Callous–Unemotional Traits and Disorganized Attachment: Links with Disruptive Behaviors in Toddlers

Children with callous–unemotional (CU) traits and children with disorganized attachment patterns are at heightened risk of poor psychological outcomes but little is known about the overlap between these constructs and their unique contributions to conduct problems in early childhood. This study examined associations between CU traits, disorganized attachment, and conduct problem (CP) severity in a sample of clinic-referred toddlers with behavioral problems. Mother–child dyads (n = 56; mean child age 19.50 months) completed parent-report questionnaires, a dyadic play session, and the Strange Situation Procedure to assess child attachment pattern. Significant positive associations were found between CU traits and disorganized attachment, independent of CP severity. CU traits but not disorganized attachment predicted CP severity. Results indicate that among toddlers with clinic-referred disruptive behavior problems, there are clear links between CU traits and attachment disorganization. Of the two constructs, however, CU traits appear to be most salient in the expression of CPs

Valosin-Containing Protein (VCP) Disease and Familial Alzheimer’s Disease: Contrasts and Overlaps

Introduction Contrasts between two entities may be illuminating because of the emphasis on what each is not. Here we describe two proteinopathies producing brain neurodegeneration in mature adults, autosomal dominant valosin-containing protein (VCP) disease and Familial Alzheimer’s disease (FAD) caused by presenillin-1 (PSEN1) mutations, illustrating both contrasting patterns of clinical presentation and known neuropathologic and imaging features, and points of congruence

Facial reactions to emotional films in young children with conduct problems and varying levels of callous-unemotional traits

Background: Elevated levels of callous-unemotional (CU) traits have proven useful for identifying a distinct subgroup of children whose conduct problems (CP) are early emerging, severe, persistent, and underpinned by aberrant emotional processing. The early childhood emotional experiences and expressions of CP subtypes are poorly understood, despite their importance to understanding the problematic attachments and atypical social affiliation experienced by children with elevated CU traits. The current study aimed to test for differences in facial emotional reactions to mood-inducing film clips in children with CP and varying levels of CU traits. Method: We compared facial emotional reactions during a developmentally appropriate mood induction task in a mixed-sex sample of clinic-referred preschool children (Mage = 3.64 years, SD = 0.63, 66.9% male) classified as CP with elevated levels of CU traits (CP + CU; n = 25) versus low CU traits (CP-only; n = 47), and typically developing children (TD; n = 28). Results: Relative to TD children, children with clinical CP showed less congruent and more incongruent facial emotional expressions to sad and happy film clips, controlling for child sex, age, and ethnicity. Conclusions: Consistent with older samples, young children with CP show atypical facial emotional expressions in response to positive and negative emotional stimuli. Findings have implications for developmental models of childhood antisocial behavior and can inform the development of targeted interventions

Pathogenic variants of Valosin-containing protein induce lysosomal damage and transcriptional activation of autophagy regulators in neuronal cells

Aim: Mutations in the valosin-containing protein (VCP) gene cause various lethal proteinopathies that mainly include inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). Different pathological mechanisms have been proposed. Here, we define the impact of VCP mutants on lysosomes and how cellular homeostasis is restored by inducing autophagy in the presence of lysosomal damage. Methods: By electron microscopy, we studied lysosomal morphology in VCP animal and motoneuronal models. With the use of western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and filter trap assay, we evaluated the effect of selected VCP mutants in neuronal cells on lysosome size and activity, lysosomal membrane permeabilization and their impact on autophagy. Results: We found that VCP mutants induce the formation of aberrant multilamellar organelles in VCP animal and cell models similar to those found in patients with VCP mutations or with lysosomal storage disorders. In neuronal cells, we found altered lysosomal activity characterised by membrane permeabilization with galectin-3 redistribution and activation of PPP3CB. This selectively activated the autophagy/lysosomal transcriptional regulator TFE3, but not TFEB, and enhanced both SQSTM1/p62 and lipidated MAP1LC3B levels inducing autophagy. Moreover, we found that wild type VCP, but not the mutants, counteracted lysosomal damage induced either by trehalose or by a mutant form of SOD1 (G93A), also blocking the formation of its insoluble intracellular aggregates. Thus, chronic activation of autophagy might fuel the formation of multilamellar bodies. Conclusion: Together, our findings provide insights into the pathogenesis of VCP-related diseases, by proposing a novel mechanism of multilamellar body formation induced by VCP mutants that involves lysosomal damage and induction of lysophagy

Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome

Angelman syndrome (AS) is a severe neurological disorder caused by a deficiency of ubiquitin protein ligase E3A (UBE3A), but the pathophysiology of the disease remains unknown. We now report that in the brains of AS mice in which the maternal UBE3A allele is mutated (m-) and the paternal allele is potentially inactivated by imprinting (p+) (UBE3A m-p+), the mitochondria are abnormal and exhibit a partial oxidative phosphorylation (OXPHOS) defect. Electron microscopy of the hippocampal region of the UBE3A m-p+ mice (n=6) reveals small, dense mitochondria with altered cristae, relative to wild-type littermates (n=6) and reduced synaptic vesicle density. The specific activity of OXPHOS complex III is reduced in whole brain mitochondria in UBE3A m-p+ (n=5) mice versus wild-type littermates (n=5). Therefore, mitochondrial dysfunction may contribute to the pathophysiology of Angelman syndrome

Peer relations and emotion regulation of children with emotional and behavioural difficulties with and without a developmental disorder

Children with emotional and behavioural difficulties (EBD) and those who also have developmental disorders, such as attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), can experience the same adverse consequences in their peer interactions and relationships. This present study compared the emotion regulation and peer relationships of children aged 8-12 years (M = 9.86 years, SD = 1.49) with EBD (N = 33) and children with EBD plus a diagnosed developmental disorder (N = 28). Multivariate analysis of variance (MANOVA) with Bonferroni adjusted alpha levels revealed no significant main effect for emotion regulation according to EBD status. There was, however, a multivariate main effect for sex, with females presenting with higher levels of negative emotional intensity (e. g., frustration, anger, aggression) than males. A second MANOVA revealed no significant main effect for peer relationships according to EBD status and sex. Significant correlations revealed that the EBD-only group experienced greater adverse peer interactions than the EBD-plus-developmental disorder group. These findings are important for educators and researchers involved in the development and evaluation of prevention and intervention programms for children with EBD

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis ⩽40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common

Callous-unemotional traits moderate the relation between prenatal testosterone (2D:4D) and externalising behaviours in children

Children who exhibit callous-unemotional (CU) traits are identified as developing particularly severe forms of externalising behaviours (EB). A number of risk factors have been identified in the development of CU traits, including biological, physiological, and genetic factors. However, prenatal testosterone (PT) remains un-investigated, yet could signal fetal programming of a combination of CU/EB. Using the 2D:4D digit ratio, the current study examined whether CU traits moderated the relationship between PT and EB. Hand scans were obtained from 79 children aged between 5 and 6 years old whose parents completed the parent report ICU (Inventory of Callous Unemotional Traits) and SDQ (Strengths and Difficulties Questionnaire). CU traits were found to moderate the relationship between PT and EB so that children who were exposed to increased PT and were higher in CU traits exhibited more EB. Findings emphasize the importance of recognising that vulnerability for EB that is accompanied by callousness may arise before birth

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry

Identification of variants in the acid α-glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Regis

Cystinosis: practical tools for diagnosis and treatment

Cystinosis is the major cause of inherited Fanconi syndrome, and should be suspected in young children with failure to thrive and signs of renal proximal tubular damage. The diagnosis can be missed in infants, because not all signs of renal Fanconi syndrome are present during the first months of life. In older patients cystinosis can mimic idiopathic nephrotic syndrome due to focal and segmental glomerulosclerosis. Measuring elevated white blood cell cystine content is the corner stone for the diagnosis. The diagnosis is confirmed by molecular analysis of the cystinosin gene. Corneal cystine crystals are invariably present in all patients with cystinosis after the age of 1 year. Treatment with the cystine depleting drug cysteamine should be initiated as soon as possible and continued lifelong to prolong renal function survival and protect extra-renal organs. This educational feature provides practical tools for the diagnosis and treatment of cystinosis