Search Results (66)

Autism spectrum disorder (ASD) is increasingly associated with microbial and metabolic disturbances, including the altered production of gut-derived uremic toxins. We investigated urinary concentrations of five representative uremic toxins—indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)—in 161 children with ASD and 71 healthy controls. Toxins were measured using LC-MS/MS and were normalized to creatinine. Subgroup analyses were performed by sex, age group (2–5.9 vs. 6–17 years), and autism severity based on the Childhood Autism Rating Scale (CARS). In addition to individual concentrations, we calculated the total toxin burden, proportional contributions, and functional ratios (IS/PCS, PCS/TMAO, and IS/ADMA). While individual toxin levels did not differ significantly between groups, stratified analyses revealed that PCS was higher in girls and in severe cases of ASD, whereas IS and TMAO were reduced in younger and more severely affected children. The functional ratios shifted consistently with severity—IS/PCS declined from 1.69 in controls to 0.99 in severe cases of ASD, while PCS/TMAO increased from 12.2 to 20.5. These patterns suggest a phenolic-dominant microbial signature and an altered host–microbial metabolic balance in ASD. Functional toxin profiling may offer a more sensitive approach to characterizing metabolic disturbances in ASD than concentration analysis alone. Full article

Although prosodic differences in autistic individuals have been widely documented, little is known about their ability to perceive and interpret specific prosodic features, such as contrastive pitch accent—a prosodic signal that places emphasis and helps listeners distinguish between competing referents in discourse. This study addresses that gap by investigating the extent to which autistic children can (1) perceive contrastive pitch accent (i.e., discriminate contrastive pitch accent differences in speech); (2) interpret contrastive pitch accent (i.e., use prosodic cues to guide real-time language comprehension); and (3) the extent to which their ability to interpret contrastive pitch accent is associated with broader language and social communication skills, including receptive prosody, pragmatic language, social communication, and autism severity. Twenty-four autistic children and 24 neurotypical children aged 8 to 14 completed an AX same–different task and a visual-world paradigm task to assess their ability to perceive and interpret contrastive pitch accent. Autistic children demonstrated the ability to perceive and interpret contrastive pitch accent, as evidenced by comparable discrimination ability to neurotypical peers on the AX task and real-time revision of visual attention based on prosodic cues in the visual-world paradigm. However, autistic children showed significantly slower reaction time during the AX task, and a subgroup of autistic children with language impairment showed significantly slower processing of contrastive pitch accent during the visual-world paradigm task. Additionally, speed of contrastive pitch accent processing was significantly associated with pragmatic language skills and autism symptom severity in autistic children. Overall, these findings suggest that while autistic children as a group are able to discriminate prosodic forms and interpret the pragmatic function of contrastive pitch accent during spoken language comprehension, differences in prosody processing in autistic children may be reflected not in accuracy, but in speed of processing measures and in specific subgroups defined by language ability. Full article

Background/Objectives: Autism Spectrum Disorder (ASD) etiology is complex, involving genetics and environmental factors, and associated with impaired energy metabolism. Mitochondrial fatty acid oxidation (mFAO) is instrumental to energy production through the oxidation of acylcarnitines (ACs). We performed a comprehensive investigation of blood AC profiles in a pediatric ASD cohort, aiming to define ASD subgroups based on AC profiles and link these profiles to key clinical features and comorbidities using a phenotype-first approach. Methods: Blood levels of 31 ACs (μmol/L) collected from 102 ASD patients and 117 healthy controls (HCs) were evaluated via tandem mass spectrometry. The percentile distribution of blood AC levels in HC samples was computed to define the normal reference range (RR) and identify values corresponding to the 10th and 90th percentiles. Cognitive levels, emotional–behavioral disturbances and the severity of ASD symptoms (Autism Diagnostic Observation Schedule-Calibrated Severity Score ADOS-CSS) were assessed. Clinical correlates of ASD groups based on AC profiles were evaluated. Results: Three ASD subgroups were identified based on the percentile distribution of AC levels: group A (ACs < 10th percentile), group B (ACs 10th–90th percentile) and group C (ACs > 90th percentile) (abnormal AC number ≥ 3). Out of the thirty-one analyzed ACs in DBSs, fifteen (48.4%) were significantly different when comparing ASD group A to ASD group C. There was a significant difference in the severity of autism symptoms (ADOS CSS) related to the repetitive and restricted behaviors domain (CSS RRB) among the different groups (χ²(2) = 6.26; p = 0.044). The post hoc Dunn’s test with Bonferroni correction showed that ADOS-CSS RRB was significantly higher in ASD group A compared to ASD group B (p = 0.013). AC C14 was more frequently decreased (<10th pc) in patients with more severe symptoms (p = 0.006); C10:1 tended to be more frequently increased (>90th pc) in patients with lower clinical severity (p = 0.052). Conclusions: This study highlights differences across blood AC levels in children with ASD and conveys novel information on clinical severity in ASD patients with abnormal blood AC profiles. Thus, examining metabolic profiles may provide helpful insights to understand the variability of ASD symptoms. Full article

Background: To date, it remains unclear which oral doses and preparation forms of melatonin should be recommended for children and adolescents with non-organic sleep disorders and autism spectrum disorder (ASD). We reviewed the current state of knowledge on this topic based on randomised placebo-controlled trials (RCTs) and diagnosis-related blood melatonin concentrations available in this age group. Method: Two investigators independently searched PubMed, PsycINFO, MEDLINE, and Cochrane CENTRAL on 1 March 2025 for the keywords “melatonin”, “autism”, and “randomised” in titles and abstracts in all languages, including an evaluation of the references of the reviews, systematic reviews, and meta-analyses published up to that date, some of which were based on searches in numerous databases. Based on this, additional in-depth searches were carried out in PubMed for pharmacokinetic, physiological, and pathophysiological data on melatonin in children and adolescents, with a special focus on ASD. Results: To date, five RCTs on non-organic sleep disorders in children and adolescents with the sole diagnosis of ASD or with subgroup analyses in the presence of several initial diagnoses such as ADHD, epilepsy, Smith–Magenis, or Fragile X syndrome are available. In these studies, rapid-release, non-delayed preparations were administered orally. In one of these studies, the clinical efficacy of a combination preparation with a sustained-release and a non-released active substance component was tested. Pharmacokinetic data with multiple determinations of melatonin concentrations in the blood are only available for children with ASD in the form of a case series (N = 9). Discussion: RCTs comparing the efficacy of delayed melatonin preparations with non-delayed rapid-release oral preparations are not yet available. Physiological data and clinical effects documented in five RCTs indicate that non-delayed melatonin preparations with an initial rapid onset of action are effective for non-organic sleep disorders in children and adolescents with ASD. Conclusions: From a clinical, pharmacokinetic, and physiological point of view, the RCTs available to date and the data on melatonin concentrations in the blood of children with ASD, measured several times over 24 h, suggest that a low oral melatonin dose and a non-delayed preparation with rapid onset should be started in children and adolescents with non-organic sleep disorders in ASD, if sleep hygiene advice and psychotherapeutic interventions have not demonstrated sufficient effects. Full article

Objectives: To analyze potential associations between three polymorphisms (rs3818188, rs941793, rs2403015) of the DYNC1H1 gene and the occurrence of autism spectrum disorder as well as the clinical phenotype of affected individuals. Methods: This family-based study included 206 children diagnosed with ASD and 364 of their biological parents. To examine the potential association between three polymorphisms of the DYNC1H1 gene and ASD occurrence, a transmission disequilibrium test was performed. Additionally, associations between the studied polymorphisms and the clinical phenotype of affected individuals were analyzed using the χ² test. Results: None of the polymorphisms studied showed an association with ASD in the overall patient group. However, an association between the rs3818188 polymorphic variant and ASD was observed in a subgroup of girls, with the G allele being transmitted more than 2.5 times as frequently as the A allele. Moreover, several associations between the tested variants and features related to neuromotor development, communication, and social skills were observed in univariate analysis. However, after correction for multiple comparisons, only the association between the rs2403015 polymorphism and transient increase in muscle tone during infancy remained statistically significant. Conclusions: This study demonstrated an association between the rs3818188 polymorphism and ASD in a subgroup of girls. Additionally, the rs2403015 polymorphism was found to be associated with transient increase in muscle tone during infancy. Full article

Autism spectrum disorder (ASD) has been associated with disruptions in tryptophan (TRP) metabolism, affecting the production of key neuroactive metabolites. Investigating these metabolic pathways could yield valuable biomarkers for ASD severity and progression. We included 44 children with ASD and 44 healthy children, members of the same family. The average age in the ASD group was 10.7 years, while the average age in the control group was 9.4 years. Urinary tryptophan metabolites were quantified via liquid chromatography—mass spectrometry operating multiple reaction monitoring (MRM). Urinary creatinine was analyzed on an Advia 2400 analyzer using the Jaffe reaction. Statistical comparisons were made between ASD subgroups based on CARS scores. Our findings indicate that children with ASD have higher TRP concentrations (19.94 vs. 16.91; p = 0.04) than their siblings. Kynurenine (KYN) was found at higher levels in children with ASD compared to children in the control group (82.34 vs. 71.20; p = 0.86), although this difference was not statistically significant. The ASD group showed trends of higher KYN/TRP ratios and altered TRP/ indole-3-acetic acid (IAA) and TRP/5-hydroxyindoleacetic acid (5-HIAA) ratios, correlating with symptom severity. Although the numbers of the two groups were different, our findings suggest that mild and severe illnesses involve separate mechanisms. However, further comprehensive studies are needed to validate these ratios as diagnostic tools for ASD. Full article

Background: Neurodevelopmental disorders (NDDs) encompass an inclusive group of conditions that appear during the developmental period but continue to persist in adulthood, ranging from particular difficulties to a global impairment of social, cognitive, and emotional functioning. The developmental trajectories associated with these conditions are highly heterogeneous. This study aimed to analyze and compare developmental and adaptive profiles of preschool-aged children with different NDDs to better characterize their developmental trajectories. Methods: We analyzed data from the initial global evaluation of 196 children with NDDs (aged 20 to 71 months), enrolled in three subgroups: 108 with autism spectrum disorder (ASD), 52 with language disorder (LD), and 36 with mixed specific developmental disorder (MSDD). A comprehensive neuropsychiatric evaluation was performed using standardized tools (Griffiths-III, ADOS-2, VABS-II, and ADI-R), and the parents completed the DP-3 and the CBCL 1½-5. Results: Our results showed that all NDDs exhibited poor psychomotor skills, with children with ASD being the most impaired, although their profiles were comparable to those of MSDD in communication and motor areas. CBCL’s pervasive developmental problem scale has been shown to provide relevant information for distinguishing children with ASD. Furthermore, DP-3 and VABS-II measure highly differentiated developmental profiles of each diagnostic group. Conclusions: Our results highlighted the importance of including parents’/caregivers’ perspectives in defining children’s functioning and the possibility of using DP-3 as a screening tool for different neurodevelopmental disorders. Full article

Background: The metabolism of plasma amino acid (AA) in children with autism spectrum disorder (ASD) has been extensively investigated, yielding inconclusive results. This study aims to characterize the metabolic alterations in AA profiles among early-diagnosed children with ASD and compare the findings with those from non-ASD children. Methods: We analyzed plasma AA profiles, measured by ion exchange chromatography, from 1242 ASD children (median age = 4 years; 81% male). Additionally, we studied AA profiles from 488 children, matched for age and free of ASD (control group). Principal component and cluster analysis were employed to explore potential associations within the ASD group and to identify subgroups. Results: We observed lower plasma levels of glutamine in children with ASD compared to non-ASD children (p < 0.001). Six essential, two conditionally essential, and four non-essential AA were found to be increased in children with ASD. The clustering analysis revealed two groups, labeled Neurological (NEU) and Nutritional (NUT), which included a majority of ASD children (94% and 78%, respectively). The NEU group exhibited high levels of taurine, aspartate, glutamic acid, and ornithine, while the NUT group showed elevated levels of branched-chain AA. Conclusions: In children with ASD, we identified some heterogeneous AA patterns that may serve as biochemical signatures of neurological impairment in some individuals, while in others they may indicate nutritional dysregulation. Full article

Background: Currently, there is a need for approaches to understand and manage the multidimensional autism spectrum and quantify its heterogeneity. The diagnosis is based on behaviors observed in two key dimensions, social communication and repetitive, restricted behaviors, alongside the identification of required support levels. However, it is now recognized that additional modifiers, such as language abilities, IQ, and comorbidities, are essential for a more comprehensive assessment of the complex clinical presentations and clinical trajectories in autistic individuals. Different approaches have been used to identify autism subgroups based on the genetic and clinical heterogeneity, recognizing the importance of autistic behaviors and the assessment of modifiers. While valuable, these methods are limited in their ability to evaluate a specific individual in relation to a normative reference sample of autistic individuals. A quantitative score based on axes of phenotypic variability could be useful to compare individuals, evaluate the homogeneity of subgroups, and follow trajectories of an individual or a specific group. Here we propose an approach by (i) combining measures of phenotype variability that contribute to clinical presentation and could impact different trajectories in autistic persons and (ii) using it with normative modeling to assess the clinical heterogeneity of a specific individual. Methods: Using phenotypic data available in a comprehensive reference sample, the Simons Simplex Collection (n = 2744 individuals), we performed principal component analysis (PCA) to find components of phenotypic variability. Features that contribute to clinical heterogeneity and could impact trajectories in autistic people were assessed by the Autism Diagnostic Interview-Revised (ADI-R), Vineland Adaptive Behavior Scales (VABS) and the Child Behavior Checklist (CBCL). Cognitive assessment was estimated by the Total Intelligence Quotient (IQ). Results: Three PCs embedded 72% of the normative sample variance. PCA-projected dimensions supported normative modeling where a multivariate normal distribution was used to calculate percentiles. A Multidimensional General Functionality Score (MGFS) to evaluate new prospective single subjects was developed based on percentiles. Conclusions: Our approach proposes a basis for comparing individuals, or one individual at two or more times and evaluating homogeneity in phenotypic clinical presentation and possibly guides research sample selection for clinical trials. Full article

Background/Objectives: Tic disorders are neurodevelopmental conditions often associated with comorbidities like attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Our aims were: (a) in a sample of youth with tic disorders to explore the clinical and psychopathological characteristics of different phenotypes based on the presence of comorbid ADHD and/or ASD and gender; (b) in a subgroup of patients treated with Aripiprazole, to evaluate symptoms variation over time and to identify potential predictors of response. Methods: A total of 95 subjects with tic disorders (age range 6 to 17.9 years, mean 11.1 ± 2.11 years, 80 males) were naturalistically recruited. Questionnaires and semi-structured interviews were administered to assess the symptomatology and investigate the presence of psychiatric comorbidities (Clinic Global Impression-Severity (CGI-S), Children’s Global Assessment Scale (C-GAS), Yale Global Tic Severity Scale (YGTSS), Premonitory Urge for Tics Scale (PUTS), Child Yale–Brown Obsessive Compulsive Scale for Children (CYBOCS), Child Behavior Checklist 6–18 (CBCL 6–18), Conners’ Parent Rating Scale-Revised—short form (CRSR-S), Reactivity Intensity Polarity Stability Questionnaire—youth version (RIPoSt-Y), and Social Communication Questionnaire—lifetime version (SCQ); Autism Diagnostic Observation Scale—second version (ADOS-2) and Autism Diagnostic Interview—revised version (ADI-R) were administered where ASD was suspected). A total of 22 subjects treated with Aripiprazole were reassessed through the use of some of the clinical measures used at baseline. Results: The presence of ADHD was associated with higher externalizing problem scores on the CBCL 6–18, while ASD was linked to higher internalizing problem scores. A positive correlation was found between the ADHD–ASD interaction and increased internalizing symptoms on CBCL 6–18 and higher ADOS-2 scores. Patients treated with Aripiprazole showed significant improvement across all scales during follow-up. ADHD was identified as a negative predictor of reduced tic severity on the YGTSS. Conclusions: Comorbid neurodevelopmental disorders, such as ADHD or ASD, result in worse emotional and behavioral functioning in patients with tic disorders. ADHD–ASD interaction may be linked to more internalizing symptoms and autistic behaviors. Aripiprazole improves overall clinical outcomes, although comorbid ADHD may hinder the reduction of tic symptoms. Full article

Background/Objectives: Mindfulness-based interventions (MBIs) have emerged in recent years as a strong candidate for the treatment of a range of difficulties faced by individuals with autism spectrum disorder (ASD), including cognitive, emotional, and social aspects. Therefore, we aimed to conduct a review that systematically examined the efficacy of MBIs for individuals with ASD and their caregivers. Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our literature search was conducted within the MEDLINE database. We included in the review only longitudinal or intervention studies focusing mainly on mindfulness principles, while we excluded mixed intervention studies. We only included studies that explicitly utilized quantitative methodologies for evaluating the outcomes of the interventions, including mental health indices (e.g., stress, anxiety, depression) and assessments of cognitive and social skills (e.g., attention, prosociality). We conducted also a risk of bias assessment through the method of the Cochrane risk of bias tool for intervention studies ROBINS-I. Results: Thirty-seven studies were included in the review, and we grouped the studies by the targets of the interventions, i.e., adults (n = 12), children and adolescents (n = 9), caregivers and medical staff (n = 13), and combined intervention for both children/adolescents and their parents/caregivers (n = 5). The reviewed papers seem to support the feasibility and utility of mindfulness interventions for persons with ASD and their caregivers, but any recommendations based on this body of evidence should be made with caution due to the overall low quality of the studies conducted so far. Conclusions: The review reveals a positive outcome, including the alleviation of psychological distress, reduced behavioral problems, and enhanced cognitive and social skills in individuals with ASD. Despite such promising results, the review notes a limitation in the scarcity of MBIs for young patients, emphasizing caution in universally endorsing the existing literature. Moreover, the results underline the urgency of the exploration of tailored interventions for different ASD subgroups, considering varying levels of autism, and expanding support to teachers in educational settings. Full article

Background: Autism spectrum disorder (ASD) is related to social communication difficulties, repetitive behaviors, and highly restricted interests beginning early in life. Currently, ASD is more diagnosed than in the past, and new models are needed. The Advanced Integrative Model (AIM) is a new model in which genes and concomitant medical problems to diagnosis (CMPD) and the impact of their rigorous and adequate treatment are considered. Methods: The role of a dynamic encephalopathy from which the individual response, susceptibilities in the brain and outside the brain, gut barrier and brain–blood-barrier permeabilities, and the plastic nature of the brain is proposed as a tool for diagnosis. The concomitant medical problems (CMP) are those at and outside the brain. The individual response to treatments of CMP is analyzed. Results: The AIM allows for classification into 3 main groups and 24 subgroups. Conclusions: The groups and subgroups in ASD are obtained taking into account CMPD treatments and individual response. Full article

Background: Sleep disorders have been poorly described in congenital (CDM) and childhood (ChDM) myotonic dystrophy despite being highly burdensome. The aims of this study were to explore sleep disorders in a cohort of Italian CDM and ChDM and to assess their association with motor and respiratory function and disease-specific cognitive and behavioral assessments. Methods: This was an observational multicenter study. Reported sleep quality was assessed using the Pediatric Daytime Sleepiness Scale (PDSS) and Pediatric Sleep Questionnaire (PSQ). Sleep quality was correlated to motor function (6 min walk test, 6MWT and grip strength; pulmonary function (predicted Forced Vital Capacity%, FVC% pred.); executive function assessed by BRIEF-2; autism traits assessed by Autism Spectrum Screening Questionnaire (ASSQ) and Repetitive Behavior Scale-revised (RBS-R); Quality of life (PedsQL) and disease burden (Congenital Childhood Myotonic Dystrophy Health Index, CCMDHI). Results: Forty-six patients were included, 33 CDM and 13 ChDM, at a median age of 10.4 and 15.1 years. Daytime sleepiness and disrupted sleep were reported by 30% children, in both subgroups of CDM and ChDM. Daytime sleepiness correlated with autism traits in CDM (p < 0.05). Disrupted sleep correlated with poorer executive function (p = 0.04) and higher disease burden (p = 0.03). Conclusions: Sleep issues are a feature of both CDM and ChDM. They correlate with behavioral issues and impact on disease burden. Full article

Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and inflammation-related molecules such as Cyclooxygenase-2 (COX-2), chitinase 3-like protein 1 (YKL-40), Interleukin-1 beta (IL-1β), Interleukin-9 (IL-9) in ASD children with and without regression compared to healthy controls. Children with ASD (n = 56) and typically developing children (TDC, n = 12) aged 1.11 to 11 years were studied. Mitochondrial activity was examined in peripheral blood mononuclear cells (PBMCs) isolated from children with ASD and from the control group, using a metabolic analyzer. Gene and protein levels of IL-1β, IL-9, COX-2, and YKL-40 were investigated in parallel. Our results showed that PBMCs of the ASD subgroup of regressed patients (ASD R(+), n = 21) had a specific pattern of mitochondrial activity with significantly increased maximal respiration, respiratory spare capacity, and proton leak compared to the non-regressed group (ASD R(-), n = 35) and TDC. Furthermore, we found an imbalance in the studied proinflammatory molecules and increased levels in ASD R(-) proving the involvement of inflammatory changes. The results of this study provide new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD. For the first time, data on a unique metabolic profile in ASD R(+) and its comparison with a random group of children of similar age and sex are provided. Our data show that mitochondrial dysfunction is more significant in ASD R(+), while in ASD R(-) inflammation is more pronounced. Probably, in the group without regression, immune mechanisms (immune dysregulation, leading to inflammation) begin initially, and at a later stage mitochondrial activity is also affected under exogenous factors. On the other hand, in the regressed group, the initial damage is in the mitochondria, and perhaps at a later stage immune dysfunction is involved. Full article

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1’s mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest. Full article