Sleep disturbances and behavioral symptoms in pediatric Sotos syndrome.

Background: Sotos syndrome (SoS) is a rare overgrowth genetic disease caused by intragenic mutations or microdeletions of the NSD1 gene located on chromosome 5q35. SoS population might present cognitive impairment and a spectrum of behavioral characteristics, with a worse profile in patients with microdeletion. Although patients with SoS are known to have impaired sleep habits, very little data are available. The present study aimed to assess the prevalence of sleep disorders (SDs) in a pediatric cohort of patients with SoS and their correlation with neuropsychiatric profiles. Methods: We included patients with a SoS diagnosis and age < 18 years; all patients underwent a comprehensive neuropsychological assessment, including evaluation of cognition, adaptive functions through the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and behavioral problems using the Achenbach Child Behavior Checklist (CBCL) and Conners' Parent Rating Scale-Revised (CPRS-R:L) questionnaire. To investigate the presence of SD parents, the Sleep Disturbance Scale for Children (SDSC) was completed. Results: Thirty-eight patients (M 61%, F 39%, mean age 11.1 ± 4.65 years) were included in the study. Although only two had a prior SD diagnosis, 71.1% (N = 27) exhibited pathological scores on SDSC. No statistically significant associations were found between positive SDSC results and genetic microdeletion, intellectual disability (ID), or other medical conditions/treatments. However, a positive correlation emerged between SDSC scores and Conners' Global Index (p = 0.048) and Restless/Impulsive (p = 0.01) scores, CBCL externalizing (p = 0.02), internalizing (p = 0.01), and total scores (p = 0.05). Conversely, a negative linear relationship was observed between the SDSC score and the ABAS GAC and ABAS CAD scores (p = 0.025). Conclusion: We detected an SD in 71.1% of our sample, with a positive relation between SD and internalizing and externalizing symptom levels, especially hyperactivity and impulsivity. Our study demonstrated a high prevalence of SD in pediatric patients with SoS, highlighting that all patients should be screened for this problem, which has a great impact on the quality of life of patients and their families.

A longitudinal characterization of the adaptive and behavioral profile in Sotos syndrome.

Delineation of a developmental and behavioral trajectory is a key-topic in the context of a genetic syndrome. Short- and long-term implications concerning school outcome, independent living, and working opportunities are strictly linked to the cognitive and behavioral profile of an individual. For the first time, we present a longitudinal characterization of the adaptive and behavioral profile of a pediatric sample of 32 individuals with Sotos Syndrome (SoS) (18 males, 14 females; mean age 9.7 ± 4 years, eight carrying the NSD1 5q35 microdeletion and 24 with an intragenic mutation). We performed two clinical assessments: at baseline (T0) and at distance evaluation (T1) of adaptive and behavioral skills with a mean distance of 1.56 ± 0.95 years among timepoints. Our study reports a stability over the years-meant as lack of statistically significant clinical worsening or improvement-of both adaptive and behavioral skills investigated, regardless the level of Intellectual Quotient and chronological age at baseline. However, participants who did not discontinue intervention among T0 and T1, were characterized by a better clinical profile in terms of adaptive skills and behavioral profile at distance, emphasizing that uninterrupted intervention positively contributes to the developmental trajectory.

Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial.

Autism spectrum disorder (ASD) is characterized by the presence of restricted/repetitive behaviors and social communication deficits. Because effective treatments for ASD remain elusive, novel therapeutic strategies are necessary. Preclinical studies show that L. reuteri selectively reversed social deficits in several models for ASD. Here, in a double-blind, randomized, placebo-controlled trial, we tested the effect of L. reuteri (a product containing a combination of strains ATCC-PTA-6475 and DSM-17938) in children with ASD. The treatment does not alter overall autism severity, restricted/repetitive behaviors, the microbiome composition, or the immune profile. However, L. reuteri combination yields significant improvements in social functioning that generalized across different measures. Interestingly, ATCC-PTA-6475, but not the parental strain of DSM-17938, reverses the social deficits in a preclinical mouse model for ASD. Collectively, our findings show that L. reuteri enhances social behavior in children with ASD, thereby warranting larger trials in which strain-specific effects should also be investigated.

Short report: Autistic symptoms in Sotos syndrome, preliminary results from a case-control study.

BACKGROUND: An extremely heterogeneous neuropsychological phenotype has been reported in Sotos Syndrome (SoS), including socio-communicative and behavioral difficulties referred to Autism Spectrum Disorder (ASD). Nonetheless, to date, only few data are available on the topic. AIM: To investigate ASD symptoms within a sample of children with SoS in comparison to a matched control group of individuals with idiopathic ASD. METHODS: A convenience sample of SoS (n = 33, age: 9.8 ± 4.1) and ASD (n = 33, age: 9.9 ± 4.1), was included. Autistic symptoms' assessment was performed through the administration of the Autism Diagnostic Observation Schedule-Second Edition- ADOS-2, the Social Responsiveness Scale -SRS and the Social Communication Questionnaire-SCQ. RESULTS: 72.7% of SoS children presented mild to moderate levels of ASD symptoms as measured by the ADOS-2. Oneway ANOVA analysis showed that SoS individuals presenting lower IQ demonstrated higher ASD symptom's level (p = 0.01). No statistically significant differences emerged between the SoS and ASD groups within the SRS total score domain (p = 0.95). CONCLUSIONS AND IMPLICATIONS: Our results support the evidence for an increased risk for ASD in SoS, suggesting that the ASD symptoms' assessment should be regularly performed in SoS children, with subsequent important implications in terms of therapeutic strategies and later outcome.

Systematic Review and Meta-analysis: Reporting and Representation of Race/Ethnicity in 310 Randomized Controlled Trials of Attention-Deficit/Hyperactivity Disorder Medications.

OBJECTIVE: To evaluate the reporting of race/ethnicity data in randomized controlled trials (RCTs) of attention-deficit/hyperactivity disorder (ADHD) medications. Secondary objectives were to estimate temporal trends in the reporting, and to compare the pooled prevalence of racial/ethnic groups in RCTs conducted in the US to national estimates. METHOD: We drew on, adapted, and updated the search of a network meta-analysis by Cortese et al. (2018) up to March 2022. We calculated the percentage of RCTs reporting data on race/ethnicity of participants in the published article or in related unpublished material. Temporal trends were estimated with logistic regression. The pooled prevalence of each racial/ethnic group across US RCTs was calculated using random-effects model meta-analyses. RESULTS: We retained 310 RCTs (including 44,447 participants), of which 231 were conducted in children/adolescents, 78 in adults, and 1 in both. Data on race/ethnicity were reported in 59.3% of the RCTs (75% of which were conducted in children/adolescents and 25% in adults) in the published article, and in unpublished material in an additional 8.7% of the RCTs. Reporting improved over time. In the US RCTs, Asian and White individuals were under- and overrepresented, respectively, compared to national estimates in the most recent time period considered. CONCLUSION: More than 30% of the RCTs of ADHD medications retained in this review did not include data on race/ethnicity in their published or unpublished reports, and more than 40% in their published articles, even though reporting improved over time. Results should inform investigators, authors, editors, regulators, and study participants in relation to efforts to tackle inequalities in ADHD research. DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Metabolomics: Perspectives on Clinical Employment in Autism Spectrum Disorder.

Precision medicine is imminent, and metabolomics is one of the main actors on stage. We summarize and discuss the current literature on the clinical application of metabolomic techniques as a possible tool to improve early diagnosis of autism spectrum disorder (ASD), to define clinical phenotypes and to identify co-occurring medical conditions. A review of the current literature was carried out after PubMed, Medline and Google Scholar were consulted. A total of 37 articles published in the period 2010-2022 was included. Selected studies involve as a whole 2079 individuals diagnosed with ASD (1625 males, 394 females; mean age of 10, 9 years), 51 with other psychiatric comorbidities (developmental delays), 182 at-risk individuals (siblings, those with genetic conditions) and 1530 healthy controls (TD). Metabolomics, reflecting the interplay between genetics and environment, represents an innovative and promising technique to approach ASD. The metabotype may mirror the clinical heterogeneity of an autistic condition; several metabolites can be expressions of dysregulated metabolic pathways thus liable of leading to clinical profiles. However, the employment of metabolomic analyses in clinical practice is far from being introduced, which means there is a need for further studies for the full transition of metabolomics from clinical research to clinical diagnostic routine.

Cognitive, adaptive and behavioral profile in Sotos syndrome children with 5q35 microdeletion or intragenic variants.

Sotos syndrome (SoS) is a congenital overgrowth syndrome with variable degree of intellectual disability caused in the 90% of cases by pathogenetic variants of the Nuclear receptor binding SET Domain protein1 (NSD1) gene. NSD1 gene functions can be abrogated by different genetic alterations (i.e., small intragenic pathogenic variants like deletions/insertions, nonsense/missense pathogenic variants, partial gene deletions and whole deletions or microdeletion of 5q35 chromosomal region). Therefore, correlation of the genotype-phenotype with a possible contribution of more implicated genes to the medical, cognitive and behavioral profile is a topic of great interest. Although a more severe learning disability has been described in individuals with 5q35 microdeletion when compared to individuals with NSD1 intragenic pathogenic variants a fully delineated cognitive and behavioral phenotype has not been described yet. The importance of providing clinical characterization in relation to the genotype comes from the necessity to early identify children more at risk of developing psychopathological disorders. We characterize the cognitive, adaptive and behavioral phenotype of a pediatric sample of 64 individuals affected by SoS, performing a standardized neuropsychological evaluation. Secondly, we compare cognitive-behavioral profiles of SoS individuals carrying and not carrying the 5q35 microdeletion. SoS participants were characterized by a mild cognitive impairment of both Intellectual Quotient and adaptive skills in association to borderline symptoms of attention deficit. Our results suggest that the 5q35 microdeletion is associated with lower scores specifically concerning the cognitive, adaptive functioning and behavioral domains. However, longitudinal studies are necessary to confirm these findings and delineate a developmental trajectory of SoS.

Maternal Multiple Sclerosis and Offspring's Cognitive and Behavioral Development: What Do We Know until Now?

Multiple Sclerosis (MS) is a chronic pathological condition representing one of the main causes of neurological disability in the female young population. MS, as an immune disorder, could impact fetus development, and, considering the need for and the possibility of pharmacological treatment during pregnancy, the possible influence of medication on developmental trajectories represents a topic of great interest. We provide an overview of the available literature on the influence of maternal Multiple Sclerosis on offspring cognitive and behavioral development. A study was conducted on Pubmed, Medline and Google Scholar, considering empirical studies and reviews exclusively in the English language. Maternal MS appears not to be associated with emotional and behavioral problems, as evaluated through retrospective studies. However, a specific cognitive and behavioral phenotype, through the administration of standardized instruments, has not been delineated yet. Available studies on the topic are characterized by poor methodology and do not lead to conclusions. This overview highlights implications for further longitudinal studies which should delineate offspring developmental trajectories, taking into consideration maternal confounding factors and the exposure to pharmacological treatment in pregnancy.

Clinical profile and conversion rate to full psychosis in a prospective cohort study of youth affected by autism spectrum disorder and attenuated psychosis syndrome: A preliminary report.

Psychosis can occur at high rates in individuals with autism spectrum disorder (ASD). However, the detection of prodromal psychotic symptoms, including attenuated psychosis syndrome (APS), conditions at high risk of converting to full psychosis, has not been extensively investigated in ASD. We longitudinally evaluate a sample of young ASD individuals (age, mean ± SD: 13 ± 2.9) with (n = 13) or without (n = 18) concomitant APS through a standardized assessment of autistic (Autism Diagnostic Observation Schedule-Second Edition; ADOS-2) and psychotic (Structured Interview for Psychosis-Risk Syndromes, SIPS) symptoms and cognitive and adaptive skills. Individuals with other neuropsychiatric disorders were excluded. We estimated the conversion rate to full psychosis (according to SIPS criteria) over time (39.6 ± 11.5 months) and explored the role of clinical variables at baseline in the transition to full psychosis. A conversion rate to full psychosis of 30.7% was found in ASD/APS. Conversion to full psychosis was not affected by the severity of the autistic and psychotic symptoms. At baseline, young individuals with ASD/APS who later converted to full psychosis showed lower cognitive performance (d = 2.05) and greater impairment of adaptive social functioning profile (d = 1.2) than those with ASD. The results of this preliminary report revealed that nearly a third of young individuals with ASD/APS convert to full psychosis over time. Conversion to full psychosis is affected by decreased cognitive and adaptive skills. Further investigations are needed to confirm the utility of APS detection and to better characterize the psychotic developmental trajectory in ASD, with consequent important implications on prognosis and therapeutic strategies.

Developmental and Intelligence Quotient in Autism: A Brief Report on the Possible Long-Term Relation.

Developmental level and cognitive skills assessment represents a crucial aspect in the delineation of the clinical phenotype and long-term outcomes of individuals with autism spectrum disorder (ASD). Nevertheless, the evaluation of cognitive development trajectory across a lifespan ranging from birth to school age appears challenging for clinicians and researchers, because of the lack of measures that coherently cover this timeframe. Thus, the main goal of this community-based study was to investigate within a sample of ASD children if the developmental quotient (DQ), evaluated through the Griffiths Mental Development Scales Extended Revised (GMDS-ER) scale, predicts the non-verbal brief intelligence quotient (IQ), measured through the Leiter-R at follow-up. The main observation of our study was a positive correlation between the level of DQ and nonverbal IQ at follow-up evaluations, highlighting that ASD children characterized by a greater developmental profile will later present higher non-verbal IQ.

Autism Spectrum Disorder and a De Novo Kcnq2 Gene Mutation: A Case Report.

The KCNQ2 gene, encoding for the Kv7.2 subunits of the Kv7 voltage potassium channel, is involved in the modulation of neuronal excitability and plays a crucial role in brain morphogenesis and maturation during embryonic life. De novo heterozygous mutations in KCNQ2 genes are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders including developmental delay and intellectual disability. However, little is known about the socio-communicative phenotype of children affected by the KCNQ2 mutation, and a detailed behavioral characterization focused on autistic symptoms has not yet been conducted. This case report describes the clinical behavioral phenotype of a 6-year-old boy carrying a de novo heterozygous KCNQ2 mutation, affected by early-onset seizures and autism spectrum disorder (ASD). We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative and autistic symptoms through the administration of standardized tools. The main contribution of this case report is to provide a detailed developmental and behavioral characterization focused on ASD symptoms in a child with [c.812 G > A; p. (Gly271Asp)]mutation in the KCNQ2 gene.

Recognizing Psychosis in Autism Spectrum Disorder.

There is strong evidence for the existence of a high comorbidity between autism and psychosis with percentages reaching up to 34. 8% and several significant implications for treatment and prognosis of these patients. However, the identification of comorbid psychosis in patients with Autism Spectrum Disorder represents a complex challenge from a psychopathological point of view, in particular in patients with greater deficits in verbal communication. Intercepting the onset of a psychotic breakdown in autism may be very difficult, both disorders in fact occur along a phenotypic continuum of clinical severity and in many cases, psychotic symptoms are present in an attenuated form. In this paper, we reviewed the available scientific literature about comorbidity between psychosis and autism, focusing our attention on four specific dimensions: delusions, hallucinations, negative symptoms, and clinical course. The aim of this paper is to provide clinical tools to identify these psychotic phenomena in autistic patients, even when they occur in their attenuated form.

High Intellectual Potential and High Functioning Autism: Clinical and Neurophysiological Features in a Pediatric Sample.

High Intellectual Potential (HIP) and High Functioning Autism (HFA) are two different conditions sharing some clinical and neurobiological features. The aim of the present study was to characterize a sample of HIP children (n: 16; M/F: 14/2; median age: 10 years) in comparison to those with HFA (n: 17; M/F: 16/1; median age: 13 years) and to neurotypically developed (NTD) children (n: 10; M/F: 4/6; median age: 11 years) from a clinical and neurophysiological perspective. Specifically, a standardized clinical assessment of cognitive and adaptive skills, autistic symptoms, executive functions and behavioral features was performed. Moreover, event-related potentials (ERPs) were recorded, referring specifically to the mismatch negativity (MMN) and P300 paradigm. Our data highlighted the presence of similarities between the intellectually gifted individuals and the ones with autism (i.e., a nonhomogeneous intellective profile, an adaptive skills impairment, subthreshold autistic symptoms and increased perfectionism). Interestingly, a distinct neurophysiological characterization between groups came out, with evidence of a reduced MMN amplitude only in the HFA group. Furthermore, no differences within groups in the P300 component emerged. Therefore, our results start to provide a more informative characterization of the HIP phenotype in comparison to those of HFA and NTD, highlighting the potential role of the MMN amplitude index in helping clinicians and researchers to distinguish between HIP and HFA. Nevertheless, further research on the topic is strongly needed.

Maternal Perinatal Depression and Risk of Neurodevelopmental Disorders in Offspring: Preliminary Results from the SOS MOOD Project.

The latest research is attempting to define whether there may be an association between maternal Perinatal Depression (PD), the use of psychotropic medications during pregnancy, and a higher risk of neurodevelopmental disorders in children, including Autism Spectrum Disorder (ASD). A better understanding of the relation between PD and ASD is a key element to develop early interventions. This study has been developed in the context of the SOS MOOD project. Its aim is to evaluate the possible impact of maternal PD on the child's cognitive and behavioral phenotype with a focus on ASD. Women included in the project were screened during pregnancy (1st, 2nd trimester) for PD-categorized as affected or not-and if necessary were prescribed pharmacological therapy; offspring of both groups of women underwent at a mean age of 43 months a standardized neuropsychiatric evaluation of developmental and cognitive skills, behavioral problems, autism symptoms and parental stress. Preliminary results on 59 women and 59 children do not suggest significant long-term effects of maternal PD on offspring's development and behavior. Nonetheless further studies on wider samples are necessary in order to confirm such results and disentangle the role of possible confounding factors associated to the maternal illness.

Parental Stress and Disability in Offspring: A Snapshot during the COVID-19 Pandemic.

Parenting a child with a disability, such as neurodevelopmental disorders and genetic syndromes, implies a high level of stress. During the COVID-19 outbreak-as a period implying additional challenges-few studies have specifically investigated caregivers' distress among neurodevelopmental disabilities. The objective of the study is to investigate whether during the COVID-19 pandemic, the level of parental stress differs between four disability groups including neurodevelopmental disorders (autism spectrum disorder (ASD), attention deficit and hyperactivity disorder (ADHD)) and genetic syndromes (Rett syndrome (RTT), Sotos syndrome (SS)) in comparison to families with typical development offspring (TD). In total, 220 Italian parents of children affected by neurodevelopmental disabilities (74 ASD, 51 ADHD, 34 SS, 21 RTT, 40 TD; age M 9.4 ± SD 4.2) underwent a standardized evaluation for stress related to parenting through the self-report questionnaire, Parental Stress Index-Short Form (PSI-SF). The main findings show greater levels of parental stress-mainly linked to child behavioral characteristics rather than parental sense of competence-in parents of children affected by a disability in comparison to children with typical development. This study highlights the need to support not only individuals with special needs but also their own caregivers: core figures in the management and outcome of children disorders.

TrASDition Training: An online parental training for transition-age youth with autism spectrum disorder.

Transition to the adult age represents a rather challenging period of life for youth with Autism Spectrum Disorder (ASD) and for their families. Given the actual lack of integrated healthcare systems for autistic young-adults, enhancing parental skills could represent a feasible program to improve skills preparatory for transition in adult life. The online approach, providing easy access to services which otherwise would burden a daily family organization, already strenuous for a family with an autistic person, can represent an innovative way of delivering intervention. Therefore, we developed an online psychoeducational parental training, named TrASDition Training, with a 6 months duration, addressed to parents of autistic youth with and without Intellectual Disability during the transition age. The aim of this study was to longitudinally evaluate the impact of the online parental training on the adaptive functioning, on the repetitive and problematic behaviors of ASD youth (n = 23) and on parental stress. After 6 months of Training, we found a significant improvement in adaptive functioning of ASD participants and a reduction of parental stress.

Sex Differences in Autism Spectrum Disorder: Repetitive Behaviors and Adaptive Functioning.

Sex differences in restricted and repetitive behaviors (RRBs) in individuals with Autism Spectrum Disorder (ASD) have been explored with mixed findings. We aimed to investigate sex differences in RRBs through a specific measure-i.e., the Repetitive Behavior Scale Revised (RBS-R)-in a sample of preschool-age and school-age children with ASD. Additionally, we evaluated if RRBs were differently related to adaptive functioning within the male and the female age groups. A sample of 210 ASD individuals (3-18 years; 145 males, 65 females) underwent an in-depth assessment including a cognitive, adaptive functioning evaluation (i.e., the Adaptive Behavior Assessment System, Second Edition (ABAS-II)) and RRBs assessment (i.e., RBS-R). No significant sex differences on the RBS-R total score or any RBS-R subscale emerged. Within the group of older participants, RRBs were negatively associated with all adaptive skill domains independently from sex and age. Our results suggest a lack of sex differences in RRBs in our sample. Additionally, our findings highlight the possible negative impact of RRBs on adaptive skills in older individuals with autism, emphasizing the need for autistic individuals of both sexes to undergo an early intervention targeting RRBs, in order to improve their adaptive skills.