = 0.54, P < 0.001) and depressive symptoms (r = 0.60, P < 0.001). At the group level, SSD-12 scores could differentiate between different patient groups (e.g. with and without chronic illness). Conclusions: The SSD-12 appears to be a reliable, valid and time-efficient self-report measure of the psychological characteristics related to the experience of somatic symptoms which is suitable for primary care. Future research should evaluate its responsiveness to treatment and feasibility as a screening tool in different clinical settings.

Core Outcome Domains for Clinical Trials on Somatic Symptom Disorder, Bodily Distress Disorder, and Functional Somatic Syndromes: European Network on Somatic Symptom Disorders Recommendations.

OBJECTIVE: The harmonization of core outcome domains in clinical trials facilitates comparison and pooling of data, and simplifies the preparation and review of research projects and comparison of risks and benefits of treatments. Therefore, we provide recommendations for the core outcome domains that should be considered in clinical trials on the efficacy and effectiveness of interventions for somatic symptom disorder, bodily distress disorder, and functional somatic syndromes. METHODS: The European Network on Somatic Symptom Disorders group of more than 20 experts in the field met twice in Hamburg to discuss issues of assessment and intervention research in somatic symptom disorder, bodily distress disorder, and functional somatic syndromes. The consensus meetings identified core outcome domains that should be considered in clinical trials evaluating treatments for somatic symptom disorder and associated functional somatic syndromes. RESULTS: The following core domains should be considered when defining ascertainment methods in clinical trials: a) classification of somatic symptom disorder/bodily distress disorder, associated functional somatic syndromes, and comorbid mental disorders (using structured clinical interviews), duration of symptoms, medical morbidity, and prior treatments; b) location, intensity, and interference of somatic symptoms; c) associated psychobehavioral features and biological markers; d) illness consequences (quality of life, disability, health care utilization, health care costs; e) global improvement and treatment satisfaction; and f) unwanted negative effects. CONCLUSIONS: The proposed criteria are intended to improve synergies of clinical trials and to facilitate decision making when comparing different treatment approaches. These recommendations should not result in inflexible guidelines, but increase consistency across investigations in this field.

Development and Validation of the Somatic Symptom Disorder-B Criteria Scale (SSD-12).

OBJECTIVE: To develop and validate a new self-report questionnaire for the assessment of the psychological features of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition somatic symptom disorder. METHODS: The Somatic Symptom Disorder-B Criteria Scale (SSD-12) was developed in several steps from an initial pool of 98 items. The SSD-12 is composed of 12 items; each of the three psychological subcriteria is measured by four items. In a cross-sectional study, the SSD-12 was administered to 698 patients (65.8% female, mean [standard deviation] age = 38.79 [14.15] years) from a psychosomatic outpatient clinic. Item and scale characteristics as well as measures of reliability and validity were determined. RESULTS: The SSD-12 has good item characteristics and excellent reliability (Cronbach α = .95). Confirmatory factor analyses suggested that a three-factorial structure that reflects the three psychological criteria interpreted as cognitive, affective, and behavioral aspects (n = 663, Comparative Fit Index > 0.99, Tucker-Lewis Index > 0.99, Root Mean Square Error of Approximation = 0.06, 90% confidence interval = 0.01-0.08). SSD-12 total sum score was significantly associated with somatic symptom burden (r = 0.47, p < .001) and health anxiety (r = 0.71, p < .001), and moderately associated with general anxiety (r = 0.35, p < .001) and depressive symptoms (r = 0.22, p < .001). Patients with a higher SSD-12 psychological symptom burden reported higher general physical and mental health impairment and significantly higher health care use. CONCLUSIONS: The SSD-12 is the first self-report questionnaire that operationalizes the new psychological characteristics of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition somatic symptom disorder. Initial assessment indicates that the SSD-12 has sufficient reliability and validity to warrant further testing in both research and clinical settings.

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy.

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.

Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy.

Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin (MTM1), whereas mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 (BIN1) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR (Bin1/amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.

Defective membrane remodeling in neuromuscular diseases: insights from animal models.

Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches.

Intersectional inequalities in somatic symptom severity in the adult population in Germany found within the SOMA.SOC study.

Somatic symptoms are common in a wide range of medical conditions. In severe cases, they are associated with high individual and economic burden. To explore social inequalities in somatic symptom severity (SSS) and to identify social groups with highest SSS, we applied an intersectional research approach. Analyses are based on cross-sectional data of the adult population living in Germany (N = 2413). SSS was assessed with the Somatic Symptom Scale-8. A multiple linear regression model with three-way interaction of gender, income and history of migration and post-hoc pairwise comparison of estimated marginal means was conducted. Analyses revealed intersectional inequalities in SSS along the axis of gender, income, and history of migration. Highest SSS was found in males with low income whose parent(s) immigrated, females with low income who immigrated themselves, and females with low income and no history of migration. Intersectional approaches contribute to a more comprehensive understanding of health disparities. To reduce disparities in SSS, proportionate universal interventions combining universal screening and targeted treatment seem promising.

Psychological risk factors of somatic symptom disorder: A systematic review and meta-analysis of cross-sectional and longitudinal studies.

OBJECTIVE: Current diagnostic concepts of somatic symptom disorder (SSD) in DSM-5 and bodily distress disorder (BDD) in ICD-11 require certain psychological criteria, but researchers have called for further specification. Therefore, in a first step, this systematic review and meta-analysis aimed to summarize the current evidence on psychological factors associated with SSD/BDD and/or disorder-relevant clinical outcomes such as symptom severity and impairment. METHODS: Psychological factors were systematically searched using Pubmed, Cochrane Library and Psycinfo via EBSCO. Studies providing original data in English or German, after 2009 were included. Cross-sectional, cohort and case-control studies investigating at least one psychological factor in individuals with SSD/BDD in the context of disorder-relevant outcomes were included. RESULTS: Forty-three eligible studies (n = 3760 patients) in SSD (none in BDD) provided data on at least one psychological factor, 37 in case-control format, 10 cross-sectional and 5 longitudinal. Meta-analyses of the case-control studies found patients with SSD to be more impaired by depression (SMD = 1.80), anxiety (SMD = 1.55), health anxiety (SMD = 1.31) and alexithymia (SMD = 1.39), compared to healthy controls. Longitudinal results are scarce, mixed, and require refining, individual studies suggest self-concept of bodily weakness, anxiety and depression to be predictive for persistent SSD and physical functioning. CONCLUSION: This review provides a detailed overview of the current evidence of psychological factors in relation to SSD/BDD. Future studies on SSD and BDD should include under-studied psychological factors, such as negative affect, fear avoidance, or emotion regulation. More longitudinal studies are needed to assess the predictive value of these factors.