Low vitamin C status and hypermobility-related disorders in patients with bleeding disorder of unknown cause.

INTRODUCTION: Bleeding disorder of unknown cause (BDUC) is a challenging diagnosis that predominantly affects women. Previous investigations into connective tissue disorders (CTD) and vitamin C have not been conducted. AIM: To examine the association between hypermobility-related disorders, vitamin C status and BDUC. METHODS: Patients were selected following laboratory and genetic screening that yielded negative results for known hemostasis disorders. Sixty patients with BDUC and an ISTH BAT score ≥ 10 underwent clinically examination for skin hyperextensibility and for hypermobility assessed by Beighton score. Vitamin C was analyzed by high-performance liquid chromatography. Genetic screening for causal variants in 42 CTD genes was performed. RESULTS: The majority of patients were female (56/60). Median ISTH BAT score was 13 (range 10-23). Beighton score was positive in 29/60 patients compared to 1/20 healthy controls (HC) (p < .001). Hyperextensive skin was observed in (18/60) patients, and none (0/20) of the HC (p = .0041). Ten patients met the clinical diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS), and one patient was diagnosed with Noonan syndrome. Genetic screening excluded various subtypes of EDS with known genetic backgrounds. Average vitamin C level was adequate, but lower than in HC (55.9 vs. 70.4 µmol/L; p = .001). Suboptimal, or low vitamin C were identified in 19/60 compared to 1/20 HC (p = .018). CONCLUSION: Our study demonstrates that BDUC is frequently associated with hypermobility disorders and low vitamin C status. Our results could pave the way for a randomized study of vitamin C supplementation in patients with BDUC.

A Rare Case of De Novo Beta-Thalassemia Diagnosed by Whole-Genome Sequencing in an Ethnically Danish Newborn.

In 2020, a 2-month-old ethnically Danish girl was diagnosed with ß-thalassemia after presenting with persistent jaundice. The peripheral blood smear showed significant aniso- and poikilocytosis, increased number of reticulocytes and erythroblastosis. Trio analysis of the index patient and both parents was performed by whole-genome sequencing. Here, both parents were found normal, however the analysis revealed an apparently de novo HBB:c.444A > C variant in the child. The child has recently been discharged three months after a successful bone marrow transplantation with a matched sibling-donor.

Psychiatric comorbidity: a concept in need of a theory.

Despite being a relatively new concept, psychiatric comorbidity, i.e. the co-occurrence of two or more mental disorders, has become widespread in clinical practice and psychiatric research. In this article, we trace the origin of the concept of psychiatric comorbidity, discuss the conceptual literature and point to basic problems concerning inadequate definition of the concept, differential diagnostic issues, and reification of mental disorders. We illustrate how these problems may have consequences for diagnostic assessment in current clinical practice and psychiatric research. To address some of the problems related to psychiatric comorbidity, we discuss potential principles for assessing psychiatric comorbidity. Inspired by Feinstein's original concept of comorbidity in general medicine and his differential diagnostic principles, we emphasize the importance of independence of mental disorders when assessing psychiatric comorbidity. We suggest that knowledge of trait v. state conditions and of the multitudinous clinical manifestations beyond what is captured in the diagnostic manuals may be helpful for assessing the independence of mental disorders and thus psychiatric comorbidity. We further argue that a more hierarchical diagnostic system and explicit exclusionary rules could improve clinical practice and research by reducing informational complexity and combating unwarranted psychiatric comorbidity.

Quartz-Enhanced Photoacoustic Spectroscopy Assisted by Partial Least-Squares Regression for Multi-Gas Measurements.

We report on the use of quartz-enhanced photoacoustic spectroscopy (QEPAS) for multi-gas detection. Photoacoustic (PA) spectra of mixtures of water (H2O), ammonia (NH3), and methane (CH4) were measured in the mid-infrared (MIR) wavelength range using a mid-infrared (MIR) optical parametric oscillator (OPO) light source. Highly overlapping absorption spectra are a common challenge for gas spectroscopy. To mitigate this, we used a partial least-squares regression (PLS) method to estimate the mixing ratio and concentrations of the individual gasses. The concentration range explored in the analysis varies from a few parts per million (ppm) to thousands of ppm. Spectra obtained from HITRAN and experimental single-molecule reference spectra of each of the molecular species were acquired and used as training data sets. These spectra were used to generate simulated spectra of the gas mixtures (linear combinations of the reference spectra). Here, in this proof-of-concept experiment, we demonstrate that after an absolute calibration of the QEPAS cell, the PLS analyses could be used to determine concentrations of single molecular species with a relative accuracy within a few % for mixtures of H2O, NH3, and CH4 and with an absolute sensitivity of approximately 300 (±50) ppm/V, 50 (±5) ppm/V, and 5 (±2) ppm/V for water, ammonia, and methane, respectively. This demonstrates that QEPAS assisted by PLS is a powerful approach to estimate concentrations of individual gas components with considerable spectral overlap, which is a typical scenario for real-life adoptions and applications.

Chronic migraine: Genetics or environment?

BACKGROUND: The transition from episodic migraine to chronic migraine, migraine chronification, is usually a gradual process, which involves multiple risk factors. To date, studies of the genetic risk factors for chronic migraine have focused primarily on candidate-gene approaches using healthy individuals as controls. AIMS AND METHODS: In this study, we used a large cohort of migraine families and unrelated migraine patients (n > 2200) with supporting genotype and whole-genome sequencing data. We evaluated whether there are any genetic variants, common or rare, with a specific association to chronic migraine compared with episodic migraine. RESULTS: We found no aggregation of chronic migraine in families with a clustering of migraine. No specific rare variants gave rise to migraine chronification, and migraine chronification was not associated with a higher polygenic risk score. Migraine chronification was not associated with allelic associations with an odds ratio above 2.65. Assessment of effect sizes with genome-wide significance below an odds ratio of 2.65 requires a genome-wide association study of at least 7500 chronic migraine patients. CONCLUSION: Our results suggest that migraine chronification is caused by environmental factors rather than genetic factors.

Functional gene networks reveal distinct mechanisms segregating in migraine families.

Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.

Higher burden of rare frameshift indels in genes related to synaptic transmission separate familial hemiplegic migraine from common types of migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare form of migraine with aura that often has an autosomal dominant mode of inheritance. Rare mutations in the CACNA1A, ATP1A2 and SCN1A genes can all cause FHM revealing genetic heterogeneity in the disorder. Furthermore, only a small subset of the affected individuals has a causal mutation. We set out to investigate what differentiates patients with FHM with no mutation in any known FHM gene from patients with common types of migraine in both familial and sporadic cases. METHODS: 2558 male and female participants from a migraine cohort from the Danish Headache Center were included. 112 had FHM; 743 had familial migraine; and 1703 had sporadic migraine. Using a linear regression model, we analysed for over-representation of rare functional variants in FHM versus familial migraine and sporadic migraine. Post hoc analyses included pathway analysis and testing for tissue specificity. RESULTS: We found that patients with FHM have significantly more rare frameshift indels compared with patients with familial migraine and sporadic migraine. Pathway analysis revealed that the 'ligand-gated ion channel activity' and 'G protein-coupled receptor downstream signalling' pathways were significantly associated with mutated genes. We moreover found that the mutated genes showed tissue specificity towards nervous tissue and muscle tissue. CONCLUSION: We show that patients with FHM compared with patients with common types of migraine suffer from a higher load of rare frameshift indels in genes associated with synaptic signalling in the central nervous system and possibly in muscle tissue contributing to vascular dysfunction.

Disordered Selfhood in Schizophrenia and the Examination of Anomalous Self-Experience: Accumulated Evidence and Experience.

Disordered selfhood in schizophrenia was rediscovered at the turn of the millennium. In 2005, Psychopathology published the psychometric instrument, the Examination of Anomalous Self-Experience (EASE). In this article, we summarize the historical background of the creation of the EASE, explicate the notion of the disorder of basic or minimal self with the help of phenomenological philosophy, and provide a brief description of clinical manifestations targeted by the EASE. We also present our personal experience using and teaching the EASE and summarize the empirical evidence obtained so far. We conclude that the basic self-disorder represents a crucial phenotype of schizophrenia spectrum disorders and that this phenotype offers a potential avenue to empirical pathogenetic research and psychotherapeutic treatment.

Familial analysis reveals rare risk variants for migraine in regulatory regions.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

INTRODUCTION: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants. MATERIALS AND METHODS: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex. RESULTS: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption. DISCUSSION: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.

Schizophrenia-spectrum psychopathology in obsessive-compulsive disorder: an empirical study.

The differential diagnosis of obsessive-compulsive disorder (OCD) and schizophrenia-spectrum disorders can be difficult. In the current diagnostic criteria, basic concepts such as obsession and delusion overlap. This study examined lifetime schizophrenia-spectrum psychopathology, including subtle schizotypal symptomatology and subjective anomalies such as self-disorders, in a sample diagnosed with OCD in a specialized setting. The study also examined the differential diagnostic potential of the classic psychopathological notions of true obsession ('with resistance') and pseudo-obsession. The study involved 42 outpatients diagnosed with OCD at two clinics specialized in the treatment of OCD. The patients underwent semi-structured, narrative interviews assessing a comprehensive battery of psychopathological instruments. The final lifetime research-diagnosis was based on a consensus between a senior clinical psychiatrist and an experienced research clinician. The study found that 29% of the patients fulfilled criteria of schizophrenia or another non-affective psychosis as main, lifetime DSM-5 research-diagnosis. Another 33% received a research-diagnosis of schizotypal personality disorder, 10% a research-diagnosis of major depression and 29% a main research-diagnosis of OCD. Self-disorders aggregated in the schizophrenia-spectrum groups. True obsessions had a specificity of 93% and a sensitivity of 58% for a main diagnosis of OCD. In conclusion, a high proportion of clinically diagnosed OCD patients fulfilled diagnostic criteria of a schizophrenia-spectrum disorder. The conspicuous obsessive-compulsive symptomatology may have resulted in a disregard of psychotic symptoms and other psychopathology. Furthermore, the differentiation of obsessions from related psychopathological phenomena is insufficient and a conceptual and empirical effort in this domain is required in the future.

EAFI: Examination of Anomalous Fantasy and Imagination.

The Examination of Anomalous Fantasy and Imagination (EAFI) is an instrument for a semistructured, phenomenological exploration of psychopathology of imagination. The EAFI provides a conceptual-descriptive framework to address such experiences. It consists of 16 main items, sometimes divided into subtypes. We suggest that the anomalies of imagination explored by the EAFI reflect an alteration in the structure of consciousness and belong to a fundamental, generative layer of psychopathology with relevance to differential diagnostic purposes.

A Phenomenological Approach to Psychopathology of Imagination: Development of a Descriptive Instrument - Examination of Anomalous Fantasy and Imagination.

This paper serves as an introduction to the Examination of Anomalous Fantasy and Imagination (EAFI) - a novel instrument for a semistructured, phenomenological exploration of psychopathology of imagination. We present an account of the phenomenology of imagination and proceed to a presentation of the disorders of imagination that are addressed in the EAFI. Furthermore, the interrater reliability of the EAFI was examined in a diagnostically heterogeneous sample of 20 in-patients. The interrater agreement ranged from 0.6 to 1.0, with an average κ of 0.84. The internal consistency of the EAFI as measured by Cronbach's α was above 0.88. We suggest that the anomalies of imagination explored by the EAFI reflect an alteration of the structure of consciousness and belong to a fundamental, generative layer of psychopathology. These disorders may have relevance for differential diagnostic purposes, especially in first-contact, young patients.

Anomalies of Imagination and Disordered Self in Schizophrenia Spectrum Disorders.

Vivid mental imagery occurs frequently in schizophrenia spectrum disorders (SSDs). Overlapping phenomena, such as obsessions or ruminations, are also frequent in other psychiatric disorders, raising significant diagnostic challenges. Unfortunately, contemporary operational psychopathology lacks the epistemological and phenomenological framework to address such questions. Using the resources of phenomenology and philosophy of mind, we articulate the structure of imagination and describe its distinctive modifications in the SSDs. Drawing on pilot data with patients' self-descriptions, we present the notion of perceptualized imagery. The anomalous imagery acquires spatialization, spatiotemporal constancy, explorability, autonomy and a sense of experiential distance between the subject and the image. As a quasi-perceptual, stable object, such imagery often evokes an intense affective response, whereas the normal sense of 'irreality' of the fantasy may become compromised. We articulate these anomalies of imagination as being entailed by the underlying generative disorder of schizophrenia, namely the disorder of minimal self (unstable ipseity or first-person perspective). We propose that pathology of imagination is an important psychopathological aspect of the schizophrenia spectrum, with significant relevance for early diagnosis and differential diagnosis.

Anomalies of imagination and development of psychosis: A phenomenological account.

In 20th century psychiatry, various disturbances of imagination were discussed in the context of schizophrenia. Today, these notions have almost completely vanished from mainstream psychopathology. However, recent work has suggested that specific phenomena within this area have a relevance for differential diagnosis and early detection of psychosis. This paper first provides an overview of 20th century psychopathological literature, as well as more recent neurocognitive studies, addressing disturbances of imagination and their role for symptom formation in schizophrenia. It then discusses recent empirical investigations of subjective anomalies of imagination in schizophrenia-spectrum disorders and suggests a clinical-phenomenological account of their role in the development of psychotic symptoms. Empirically and conceptually, these subjective anomalies are linked with disturbances of basic self. Patients' descriptions of the development of their anomalous experiences and symptoms indicate that increased spatial (object-like) articulation and instability of the first-personal manifestation of imaginative experience can be involved in the emergence of delusions and hallucinatory phenomena. Finally, a potential link between subjective anomalies of imagination and the neurocognitive construct of source monitoring deficits is discussed.

Glucose phosphate isomerase deficiency demasked by whole-genome sequencing: a case report.

BACKGROUND: Glucose-6-phosphate isomerase deficiency is a rare genetic disorder causing hereditary nonspherocytic hemolytic anemia. It is the second most common glycolytic enzymopathy in red blood cells. About 90 cases are reported worldwide, with symptoms including chronic hemolytic anemia, jaundice, splenomegaly, gallstones, cholecystitis, and in severe cases, neurological impairments, hydrops fetalis, and neonatal death. CASE PRESENTATION: This paper details the case of the first Danish patient diagnosed with glucose-6-phosphate isomerase deficiency. The patient, a 27-year-old white female, suffered from lifelong anemia of unknown origin for decades. Diagnosis was established through whole-genome sequencing, which identified two GPI missense variants: the previously documented variant p.(Thr224Met) and a newly discovered variant p.(Tyr341Cys). The pathogenicity of these variants was verified enzymatically. CONCLUSIONS: Whole-genome sequencing stands as a potent tool for identifying hereditary anemias, ensuring optimal management strategies.

Pseudoneurotic Symptoms in the Schizophrenia Spectrum: A Longitudinal Study of Their Relation to Psychopathology and Clinical Outcomes.

BACKGROUND AND HYPOTHESIS: Nonpsychotic symptoms (depression, anxiety, obsessions, etc.) are frequent in schizophrenia-spectrum disorders and are usually conceptualized as comorbidity or transdiagnostic symptoms. However, in twentieth century foundational psychopathological literature, many nonpsychotic symptoms with specific phenomenology (here termed pseudoneurotic symptoms) were considered relatively typical of schizophrenia. In this prospective study, we investigated potential associations of pseudoneurotic symptoms with diagnostic status, functional outcome as well as psychopathological dimensions of schizophrenia. STUDY DESIGN: First-admitted patients (N = 121) diagnosed with non-affective psychosis, schizotypal disorder, or other mental illness were examined at initial hospitalization and 5 years later with a comprehensive assessment of psychopathology. Informed by the literature, we constructed scales targeting pseudoneurotic symptoms and other, more general, nonpsychotic symptoms. STUDY RESULTS: Pseudoneurotic symptoms aggregated in schizophrenia-spectrum groups compared to other mental illnesses and occurred at similar levels at baseline and follow-up. They longitudinally predicted poorer social and occupational functioning in schizophrenia-spectrum patients over a 5-year-period but not transition to schizophrenia-spectrum disorders from other mental illnesses. Finally, the level of pseudoneurotic symptoms correlated with disorder of basic self at both assessments and with positive and negative symptoms at follow-up. The scale targeting general nonpsychotic symptoms did not show this pattern of associations. CONCLUSIONS: The study supports that a group of nonpsychotic symptoms, ie, pseudoneurotic symptoms, are associated with schizophrenia-spectrum disorders and linked with temporally stable psychopathology, particularly disorder of the basic self. Their prospective association with social and occupational functioning needs replication.

The self, neuroscience and psychosis study: Testing a neurophenomenological model of the onset of psychosis.

AIM: Basic self disturbance is a putative core vulnerability marker of schizophrenia spectrum disorders. The primary aims of the Self, Neuroscience and Psychosis (SNAP) study are to: (1) empirically test a previously described neurophenomenological self-disturbance model of psychosis by examining the relationship between specific clinical, neurocognitive, and neurophysiological variables in UHR patients, and (2) develop a prediction model using these neurophenomenological disturbances for persistence or deterioration of UHR symptoms at 12-month follow-up. METHODS: SNAP is a longitudinal observational study. Participants include 400 UHR individuals, 100 clinical controls with no attenuated psychotic symptoms, and 50 healthy controls. All participants complete baseline clinical and neurocognitive assessments and electroencephalography. The UHR sample are followed up for a total of 24 months, with clinical assessment completed every 6 months. RESULTS: This paper presents the protocol of the SNAP study, including background rationale, aims and hypotheses, design, and assessment procedures. CONCLUSIONS: The SNAP study will test whether neurophenomenological disturbances associated with basic self-disturbance predict persistence or intensification of UHR symptomatology over a 2-year follow up period, and how specific these disturbances are to a clinical population with attenuated psychotic symptoms. This may ultimately inform clinical care and pathoaetiological models of psychosis.

DAHEAN: A Danish nationwide study ensuring quality assurance through real-world data for suspected hereditary anemia patients.

BACKGROUND: Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. RESULTS: The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. CONCLUSIONS: The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias.