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CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29‐year‐old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled‐coil‐helix‐coiled‐coil‐helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild‐type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N‐terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide‐bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.

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The categorical approach of diagnosing mental disorders entails the problem of frequently occurring comorbidities, suggesting a more parsimonious structure of psychopathology. In this study, we therefore aim to assess how affective dysregulation (AD) is associated with attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) in children. To assess AD in children aged 8–12 years (n = 391), we employed the parent version of a newly constructed parent rating scale. Following item reduction, we conducted exploratory and confirmatory factor analyses to establish a factorial structure of AD. One core dimension was identified, comprising irritability and emotional impulsivity, and two smaller dimensions, comprising positive emotionality and exuberance. Subsequently, we examined five different latent factor models – a unidimensional model, a first-order correlated factor model, a second-order correlated factor model, a traditional bifactor model, and a bifactor S-1 model, in which the first-order factor AD-Irritability/Emotional Impulsivity (II) was modeled as the general reference factor. A bifactor S-1 model with the a priori defined general reference domain AD-II provided the best fit to our data and was straightforward to interpret. This model showed excellent model fit and no anomalous factor loadings. This still held true, when comparing it to bifactor S-1 models with ADHD/ODD-related reference factors. Differential correlations with emotion regulation skills and the established Parent Proxy Anger Scale validate the interpretation of the different dimensions. Our results suggest that irritability/emotional impulsivity might be a common core feature of ADHD and ODD.

The trait impulsivity theory suggests that a single, highly heritable externalizing liability factor, expressed as temperamental trait impulsivity, represents the core vulnerability for externalizing disorders. The present study sought to test the application of latent factor models derived from this theory to a clinical sample of children. Participants were 474 German children (age 6-12 years, 81% male) with symptoms of attention-deficit/hyperactivity disorder and externalizing behavior problems participating in an ongoing multicenter intervention study. Using confirmatory factor analyses (CFA) and exploratory structural equation modeling (ESEM), we evaluated several factor models of externalizing spectrum disorders (unidimensional; first-order correlated factors; higher-order factor; fully symmetrical bifactor; bifactor S-1 model). Furthermore, we assessed our prevailing factor models for measurement invariance across raters (clinicians, parents, teachers) and assessment modes (interview, questionnaires). While both CFA and ESEM approaches provided valuable insights into the multidimensionality, ESEM solutions were generally superior since they showed a substantially better model fit and less biased factor loadings. Among the models tested, the bifactor S-1 CFA/ESEM models, with a general hyperactivity-impulsivity reference factor, displayed a statistically sound factor structure and allowed for straightforward interpretability. Furthermore, these models showed the same organization of factors and loading patterns, but not equivalent item thresholds across raters and assessment modes, highlighting cross-situational variability in child behavior. Our findings are consistent with the assumption of the trait impulsivity theory that a common trait, presented as hyperactivity-impulsivity symptoms, underlies all externalizing disorders.

Objective To examine and validate the self-report Questionnaire on the Regulation of Unpleasant Moods in Children (FRUST), which is a modified and shortened version of the Questionnaire for the Assessment of Emotion Regulation in Children and Adolescents (FEEL-KJ). Methods The data comprised child and parent ratings of a community-screened sample with differing levels of affective dysregulation (AD) (N = 391, age: M = 10.64, SD = 1.33, 56% male). We conducted latent factor analyses to establish a factor structure. Subsequently, we assessed measurement invariance (MI) regarding age, gender, and AD level and evaluated the internal consistencies of the scales. Finally, we examined the convergent and divergent validity of the instrument by calculating differential correlations between the emotion regulation strategy (ERS) scales and self- and parent-report measures of psychopathology. Results A four-factor model, with one factor representing Dysfunctional Strategies and the three factors Distraction, Problem-Solving and Social Support representing functional strategies provided the best fit to our data and was straightforward to interpret. We found strong MI for age and gender and weak MI for AD level. Differential correlations with child and parent ratings of measures of psychopathology supported the construct validity of the factors. Conclusions We established a reliable and valid self-report measure for the assessment of ERS in children. Due to the reduced number of items and the inclusion of highly specific regulatory behaviors, the FRUST might be a valuable contribution to the assessment of ER strategies for diagnostic, therapeutic, and research purposes.

The present study sought to refine knowledge about the structure underlying externalizing dimensions. From a “top-down” ICD/DSM-based perspective, externalizing symptoms can be categorized into attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). From a “bottom-up” developmental theory-based perspective, disruptive behaviors can be meaningfully described as aggressive (AGG) and rule-breaking (RB) behaviors. We analyzed five large data sets comprising externalizing symptom ratings obtained with a screening instrument using different sources (parents, teachers, self-ratings) from different samples. Using confirmatory factor analyses, we evaluated several factor models (unidimensional; correlated factors; bifactor (S-1) models) derived from an ICD/DSM- and theory-based perspective. Our optimally fitting models were assessed for measurement invariance across all sources, sample settings, and sex. Following several model-based criteria (model fit indices; factor loadings; omega statistics; model parsimony), we discarded our models stepwise and concluded that both the ICD/DSM-based model with three correlated factors (ADHD, ODD, CD) and the developmental theory-based model with three correlated factors (ADHD, AGG, RB) displayed a statistically sound factor structure and allowed for straightforward interpretability. Furthermore, these two models demonstrated metric invariance across all five samples and across sample settings (community, clinical), as well as scalar invariance across sources and sex. While the dimensions AGG and RB may depict a more empirically coherent view than the categorical perspective of ODD and CD, at this point we cannot clearly determine whether one perspective really outperforms the other. Implications for model selection according to our model-based criteria and clinical research are discussed.

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