Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.

Clinical and molecular characterization of patients with YWHAG-related epilepsy.

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Molecular and Phenotypic Characterization of the RORB-Related Disorder.

BACKGROUND AND OBJECTIVES: Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. METHODS: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. RESULTS: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. DISCUSSION: In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.

COVID-19 pandemic impact among adolescents with eating disorders referred to Italian psychiatric unit.

PROBLEM: The COVID-19 pandemic has triggered or exacerbated eating disorders (EDs), especially in adolescents. This study examined the prevalence of admissions of patients with EDs at the Child and Adolescent Psychiatry Unit from the pre-COVID-19 pandemic to March 2023 and explored the differences in dimensions of ED's symptomatology according to the year of access. METHODS: We included 174 children and adolescents, 94.3% females and 5.7% males, with a diagnosis of ED (Mage = 14.87; SD = 1.72). The Eating Disorder Inventory-3 (EDI-3), the Body Uneasiness Test (BUT) and Youth Self Report ASEBA (YSR) were assessed. A one-way analysis of variance test was performed. FINDINGS: EDs' hospitalization prevalence was higher in the years 2020 and 2021 compared to pre-COVID-19 and the year 2022. Considering the ED psychopathology (EDI-3), findings showed a higher score in the dimension of the push to thinness, body dissatisfaction, asceticism, and fear of maturity in the year 2021 compared to pre-pandemic. Regarding the discomfort related to the image of one's own body (BUT), results showed an increase in the global severity index in the year 2022 compared to pre-pandemic and in weight phobia in the year 2021 compared to the year 2020. Concerning the internalizing symptoms (YSR), a tendency was found for withdrawal/depression, with higher levels in the year 2022 compared to the year 2020. CONCLUSIONS: Our study highlighted the increase of different types of EDs symptomatology related to concerns about weight, especially 2 and 3 years after the outbreak of the pandemic, on which the literature is still scarce, especially in the Italian context.

Statistical and artificial intelligence techniques to identify risk factors for suicide in children and adolescents.

BACKGROUND: Suicidal Behaviors and Thoughts are a relevant public health issue that includes suicidal ideation, non-suicidal self-harm, attempted suicide, and failed suicides. Since there is a progression of suicidal behaviors, whereby suicide is more likely to be completed if there have already been previous behaviors or attempts to harm oneself, WHO has highlighted the need to detect early predictors of such suicidal behaviors, which can help identify individuals at risk, plan prevention strategies and implement specific therapeutic interventions, particularly in young people, thus reducing the number of deaths. This retrospective observational study aimed to identify early predictors of suicidal risk in 237 inpatients admitted for Suicidal Behaviors and Thoughts at Child and Adolescent Psychiatry Emergency Unit of the Meyer Children's Hospital, Florence, Italy. METHODS: The study was subdivided into three phases: data collection, statistical analysis, and neural network. For each patient, we collected epidemiological and psychopathological data. We stratified the inpatients into two groups: "suicidal volition patients" and "suicidal motivation patients." RESULTS: The hospitalization rate for suicidal behaviors and thoughts showed a growing trend from 2016 to 2020 (27.69 to 45.28%). Under 12 years of age, diagnosis of disruptive, impulse-control and conduct disorder, previous specialist care, history of attempted suicide, and intoxication as methods of suicide were statistically correlated to an increased risk of suicidal behaviors. Artificial intelligence, with an accuracy of 86.7%, confirmed these risk factors. LIMITATIONS: The most important limitation of the study is its retrospective nature. CONCLUSIONS: Our study identifies new early predictors of suicidal risk: age less than 12, diagnosis of disruptive, impulse-control and conduct disorder. In addition, suicidal volition behavior emerges as an important and underestimated risk factor. The use of artificial intelligence methods could be supporting the clinician in assessing suicidal risk.

Mental Health of Children and Adolescents before and during the COVID-19 Pandemic: How Did the Lockdown Modify Psychiatric Emergencies in Tuscany, Italy?

The COVID-19 pandemic has deeply impacted several aspects of the lives of children and adolescents. We analyzed the trends of psychiatric disorders in the emergency room. The analysis comprised the pre-pandemic (2018-2019) and the pandemic years (2020-2021). We conducted a retrospective observational epidemiological study that compared admissions during the two periods on a sample of 1311 patients aged between 4 and 18, focusing on new admissions vs. relapse, demographic variables, lockdown severity, presentation of psychiatric symptoms, diagnosis, severity, and outcome. Over the two-year pandemic period, we observed a 33% decrease in admissions to the emergency room for non-psychiatric disorders and a 200% increase in admissions for psychiatric emergencies. This increase is concentrated in periods with fewer restrictions and in the second year of the pandemic. We also observed a greater impact of psychiatric disorders on female patients, a greater severity of psychiatric disorders, a change in diagnoses associated with the presentation of symptoms, and an increase in hospitalizations. The children's psychiatric emergency service faced an "emergency within the emergency". In the future, it will be necessary to continue the follow-up of these patients, strengthen the field of study of gender psychiatry, and intensify our efforts towards prevention.

Peer victimization and developmental psychopathology in childhood and adolescence Italian psychiatric emergency unit. A single center retrospective observational study.

Peer victimization is a public health concern that affects a significant proportion of children and adolescents. The study evaluated the prevalence of peer victimization among 440 subjects referred to Emergency Department for a psychiatric consultation and analyzed the association with psychopathological symptoms. Sample was divided into two categories (6-13 and 14-18 years old). Logistics regression analysis was performed. Peer victimized were reported in 16.3% of subjects; 27.7% were younger than13 years old and 72.3% were between 14-18 years old, representing the main targets for peer victimization.A significant association was found between being peer victimized and depressive disorder (OR=4.57) in subjects younger than 13 years old and, with post-traumatic stress disorder (PTSD)(OR=6.52) in subjects older than 13 years old. Furthermore, linkage between being peer victimized and obsessive-compulsive disorder (OCD)(OR=4.45) was noted. Increased frequency of repeated hospitalizations was also documented.This is the first Italian study about children and adolescent peer victimization in psychiatric setting, showing a significant higher risk for depressive disorder in subjects younger than 13 years old and PTSD and OCD in subjects older than 13 years old. Investigating experiences of peer victimization provides an early diagnosis and a more efficient treatment plans, guaranteeing an improved clinical outcome.

Centrality and interhemispheric coordination are related to different clinical/behavioral factors in attention deficit/hyperactivity disorder: a resting-state fMRI study.

Eigenvector-Centrality (EC) has shown promising results in the field of Psychiatry, with early results also pertaining to ADHD. Parallel efforts have focused on the description of aberrant interhemispheric coordination in ADHD, as measured by Voxel-Mirrored-Homotopic-Connectivity (VMHC), with early evidence of altered Resting-State fMRI. A sample was collected from the ADHD200-NYU initiative: 86 neurotypicals and 89 participants with ADHD between 7 and 18 years old were included after quality control for motion. After preprocessing, voxel-wise EC and VMHC values between diagnostic groups were compared, and network-level values from 15 functional networks extracted. Age, ADHD severity (Connor's Parent Rating-Scale), IQ (Wechsler-Abbreviated-Scale), and right-hand dominance were correlated with EC/VMHC values in the whole sample and within groups, both at the voxel-wise and network-level. Motion was controlled by censoring time-points with Framewise-Displacement > 0.5 mm, as well as controlling for group differences in mean Framewise-Displacement values. EC was significantly higher in ADHD compared to neurotypicals in the left inferior Frontal lobe, Lingual gyri, Peri-Calcarine cortex, superior and middle Occipital lobes, right inferior Occipital lobe, right middle Temporal gyrus, Fusiform gyri, bilateral Cuneus, right Precuneus, and Cerebellum (FDR-corrected-p = 0.05). No differences were observed between groups in voxel-wise VMHC. EC was positively correlated with ADHD severity scores at the network level (at p-value < 0.01, Inattentive: Cerebellum rho = 0.273; Hyper/Impulsive: High-Visual Network rho = 0.242, Cerebellum rho = 0.273; Global Index Severity: High-Visual Network rho = 0.241, Cerebellum rho = 0.293). No differences were observed between groups for motion (p = 0.443). While EC was more related to ADHD psychopathology, VMHC was consistently and negatively correlated with age across all networks.

Phosphatase and tensin homolog (PTEN) variants and epilepsy: A multicenter case series.

PURPOSE: EEG anomalies and epilepsy are a not so rare clinical manifestation in patients with Phosphatase and tensin homolog (PTEN) variants. The main aim of this study is to analyze the characteristics of EEG traces, neuroimaging findings and epilepsy to better define the neurological aspects in a set of patients with PTEN variants collected in four Italian Centres. As a secondary aim, we describe the neurodevelopmental profile and the psychiatric comorbidities of this cohort. METHODS: Patients with PTEN variants, identified by Sanger sequencing or target resequencing, were enrolled. For each subjects, clinical data were retrospectively extracted from medical charts, with a focus on epilepsy and neuroimaging data. RESULTS: 54 patients with PTEN variants were enrolled, with a mean age of 18.8 years. 72.2% have at least one psychiatric diagnosis, being Autism Spectrum Disorder and Intellectual Disability the most frequent diagnosis (29 and 25 cases, respectively). 22 subjects show an abnormal EEG and 8 received a diagnosis of epilepsy, mainly focal epilepsy (7/8), with a mean age at seizure onset of 3.8 years. 3/8 subjects have a drug resistant epilepsy, independently from the underlying neuroimaging pattern. The finding of a Focal cortical dysplasia is significantly associated with both an abnormal EEG (p = 0.02) and the occurrence of seizures (p = 0.002). CONCLUSION: EEG should be taken into consideration in the first-line diagnostic flowchart of subjects with PTEN variants. The onset of a focal epilepsy, independently from its response to antiepileptic drugs, highly recommends to carry out a neuroimaging exam.

Epidemiological and Psychopharmacological Study About Off-Label Treatment in Child and Adolescent Psychiatric Emergencies: A Tertiary/Single Center Experience.

OBJECTIVE: The study used an epidemiological and pharmacological description of child and adolescent psychiatric emergencies (CAPEs), during which psychotropic medications are frequently administered as off-label therapies. METHODS: We retrospectively describe CAPE in 190 patients (mean age, 14.7 years) referring in the emergency department of a single tertiary center, from June 2016 to June 2018, focusing on off-label administration rate, most of all in emergency setting. RESULTS: An intrinsic fragility was observed in this population, where 28.4% of patients present a history of self-harm, 24.7% a concomitant neurodevelopmental disorder, and 17.3% a history of substance abuse. Psychomotor agitation was the most frequent referral reason, and it represents an unspecified clinical presentation of several conditions, while self-harm showed a stronger association with depressive disorders (55.2%).Globally, 811 medications were administered both as baseline therapy (67.8% of off-label rate) and/or in the emergency setting, where the off-label rate raised to 78.3%. Benzodiazepines had the highest rate of off-label use (98.2% as baseline therapy, 92.9% in acute context). Nevertheless, in 83.5% cases of acute administrations, a singular oral benzodiazepine (mostly lorazepam) guaranteed psychomotor agitation resolution, with a lower rate of adverse effects in contrast with atypical antipsychotics. CONCLUSIONS: Off-label drug use in CAPEs is a recurrent clinical practice. An international agreement about off-label drugs is crucial to obtain standard long-term pharmacoepidemiological, safety, and efficacy data. Pharmacological pediatric trials and international guidelines are also required to regulate pharmacological treatments of CAPEs, most of all in emergency settings.

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Suicidality in adolescents with onset of anorexia nervosa.

OBJECTIVES: The mortality rate in patients with anorexia nervosa (AN) is 5 to 10 times higher than in general population and, suicide is one of the main causes of death. We evaluated the prevalence of suicidality (ideation, self-injurious behaviour, suicidal attempts) in 100 adolescents with onset of AN and we explored the correlation between suicidality, severity of AN symptoms and psychiatric comorbidity. METHODS: We subdivided AN patients into restrictive (R-AN; n = 66) and restrictive atypical (A-AN; n = 34), according to the European Guidelines criteria. Assessment was performed using the eating disorder inventory 3rd version, the schedule for affective disorders and schizophrenia for school-age children-present and lifetime version interview, and the Columbia-suicide severity rating scale. Fisher's exact test and Mann-Whitney test (with correction for multiple testing) were used to compare the distribution of categorical and continuous variables between R-AN and A-AN patients, and between patients with vs. without suicidal behaviours. RESULTS: Twenty-seven patients (27%) presented suicidality as clinical feature, expressed as at least one of the following: suicidal ideation (24%), self-cutting (19%), and suicidal attempt (6%). Patients with suicidality showed greater severity of psychiatric symptoms related to AN psychopathology and presented psychiatric comorbidity, especially depression, more often than patients who did not reported suicidality (70,4% vs 29,6%). No significant differences in terms of suicidal behaviours and AN-specific psychopathology were found between R-AN and A-AN. CONCLUSIONS: Suicidality in adolescent patients with R-AN and A-AN seems to be related to ED symptoms. These data highlight the importance of screening for suicidality among adolescents at onset of AN, and confirms that A-AN should not be considered a milder disease. LEVEL OF EVIDENCE: Level IV: Evidence obtained from multiple time series analysis such as case studies. (NB: Dramatic results in uncontrolled trials might also be regarded as this type of evidence).

The colors of our brain: an integrated approach for dimensionality reduction and explainability in fMRI through color coding (i-ECO).

Several systematic reviews have highlighted the role of multiple sources in the investigation of psychiatric illness. For what concerns fMRI, the focus of recent literature preferentially lies on three lines of research, namely: functional connectivity, network analysis and spectral analysis. Data was gathered from the UCLA Consortium for Neuropsychiatric Phenomics. The sample was composed by 130 neurotypicals, 50 participants diagnosed with Schizophrenia, 49 with Bipolar disorder and 43 with ADHD. Single fMRI scans were reduced in their dimensionality by a novel method (i-ECO) averaging results per Region of Interest and through an additive color method (RGB): local connectivity values (Regional Homogeneity), network centrality measures (Eigenvector Centrality), spectral dimensions (fractional Amplitude of Low-Frequency Fluctuations). Average images per diagnostic group were plotted and described. The discriminative power of this novel method for visualizing and analyzing fMRI results in an integrative manner was explored through the usage of convolutional neural networks. The new methodology of i-ECO showed between-groups differences that could be easily appreciated by the human eye. The precision-recall Area Under the Curve (PR-AUC) of our models was > 84.5% for each diagnostic group as evaluated on the test-set - 80/20 split. In conclusion, this study provides evidence for an integrative and easy-to-understand approach in the analysis and visualization of fMRI results. A high discriminative power for psychiatric conditions was reached. This proof-of-work study may serve to investigate further developments over more extensive datasets covering a wider range of psychiatric diagnoses.

Expanding the genetic and phenotypic spectrum of CHD2-related disease: From early neurodevelopmental disorders to adult-onset epilepsy.

CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.

Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders.

Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. In conclusion, homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development.

Coping With Adolescents Affected by Anorexia Nervosa: The Role of Parental Personality Traits.

INTRODUCTION: Anorexia nervosa (AN) promotes psychological distress in caregivers who adopt different coping strategies. Dysfunctional caregiving styles exacerbate further distress in the patient promoting the maintenance of the illness. We aimed to assess the possible contribution of personality traits of caregivers to the adoption of different coping strategies to deal with the affected relative. METHODS: About 87 adolescents with AN were recruited. Their parents completed the Family Coping Questionnaire for Eating Disorders (FCQ-EDs) and the Temperament and Character Inventory-Revised (TCI-R). Differences between mothers and fathers were assessed through the independent sample t-test. Multivariate regression analyses were run to assess if personality traits, the occurrence of psychiatry conditions in the parents, the marital status, and the duration of the illness predicted parental coping strategies. RESULTS: The group of mothers showed higher levels of avoidance and seeking for information coping strategies than the sample of fathers. Lower illness duration predicted higher collusion with the illness in both parents. Harm avoidance, cooperativeness, and self-directedness positively predicted parental coercion, collusion, and seeking for information strategies with some differences between mothers and fathers. DISCUSSION: Illness duration and personality traits of parents affect the type of parental coping strategies developed to face AN in adolescents. These variables should be considered in the assessment of families of adolescents with AN and may be addressed to promote more fine-tuned clinical interventions for caregivers.

Victimization among children and adolescents accessing the Meyer pediatric hospital: A retrospective study.

PROBLEM: The consistent prevalence and occasionally severe consequences of bullying and victimization suggest the need to include a more accurate assessment of these episodes within the Emergency Departments (ED). However, the literature on mental health related symptoms of bullying/victimization treated in the ED is still scarce. The aim of this study is to assess the prevalence of peer victimization amongst children and adolescents referred to an Italian Pediatric Emergency Department. Differences between Hospital Departments, type of victimization and ages are tested. METHODS: A retrospective observational study was conducted with 705 subjects. The age range was from 6 to 18 years old (M = 13.09; SD = 3.048). FINDINGS: 15.3% of the sample reported to be victimized (8.2% occasionally; 7.1% systematically). For the Child and Adolescent Psychiatry Unit, we found a significant association between peer victimization and being adolescent (Fisher's p = 0.003). In addition, a significant association was found between verbal victimization and Child and Adolescent Psychiatry Unit (Fisher's p = 0.02) and physical victimization and Child Abuse Department (Fisher's p < 0.001). CONCLUSION: Findings suggest the importance of an accurate assessment of victimization experiences of children and adolescents with access to ED, to prevent future re-victimization and crystallization of symptoms across time.

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.