Although early signs of autism are often observed between 18 and 36 months of age, there is considerable uncertainty regarding future development. Clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID).

To predict ID in children diagnosed with autism.

This prognostic study involved the development and validation of models integrating genetic variants and developmental milestones to predict ID. Models were trained, cross-validated, and tested for generalizability across 3 autism cohorts: Simons Foundation Powering Autism Research (SPARK), Simons Simplex Collection, and MSSNG. Autistic participants were assessed older than 6 years of age for ID. Study data were analyzed from January 2023 to July 2024.

Ages at attaining early developmental milestones, occurrence of language regression, polygenic scores for cognitive ability and autism, rare copy number variants, de novo loss-of-function and missense variants impacting constrained genes.

The out-of-sample performance of predictive models was assessed using the area under the receiver operating characteristic curve (AUROC), positive predictive values (PPVs), and negative predictive values (NPVs).

A total of 5633 autistic participants (4574 male [81.2%]) were included in this analysis. On average, participants were diagnosed with autism at 4 (IQR, 3-7) years of age and assessed for ID at 11 (8-14) years of age, with 1159 participants (20.6%) being diagnosed with ID. The model integrating all predictors yielded an AUROC of 0.653 (95% CI, 0.625-0.681), and this predictive performance was cross-validated and generalized across cohorts. This modest performance reflected that only a subset of individuals carried large-effect variants, high polygenic scores, or presented delayed milestones. However, combinations of genetic variants that are typically not considered clinically relevant by diagnostic laboratories achieved PPVs of 55% and correctly identified 10% of individuals developing ID. The addition of polygenic scores to developmental milestones specifically improved NPVs rather than PPVs. Notably, the ability to stratify ID probabilities using genetic variants was up to 2-fold higher in individuals with delayed milestones compared with those with typical development.

Results of this prognostic study suggest that the growing number of neurodevelopmental condition-associated variants cannot, in most cases, be used alone for predicting ID. However, models combining different classes of variants with developmental milestones provide clinically relevant individual-level predictions that could be useful for targeting early interventions.

(Likely) pathogenic variants in NR2F1 are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS, OMIM #615722), a rare neurodevelopmental disorder. Patients present with a variety of symptoms, including intellectual disability, developmental delay, visual impairment, muscular hypotonia, seizures, and/or autistic features. Since it was first described in 2014, the phenotype has steadily expanded. However, there is limited information regarding the natural course of the disorder. Here, we present data on genetic variants and phenotype development of 47 individuals who responded to our questionnaire. A questionnaire was developed to assess the phenotype more comprehensively and to better understand the course of symptoms. In addition, families sent medical documents and photographs. To investigate the genotype-phenotype correlation in our cohort, we compared clinical features of two genotypically distinct groups (variants in the DNA-binding domain (DBD, n = 17) versus variants elsewhere in the gene (n = 30)). We observed a range of common symptoms including developmental delay, muscular hypotonia, optic atrophy, nystagmus, strabismus, autistic features, and thin corpus callosum on brain MRI. Overall, more improvement than worsening was reported. Individuals with variants in the DBD showed a higher prevalence of severe clinical features, such as infantile spasms (46.7% vs. 3.8%, p = 0.002) or nonverbality (50% vs. 3.4%, p = 0.0004), age at diagnosis was statistically significantly different between the two genotypic groups (mean 4.7 years vs. 8.9 years, p = 0.048). Our study confirms characteristic clinical features of BBSOAS. Variants in the DBD are associated with a more severe clinical phenotype. We found no evidence that the disease progresses; rather, several symptoms are reported to improve over time. However, prospective longitudinal studies are needed to further investigate disease progression.

Developmental regression in children, in the absence of neurological damage or trauma, presents a significant diagnostic challenge. The complexity is further compounded when it is associated with psychotic symptoms.

We discuss a case series of ten children aged 6-10 years, with neurotypical development, presenting with late-onset developmental regression (>6 years of age), their clinical course and outcome at 1 year. A comprehensive clinical evaluation, laboratory investigations and neuroimaging ruled out any identifiable neurological cause.

Mean age at regression was 7.65 (s.d. 1.5) years and mean illness duration was 10.1 (s.d. 8.5) months. The symptom domains included regression (in more than two domains - cognitive, socio-emotional, language, bowel and bladder incontinence), emotional disturbances, and hallucinatory and repetitive behaviours. Response to treatment was gradual over 6 months to 1 year. At 1-year follow-up, nine children did not attain pre-regression functioning, and residual symptoms included not attaining age-appropriate speech and language, socio-emotional reciprocity and cognitive abilities.

These cases demonstrate a unique pattern of regression with psychiatric manifestations, distinct from autism spectrum disorder and childhood-onset schizophrenia. The diagnostic dilemma arises from the overlap of symptoms with childhood disintegrative disorder (CDD), childhood-onset schizophrenia and autism. This study underscores the diagnostic intricacies of this clinical presentation and highlights the need for longitudinal follow-up to unravel the transitions in phenomenology, course and outcome. For severe manifestations such as developmental regression, where the illness is still evolving, considering CDD as a non-aetiological and transitory/tentative diagnosis would aid against premature diagnostic categorisation and provide scope for ongoing aetiological search.

Autism spectrum disorder (ASD), which is caused by heterogeneous genetic and environmental factors, is characterized by diverse clinical phenotypes linked to distinct pathological mechanisms. ASD individuals with a shared clinical phenotype might contribute to revealing the molecular mechanism underlying ASD progression. Here, it is generated induced pluripotent stem cell (iPSC)-derived cerebral organoids from normocephalic individuals with ASD in a prospective birth cohort with a shared clinical diagnosis. Multiple cell lines and time series scRNA-seq combined with a histomorphological analysis revealed premature neural differentiation of neural stem cells (NSCs) and decreased expression of Fatty acid binding protein 7 (FABP7) in ASD organoids. It is subsequently revealed alterations in the phosphorylation levels of Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2), which are downstream of FABP7, and the regulation of the FABP7/MEK pathway reversed improper neural differentiation in the ASD organoids. Moreover, both Fabp7-knockdown and MEK2-overexpressing mice exhibited repetitive stereotyped behaviors and social defects relevant to autism. This study reveals the role of the FABP7/MEK pathway in abnormal NSC differentiation in normocephalic individuals with ASD, which might provide a promising therapeutic target for ASD treatment.

The main aim of our study was to explore the utility of artificial intelligence (AI) in diagnosing autism spectrum disorder (ASD). The study primarily focused on using machine learning (ML) and deep learning (DL) models to detect ASD potential cases by analyzing text inputs, especially from social media platforms like Twitter. This is to overcome the ongoing challenges in ASD diagnosis, such as the requirement for specialized professionals and extensive resources. Timely identification, particularly in children, is essential to provide immediate intervention and support, thereby improving the quality of life for affected individuals.

We employed natural language processing (NLP) techniques along with ML models like decision trees, extreme gradient boosting (XGB), k-nearest neighbors algorithm (KNN), and DL models such as recurrent neural networks (RNN), long short-term memory (LSTM), bidirectional long short-term memory (Bi-LSTM), bidirectional encoder representations from transformers (BERT and BERTweet). We extracted a dataset of 404,627 tweets from Twitter users using the platform's API and classified them based on whether they were written by individuals claiming to have ASD (ASD users) or by those without ASD (non-ASD users). From this dataset, we used a subset of 90,000 tweets (45,000 from each classification group) for the training and testing of these models.

The application of our AI models yielded promising results, with the predictive model reaching an accuracy of almost 88% when classifying texts that potentially originated from individuals with ASD.

Our research demonstrated the potential of using AI, particularly DL models, in enhancing the accuracy of ASD detection and diagnosis. This innovative approach signifies the critical role AI can play in advancing early diagnostic techniques, enabling better patient outcomes and underlining the importance of early identification of ASD, especially in children.

For several years, studies have been conducted on the contribution of social robots as an intervention tool for children with autism spectrum disorder (ASD). One of the early intervention models recommended by the French National Authority for Health is the Early Start Denver Model, an individualised, intensive programme based on play activities chosen by the child. While studies published in recent years suggest that robots provide benefits for autistic children in learning social interactions within a clinical setting, there is no scientific consensus on the widespread contribution and maintenance of their effects over time. On the other hand, a robotic solution controlled directly by a practitioner (ie, on-site telepresence system) enables greater adaptability to children's responses and choices during interventions. We believe that such a solution would enable better assessment of progress in the fundamental skills of expressive communication and imitation as well as greater engagement during interventions.

This is a prospective, monocentric, descriptive and evaluative pilot study based on single-case experimental design (SCED) methodology. The study will recruit eight children diagnosed with ASD aged between 2 and 5 years. The intervention will take place 15 min after the usual weekly care. The SCED methodology is constructed in three stages: (A) 4 weekly sessions at baseline without the robot, (B) 9 weekly sessions with intervention modification using a social robot as cotherapist and (C) 4 weekly sessions without the robot for follow-up.

Ethical approval was obtained from the South East IV Ethics Committee (CPP Sud-Est IV) (number: 2023-A00895-40) in France. Explicit consent is required from all legal representatives (parents) of children participating in this study. We aim to disseminate the results of this study through national and international conferences, international peer-reviewed journals and social media.

NCT05991791.

Although the first signs of autism are often observed as early as 18-36 months of age, there is a broad uncertainty regarding future development, and clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Here, we developed predictive models of ID in autistic children (n=5,633 from three cohorts), integrating different classes of genetic variants alongside developmental milestones. The integrated model yielded an AUC ROC=0.65, with this predictive performance cross-validated and generalised across cohorts. Positive predictive values reached up to 55%, accurately identifying 10% of ID cases. The ability to stratify the probabilities of ID using genetic variants was up to twofold greater in individuals with delayed milestones compared to those with typical development. These findings underscore the potential of models in neurodevelopmental medicine that integrate genomics and clinical observations to predict outcomes and target interventions.

This study investigated the prevalence, and the developmental, behavior and emotional outcomes of 675 preschoolers with ASD with or without a history of regression, who participated in the Study to Explore Early Development (SEED). The SEED project is a cross-sectional case-control study that collected data between 2007 and 2011. Children's history of regression, adaptive skills, and behavior problems were assessed using the Autism Diagnostic Interview-Revised (ADI-R), the Vineland Adaptive Behavior Scales-Second Edition (Vineland-2), and the Child Behavior Checklist (CBCL), respectively; and children's developmental levels were assessed using the Mullen Scales of Learning (MSEL). Findings from this study indicated that 26% of children experienced social and language regression, and of those with regression, 76% had regained lost skills upon completion of the study. Compared to children without a history of regression, children with social regression demonstrated increased internalizing problems and decreased fine motor skills, and children with language regression demonstrated poorer language skills. Also, children with language and social regression displayed poorer adaptive communication skills than children without regression. Children who experienced regression in one area of development demonstrated better outcomes than those who experience regression in multiple areas. To conclude, children with regression are at risk for poorer outcomes during their preschool years.

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.

In this prospective cohort study, we determined the phenotypic characteristics of children with regressive autism spectrum disorder (ASD) and explored the effects of rehabilitation.

We recruited 370 children with ASD aged 1.5-7 years. Based on the Regression Supplement Form, the children were assigned to two groups: regressive and non-regressive. The core symptoms and neurodevelopmental levels of ASD were assessed before and after 1 year of behavioral intervention using the Autism Diagnostic Observation Schedule (ADOS), Social Response Scale (SRS), Children Autism Rating Scale (CARS), and Gesell Developmental Scale (GDS).

Among the 370 children with ASD, 28.38% (105/370) experienced regression. Regression was primarily observed in social communication and language skills. Children with regressive ASD exhibited higher SRS and CARS scores and lower GDS scores than those with non-regressive ASD. After 1 year of behavioral intervention, the symptom scale scores significantly decreased for all children with ASD; however, a lesser degree of improvement was observed in children with regressive ASD than in those with non-regressive ASD. In addition, the symptom scores of children with regressive ASD below 4 years old significantly decreased, whereas the scores of those over 4 years old did not significantly improve. Children with regressive ASD showed higher core symptom scores and lower neurodevelopmental levels. Nevertheless, after behavioral intervention, some symptoms exhibited significant improvements in children with regressive ASD under 4 years of age.

Early intervention should be considered for children with ASD, particularly for those with regressive ASD.

We investigated the influence of developmental and social factors on the age of autism diagnosis (AoD) in a cohort of toddlers living in Chile. A cross-sectional study was conducted among 509 preschool children diagnosed with autism spectrum disorder [M = 40.2 months (SD = 8.6), girls: 32%] in the neurodevelopmental unit of a university clinic in Santiago, Chile (2015-2023). Structural changes in the annual trend of AoD were tested. Generalized linear models (gamma distribution) with and without interaction terms were used for the multivariate analysis, adjusting for gender, residential area, year of diagnosis, developmental variables (language regression, delayed walking, and use of expressive verbal language), and primary caregiver age and education level (CEL). 95% confidence intervals of the unstandardized regression coefficients (B) were calculated using 1000 bootstrap resampling to estimate associations. AoD increased between 2021-2022 and decreased in 2023. Female gender (B = 2.72 [1.21-4.23]), no history of language regression (B = 3.97 [1.66-6.28]), and the presence of expressive verbal language at diagnosis (B = 1.57 [0.05-3.08]) were associated with higher AoD. Children whose caregivers had tertiary education were diagnosed earlier than those with ≤ 12 years of formal education. Although the influence of CEL increased with caregiver age, differences between CEL groups were significant only for caregivers aged ≥ 30 years. Improved education and early screening for clinical features of autism among healthcare professionals and the community, with a focus on young children without highly apparent developmental concerns and those from vulnerable social groups, are warranted.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder. Unique ASD subtypes have been proposed based on specific genotype-phenotype combinations. The ASD subtype associated with various chromodomain helicase DNA-binding protein 8 (CHD8) mutations has been associated with an incidence of autistic regression greater than that of all-cause ASD, but the mean age of onset of this subtype remains unknown.

Here we describe a patient with a known de novo CHD8 gene mutation (heterozygous c.2565del) who experienced a profound developmental regression and neurocognitive decline at age 13 years following periods of acute viral illness.

The patient developed treatment-refractory catatonia and self-injurious behaviors leading to marked facial disfigurement. Unfortunately, interventions with immunomodulatory medications, psychotropic medications, and electroconvulsive therapy did not lead to sustained symptom improvement or a full return to baseline.

Our case demonstrates a clinical scenario in which a devastating developmental regression and neurocognitive decline occurred with profound accentuation of previously identified autistic features at an age atypical for autistic regression, following sequential viral infections, thereby raising the question of whether immune dysregulation may be a contributing factor. Regression in patients with monogenic mutations in the CHD8 gene warrants further study to elucidate the mechanisms of illness and the anticipated developmental trajectory.

Delays and loss of early-emerging social-communication skills are often discussed as unique to autism. However, most studies of regression have relied on retrospective recall and clinical samples. Here, we examine attainment and loss of social-communication skills in the population-based Norwegian Mother, Father and Child Cohort Study (MoBa).

Mothers rated their child's attainment of 10 early-emerging social-communication skills at ages 18 and 36 months (N = 40,613, 50.9% male). Prospectively reported loss was defined as skill presence at 18 months but absence at 36 months. At 36 months, mothers also recalled whether the child had lost social-communication skills. The Norwegian Patient Registry was used to capture diagnoses of Autism Spectrum Disorder (autism) and other neurodevelopmental disabilities (NDDs).

Delay in at least one skill was observed in 14% of the sample and loss in 5.4%. Recalled loss of social-communication skills was rare (0.86%) and showed low convergence with prospectively reported loss. Delay and especially loss were associated with elevated odds of an autism diagnosis (n = 383) versus no autism diagnosis (n = 40,230; ≥3 skills delayed: OR = 7.09[4.15,12.11]; ≥3 skills lost: OR = 30.66[17.30,54.33]). They were also associated with an increased likelihood of autism compared to some other NDDs. Delay (relative risk [RR] = 4.16[2.08, 8.33]) and loss (RR = 10.00[3.70, 25.00]) associated with increased likelihood of autism versus ADHD, and loss (RR = 4.35[1.28,14.29]), but not delay (RR = 2.00[0.78,5.26]), associated with increased likelihood of autism compared to language disability. Conversely, delay conferred decreased likelihood of autism versus intellectual disability (RR = 0.11[0.06,0.21]), and loss was not reliably associated with likelihood of autism versus intellectual disability (RR = 1.89[0.44,8.33]).

This population-based study suggests that loss of early social communication skills is more common than studies using retrospective reports have indicated and is observed across several NDD diagnoses (not just autism). Nevertheless, most children with NDD diagnoses showed no reported delay or loss in these prospectively measured skills.

To retrospectively explore the characteristics of plasma amino acids (PAAs) in children with autism spectrum disorder and their clinical association via case-control study. A total of 110 autistic and 55 healthy children were recruited from 2014 to 2018. The clinical phenotypes included severity of autism, cognition, adaptability, and regression. Compared with the control group, autistic children had significantly elevated glutamate, γ-Amino-n-butyric acid, glutamine, sarcosine, δ-aminolevulinic acid, glycine and citrulline. In contrast, their plasma level of ethanolamine, phenylalanine, tryptophan, homocysteine, pyroglutamic acid, hydroxyproline, ornithine, histidine, lysine, and glutathione were significantly lower. Elevated neuroactive amino acids (glutamate) and decreased essential amino acids were mostly distinct characteristics of PAAs of autistic children. Increased level of tryptophan might be associated with severity of autism.

Epilepsy is one of the most common comorbidities in individuals with autism spectrum disorders (ASDs). Risk factors include the presence of developmental delay/intellectual disability, female sex, age, and an underlying genetic condition. Due to higher prevalence of epilepsy in ASD, it is important to have a high index of suspicion for seizures and refer to a neurologist if there are concerns. Genetic testing is recommended for all children with ASD but it becomes more high yield in children with epilepsy and ASD.

The prevalence of autism spectrum disorders (ASDs) has increased over the recent years; however, little is known about the experience of parents of children with autism in Africa such as Somalia. The aim of this study is to understand the knowledge on autism of Somali parents of children with autism and their perceptions of causes and treatment of ASD.

We conducted a qualitative study involving 22 parents of children with autism who lived in Mogadishu and Hargeisa; the two largest cities in Somalia. In-depth interviews were used to collect the data. Of the 22 participants, 9 were returned immigrants and 13 were local people (non-immigrants). Data were analysed using thematic analysis.

The data revealed that most of the parents hold the belief that their children's autism were caused by the measles vaccine. The findings demonstrated that parents sought diagnosis and treatment care from outside Somalia due to the lack of experience of health providers in the diagnosis and treatment of autism. The data also revealed a lack of knowledge about autism among the public with resultant stigma and discrimination against children with autism and their families.

Efforts to increase public knowledge on autism, its causes and treatments are of paramount importance, while a public health campaign designed to eliminate the stigma subjected to children with autism is necessary to improve the quality of life of children with autism and their caregivers. Finally, to counteract vaccine hesitancy, particularly in response to the measles vaccine, health policy makers should take steps to separate the cooccurrence of the onset of autism symptoms and the provision of the measles vaccine.

Autism spectrum disorder (ASD) is a common condition with lifelong implications. The last decade has seen dramatic improvements in DNA sequencing and related bioinformatics and databases. We analyzed the raw DNA sequencing files on the Variantyx® bioinformatics platform for the last 50 ASD patients evaluated with trio whole-genome sequencing (trio-WGS). "Qualified" variants were defined as coding, rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV), additionally, were present in genes directly linked to ASD and matched clinical correlation. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) cases with heterozygous de novo and 10 (20%) with inherited variants. De novo variants in genes directly associated with ASD were far more likely to be Qualifying than non-Qualifying versus a control group of genes (p = 0.0002), validating that most are indeed disease related. Sequence reanalysis increased diagnostic yield from 28% to 68%, mostly through inclusion of de novo PDVs in genes not yet reported as ASD associated. Thirty-three subjects (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate a high yield of trio-WGS for revealing molecular diagnoses in ASD, which is greatly enhanced by reanalyzing DNA sequencing files. In contrast to previous reports, de novo variants dominate the findings, mostly representing novel conditions. This has implications to the cause and rising prevalence of autism.

Developmental regression describes when a child loses previously established skills, such as the ability to speak words and is most recognised in neurodevelopmental conditions including Autism; Developmental Epileptic Encephalopathies, such as Landau Kleffner syndrome, and genetic conditions such as Rett syndrome and Phelan McDermid syndrome. Although studies have reported developmental regression for over 100 years, there remain significant knowledge gaps within and between conditions that feature developmental regression. The certainty of evidence from earlier work has been limited by condition-specific studies, retrospective methodology, and inconsistency in the definitions and measures used for classification. Given prior limitations in the field, there is a paucity of knowledge about neurocognitive mechanisms, trajectories and outcomes for children with developmental regression, and their families. Here we provide a comprehensive overview, synthesise key definitions, clinical measures, and aetiological clues associated with developmental regression and discuss impacts on caregiver physical and mental health to clarify challenges and highlight future directions in the field.

Chromosomal Xq28 region duplication encompassing methyl-CpG-binding protein 2 (MECP2) results in an identifiable phenotype and global developmental delay known as MECP2 duplication syndrome (MDS). This syndrome has a wide range of clinical manifestations, including abnormalities in appearance, neurodevelopment, and gastrointestinal motility; recurrent infections; and spasticity. Here, we report a case of confirmed MDS at our institution.

A 12-year-old Chinese boy presented with intellectual disability (poor intellectual [reasoning, judgment, abstract thinking, and learning] and adaptive [lack of communication and absent social skills, apraxia, and ataxia] functioning) and dysmorphism. He had no history of recurrent infections, seizures, or bowel dysfunction, which is different from that in reported cases. Microarray comparative genomic hybridization confirmed MECP2 duplication in the patient and his mother who is a carrier. The duplication size was the same in the patient and his mother. No prophylactic antibiotic or anti-seizure therapy was offered to the patient or his mother before or after the consultation.

MDS is rare and has various clinical presentations. Clinical suspicion is critical in patients presenting with developmental delays.

Autism spectrum disorders (ASD) can present with different onset and timing of symptom development; children may manifest symptoms early in their first year of life, i.e., early onset (EO-ASD), or may lose already achieved skills during their second year of life, thus showing a regressive-type onset (RO-ASD). It is still controversial whether regression represents a neurobiological subtype of ASD, resulting from distinct genetic and environmental causes. We focused this study on the 25 kD synaptosomal-associated protein (SNAP-25) gene involved in both post-synaptic formation and adhesion and considered a key player in the pathogenesis of ASD. To this end, four single nucleotide polymorphisms (SNPs) of the SNAP-25 gene, rs363050, rs363039, rs363043, and rs1051312, already known to be involved in neurodevelopmental and psychiatric disorders, were analyzed in a cohort of 69 children with EO-ASD and 58 children with RO-ASD. Both the rs363039 G allele and GG genotype were significantly more frequently carried by patients with EO-ASD than those with RO-ASD and healthy controls (HC). On the contrary, the rs1051312 T allele and TT genotype were more frequent in individuals with RO-ASD than those with EO-ASD and HC. Thus, two different SNAP-25 alleles/genotypes seem to discriminate between EO-ASD and RO-ASD. Notably, rs1051312 is located in the 3' untranslated region (UTR) of the gene and is the target of microRNA (miRNA) regulation, suggesting a possible epigenetic role in the onset of regressive autism. These SNPs, by discriminating two different onset patterns, may represent diagnostic biomarkers of ASD and may provide insight into the different biological mechanisms towards the development of better tailored therapeutic and rehabilitative approaches.

Autism spectrum disorder with regression (ASD-R) is characterized by the loss of previously acquired skills during the initial year of life. This study aimed to investigate the clinical characteristics, patterns of regression, and potential risk factors associated with ASD-R in the Chinese Han population. A case-control study was conducted between September 2020 and March 2022. A total of 186 children were enrolled, including 58 children with ASD-R, 70 with ASD without regression (ASD-NR), and 58 typically developing children. Demographic information, clinical characteristics, and potential risk factors related to ASD-R were assessed using a combination of questionnaires, interviews, and physician assessments. The results revealed that children with ASD-R exhibited more severe impairments in social communication and stereotyped behaviors compared with those with ASD-NR. Language regression, constituting 40% of cases within the ASD-R group, was found to be the most common type of regression. Furthermore, our analysis revealed that fever (OR = 4.01, 95% CI: 1.26-12.76) and diarrhea (OR = 6.32, 95% CI: 1.38-29.03) were identified as significant risk factors for ASD-R. These findings contribute to our understanding of the heterogeneity of ASD and highlight the importance of considering immune responses and gastrointestinal factors in the etiology of ASD-R.

To explore the relationship between autistic clinical profiles and age at first concern and diagnosis among children with autism spectrum disorder. The clinical profiles included the severity of autism, cognition, adaptability, language development, and regression.

The multivariate linear regression model was used to examine the association of diagnostic age and first-concern age with autistic clinical profiles and with further stratification analysis.

A total of 801 autistic children were included. Language delay and regression were associated with earlier diagnostic age (language delay: crudeβ: -0.80, 95%CI%: -0.92--0.68; regression: crudeβ: -0.21, 95%CI%: -0.43--0.00) and the age of first concern of autistic children (language delay: crudeβ: -0.55, 95%CI%: -0.65--0.45; regression: crudeβ: -0.17, 95%CI%: -0.34--0.00). After stratification by sex, language delay tended to be more associated with the earlier diagnostic age among boys (crudeβ: -0.85, 95%CI%: -0.98--0.72) than among girls (crudeβ: -0.46, 95%CI%: -0.77--0.16). After stratification by maternal education level or family income level, language delay was most associated with the earlier diagnostic age in autistic children from families with higher socioeconomic levels.

Language delay, rather than other symptoms, promoted an earlier diagnostic age. Among male autistic children or children from families with higher socioeconomic levels, language delay was most significantly associated with an earlier age of diagnosis. Cognitive delay, or adaptive delay, was associated with a later age at diagnosis and presented only in autistic children from families with lower socioeconomic levels. There may be sex or socioeconomic inequality in the diagnostic age for autistic children. More publicity and public education about the diversity of autistic symptoms are urgently needed in the future, especially for low-socioeconomic families.

Despite the high prevalence of epilepsy in individuals with autism spectrum disorder (ASD), there is little information regarding whether seizure characteristics and treatment effectiveness change across age. Using an online survey, seizure characteristics, effectiveness of antiepileptic treatments, comorbidities, potential etiologies, and ASD diagnosis were collected from individuals with ASD and seizures. We previously reported overall general patterns of treatment effectiveness but did not examine the effect of seizure characteristics or age on antiepileptic treatment effectiveness. Such information would improve the personalized medicine approach to the treatment of seizures in ASD. Survey data from 570 individuals with ASD and clinical seizures were analyzed. Seizure severity (seizure/week) decreased with age of onset of seizures, plateauing in adolescence, with a greater reduction in generalized tonic-clonic (GTC) seizures with age. Seizure severity was worse in those with genetic disorders, neurodevelopmental regression (NDR) and poor sleep maintenance. Carbamazepine and oxcarbazepine were reported to be more effective when seizures started in later childhood, while surgery and the Atkins/modified Atkins Diet (A/MAD) were reported to be more effective when seizures started early in life. A/MAD and the ketogenic diet were reported to be more effective in those with NDR. Interestingly, atypical Landau-Kleffner syndrome was associated with mitochondrial dysfunction and NDR, suggesting a novel syndrome. These interesting findings need to be verified in independent, prospectively collected cohorts, but nonetheless, these data provide insights into novel relationships that may assist in a better understanding of epilepsy in ASD and provide insight into personalizing epilepsy care in ASD.

This article reviews the current knowledge state on pragmatic and structural language abilities in autism and their potential relation to extralinguistic abilities and autistic traits. The focus is on questions regarding autism language profiles with varying degrees of (selective) impairment and with respect to potential comorbidity of autism and language impairment: Is language impairment in autism the co-occurrence of two distinct conditions (comorbidity), a consequence of autism itself (no comorbidity), or one possible combination from a series of neurodevelopmental properties (dimensional approach)? As for language profiles in autism, three main groups are identified, namely, (i) verbal autistic individuals without structural language impairment, (ii) verbal autistic individuals with structural language impairment, and (iii) minimally verbal autistic individuals. However, this tripartite distinction hides enormous linguistic heterogeneity. Regarding the nature of language impairment in autism, there is currently no model of how language difficulties may interact with autism characteristics and with various extralinguistic cognitive abilities. Building such a model requires carefully designed explorations that address specific aspects of language and extralinguistic cognition. This should lead to a fundamental increase in our understanding of language impairment in autism, thereby paving the way for a substantial contribution to the question of how to best characterize neurodevelopmental disorders.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder whose pathogenesis is still unclear. MicroRNAs (miRNAs) are a kind of endogenous small non-coding RNAs that play important roles in the post-transcriptional regulation of genes. Recent researches show that miRNAs are edited in multiple ways especially in central nervous systems. A-to-I editing of RNA catalyzed by Adenosine deaminases acting on RNA (ADARs) happens intensively in brain and is also noticed in other organs and tissues. Although miRNAs are widely edited in human brain, miRNA editing in ASD is still largely unexplored. In order to reveal the editing events of miRNAs in ASD, we analyzed 131 miRNA-seq samples from 8 different brain regions of ASD patients and normal controls. We identified 834 editing sites with significant editing levels, of which 70 sites showed significantly different editing levels in the superior frontal gyrus samples of ASD patients (ASD-SFG) when compared with those of control samples. The editing level of an A-to-I editing site in hsa-mir-376a-1 (hsa-mir-376a-1_9_A_g) in ASD-SFG is higher than that of normal controls, and the difference is exaggerated in individuals under 10 years. The increased expression of ADAR1 is consistent with the increased editing level of hsa-mir-376a-1_9_A_g in ASD-SFG samples compared to normal SFG samples. Furthermore, we verify that A-to-I edited hsa-mir-376a-5p directly represses GPR85 and NAPB, which may contribute to the abnormal neuronal development of ASD patients. These results provide new insights into the mechanism of ASD.

Regression, while not a core symptom of autism spectrum disorder (ASD), has been suggested to be a distinct subtype by previous studies. Therefore, this study aimed to explore the prevalence and clinical differences between those with and without regression in children with ASD.

This study includes data from toddlers and young children aged 2-7 years acquired from other projects at Seoul National University Bundang Hospital. The presence and characteristics of regression were explored using question items #11-28 from the Autism Diagnostic Interview-Revised. Chi-square and independent t-tests were used to compare various clinical measurements such as autistic symptoms, adaptative behavior, intelligence, and perinatal factors.

Data from 1438 young children (1020 with ASD) were analyzed. The overall prevalence rate of regression, which was mainly related to language-related skills, was 10.2% in the ASD group, with an onset age of 24 months. Regarding clinical characteristics, patients with ASD and regression experienced ASD symptoms, especially restricted and repetitive interests and behaviors, with greater severity than those without regression. Furthermore, there were significant associations between regression and hypertension/placenta previa.

In-depth surveillance and proactive interventions targeted at young children with ASD and regression should focus on autistic symptoms and other areas of functioning.

Early regression (ER) is often reported in autistic children with a prototypical phenotype and has been proposed as a possible pathognomonic sign present in most autistic children. Despite the uncertainties attached to its definition and report, using ER to anchor the autism phenotype could help identify the signs that best contribute to an autism diagnosis. We extracted retrospective data from 1547 autistic children between the ages of 6 and 18 years from the Simons Simplex collection. Logistic regression identified the atypicalities associated with a history of ER. Stepwise variable selection using logistic regression analysis followed by a bootstrap procedure of 1000 iterations identified the cluster of atypicalities best associated with ER. Linear and logistic regressions measured the association between combinations of atypicalities within the identified cluster and adaptative behaviors, diagnostic areas of severity, and other categories. Seven atypicalities significantly increased the likelihood of having experienced ER (OR = 1.73-2.13). Four ("hand leading-ever", "pronominal reversal-ever", "never shakes head at age 4-5" and "stereotypic use of objects or interest in parts of objects-ever"), when grouped together, best characterized the phenotype of verbal autistic children with ER. This clustering of signs was associated with certain persistent language difficulties, higher summary scores on a diagnostic scale for autism, and greater odds of receiving an "autistic disorder" diagnosis instead of another pervasive developmental disorder (PDD) diagnosis. These results raise questions about using language as a clinical specifier, defining cross-sectional signs independent of their relationship with an early developmental trajectory, and relying on polythetic criteria or equivalent weighted autistic atypicalities.

Language regression, broadly defined as the loss of acquired language skills in early childhood, is a distinctive feature of autism. Little is known about the factors underlying regression or the prognosis of children who exhibit regression. We examine potential predictors of language regression and test its association with language development in a prospective longitudinal sample of children with autism spectrum disorder (ASD) from diagnosis to age 10 years.

We analysed data from Pathways in ASD, a prospective longitudinal study of 421 children enrolled around the time of an autism diagnosis between 2 and 5 years. Autism Diagnostic Interview-Revised data were available for 408 children, of whom 90 (22%) were classified as having language regression.

Demographic and other health factors including caregiver education, family income, child sex, reported seizures, and age of enrolment did not differ between children with and without language regression. Children with language regression walked earlier and attained first words sooner than those without regression. However, both groups attained phrase speech at comparable ages. Those with regression exhibited greater delays in expressive and receptive communication over the follow-up period, although this effect was attenuated when accounting for baseline differences in motor and cognitive ability. Overall, those with language regression continued to exhibit expressive but not receptive communication delay compared to those without regression. Communication trajectories were heterogeneous to age 10 years, irrespective of regression status.

Although language regression can be alarming, our findings confirm that its occurrence does not necessarily foreshadow worse developmental outcomes relative to those without regression. Although a discrepancy in age-equivalent communication skills may persist, this can be expected to be of less practical importance with rising average levels of skills. Future studies need to account for the significant variability in language trajectories by considering factors beyond developmental regression.

Neurodevelopmental disorders are a heterogeneous group of conditions that manifest as delays or deviations in the acquisition of expected developmental milestones and behavioral changes. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication and social interaction and by repetitive and restricted patterns of behavior, interests and activities. The aim of this review is to discuss the clinical features of the differential diagnoses of ASD that are prevalent among preschoolers, focusing on their similarities and disparities.

The international medical literature search was conducted using PubMed and was revised regarding the subject using single and/or combined keywords as follows: differential diagnosis, preschoolers, diagnostic challenge, attention deficit hyperactivity disorder, intellectual disability, high abilities/giftedness, childhood apraxia of speech, social communication disorder, Landau-Kleffner syndrome, stereotyped movement disorder and excessive screen time.

We describe conditions commonly found in clinical practice, taking ASD as a reference. We addressed converging and divergent aspects of behavior, cognition, communication, language, speech, socialization, and stereotypes for the diagnosis of ASD and other disorders identified as potential differential or comorbid diagnoses.

The ranking and characterization of symptoms appear to be essential for better understanding the underlying common ground between children with developmental disorders and children with ASD, thus properly diagnosing and directing social, professional, or medication interventions. This detailed discussion adds to the literature since, although ASD differential diagnoses are frequently mentioned and discussed in textbooks and journal articles, they rarely occupy a prominent place as we aimed herein.

Zac is a 13-year-old boy who presented with his parents to developmental-behavioral pediatrics seeking diagnostic clarity. He was born by vaginal delivery at full term after an uncomplicated pregnancy. Developmental milestones were met at typical ages until he was noted to have language delay and to be hyperactive and impulsive on entering preschool at age 4 years. Although he used some phrases in speech, he often used physical force to take toys from other children, rather than using words.On entering preschool at age 4 years, he was noted to have language delay (i.e., continued use of phrase speech only) and to be hyperactive and impulsive. An evaluation to determine eligibility for an Individualized Education Program (IEP) was completed and found him to have delays in cognition, receptive language, expressive language, social-emotional, and adaptive skills. His fine motor skills were in the low average range, and his gross motor skills were in the average range. He was admitted into an early childhood special education program, and aggressive behavior and hyperactivity decreased in the structured classroom.At age 7 years, Zac was re-evaluated by the school district and found to have moderate intellectual disability (ID). Chromosomal microarray analysis and testing for Fragile X syndrome were normal. He was noted to enjoy interacting with other children and adults, but his play was very immature (e.g., preference for cause/effect toys). He was able to respond appropriately when asked his name and age, but he also frequently demonstrated echolalia. He was also evaluated by his primary care physician and found to meet the criteria for attention-deficit/hyperactivity disorder, combined presentation (ADHD). Treatment with methylphenidate was initiated but discontinued after a brief time because of increased aggressive behaviors.Owing to continued significant tantrums, aggressive tendencies, and inability to communicate his basic needs, Zac was evaluated at a local Regional Center (statewide system for resources and access to services for individuals with developmental disabilities) at age 10 years and found to meet the criteria for autism spectrum disorder (ASD), and previous diagnosis of ID was confirmed. Zac received applied behavior analysis (ABA), but this was discontinued after 1 year because of a combination of a change in the insurance provider and parental perception that the therapy had not been beneficial.Zac became less hyperactive and energetic as he grew older. By the time Zac presented to the developmental-behavioral clinic at age 13 years, he was consistently using approximately 30 single words and was no longer combining words into phrases. He had a long latency in responding to verbal and nonverbal cues and seemed to be quite withdrawn. Physical examination revealed scoliosis and hand tremors while executing fine motor tasks. Seizures were not reported, but neuromotor regression was apparent from the examination and history. Laboratory studies including thyroid-stimulating hormone, free T4, creatine kinase, very-long-chain fatty acids, lactate, pyruvate, urine organic acids, and plasma amino acids were normal. Cranial magnetic resonance imaging demonstrated abnormal T2 hyperintensities in the periventricular and deep cerebral white matter and peridentate cerebellar white matter, consistent with a "tigroid" pattern seen in metachromatic leukodystrophy (MLD) and other white matter neurodegenerative diseases. Arylsulfatase A mutation was detected with an expanded ID/ASD panel, and leukocyte arylsulfatase activity was low, confirming the diagnosis of juvenile-onset MLD.Are there behavioral markers and/or historical caveats that clinicians can use to distinguish between ASD/ID with coexisting ADHD and a neurodegenerative disorder with an insidious onset of regression?

Childhood Disintegrative Disorder (CDD) is a rare condition characterized by regression of developmental and behavioral functioning after a period of apparently normal development, with an age of onset around 4 years. CDD is not included within the latest edition of the Diagnostic and Statistical Manual of Mental Disorders. We present a case report of an 11-year-old male who achieved normal development for up to 7 years followed by a deterioration of previously acquired linguistic, intellectual, and social skills. Following treatment with lithium carbonate combined with risperidone, the patient experienced a reduction in irritability and aggression. CDD is a rare condition; therefore, the data presented may be useful to investigate its characteristics of the onset, to improve the understanding of the aspects of differentiation from the Autism Spectrum Disorder and finally to propose the possibility of treatment.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a worldwide prevalence of about 1%, characterized by impairments in social interaction, communication, repetitive patterns of behaviors, and can be associated with hyper- or hypo-reactivity of sensory stimulation and cognitive disability. ASD comorbid features include internalizing and externalizing symptoms such as anxiety, depression, hyperactivity, and attention problems. The precise etiology of ASD is still unknown and it is undoubted that the disorder is linked to some extent to both genetic and environmental factors. It is also well-documented and known that one of the most striking and consistent finding in ASD is the higher prevalence in males compared to females, with around 70% of ASD cases described being males. The present review looked into the most significant studies that attempted to investigate differences in ASD males and females thus trying to shade some light on the peculiar characteristics of this prevalence in terms of diagnosis, imaging, major autistic-like behavior and sex-dependent uniqueness. The study also discussed sex differences found in animal models of ASD, to provide a possible explanation of the neurological mechanisms underpinning the different presentation of autistic symptoms in males and females.

Language skills as well as general cognitive skills show a considerable variation in children with autism spectrum disorder (ASD). In previous studies, at least three profiles based on these skills have been suggested; autism with language and non-verbal cognitive skills within the average/normal range (ALN), autism with language disorder (ALD) without concurrent non-verbal cognitive disability, and autism with language disorder and cognitive disability, i.e. autism with a more general delay (AGD). The aim of the present longitudinal case study is to illustrate these three groups more thoroughly by presenting the developmental trajectories of children belonging to each profile. Six children were chosen based on their language and cognitive profiles from the first age 3-year assessment. They came from a larger group of children with ASD identified by autism screening at child health-care centres at age 2.5 years. These six children represent one boy and one girl from each of the three subgroups ALN, ALD and AGD, and were assessed a second time at age 5 and a third time at age 8 years, regarding expressive and receptive language skills, autistic severity and non-verbal cognitive skills. Although preliminary, our results indicate a rather stable developmental trajectory from age 3 to 8 years characterising children with autism based on language and non-verbal cognitive functioning. Thus, in order to help intervention planning and increase predictions of outcome, it seems important to specify both linguistic and cognitive level already at the first assessment in children with ASD.

This study investigated receptive and expressive language outcomes in children with autism spectrum disorder (ASD) with and without a history of language/communication regression, employing three progressively less stringent definitions of regression. Data were derived from a large, longitudinal sample of children with ASD in which regression was assessed at approximately 30 months. Results indicated poorer receptive language and larger discrepancies between receptive and expressive language in the regression group than the group without regression at 44 months but not 66 months. Number of words used before loss predicted receptive language at 44 months. Overall, results suggest that a regression profile in ASD is associated with modest and transient impacts on language outcomes that are no longer discernable at school entry.

Subgroups of children with different speech profiles have been described however, little is known about the trajectories of speech development or stability of subgroups over time. This longitudinal study described both speech trajectories and subgroup stability of 22 autistic children, aged 2;0-6;11 years, over 12 months. Independent and relational speech analyses, vocabulary size and nonverbal communication were used in clustering. Results suggest varied speech trajectories, particularly for children with 'low language and low speech' at Time 1. Receptive vocabulary and consonant inventory at Time 1 may predict speech outcomes after 12 months. A small subgroup of children (n = 3) present with low expressive vocabulary and speech but higher receptive vocabulary and use of gestures. This unique profile remained stable.

This study aimed to investigate the prevalence of developmental regression in children with Autism Spectrum Disorder (ASD) and to explore its relationship with disease severity.

We finally included 1,027 ASD children aged 2-5 years from 13 cities in China: 138 with regressive ASD and 889 with non-regressive ASD. The Social Responsiveness Scale (SRS), Autism Behavior Checklist (ABC), Child Autism Rating Scale (CARS), and Children Neuropsychological and Behavioral Scale-Revision 2016 (CNBS-R2016) were used to evaluate the core symptoms and developmental status of children in the two groups.

Among the 1,027 ASD children eventually included, 138 (13.44%) cases showed regressive behavior and the average regression occurring age was 24.00 (18.00-27.00) months. Among the regressive children, 105 cases (76.09%) had language regression, 79 cases (57.25%) had social regression, and 4 cases (2.90%) had motor regression. The total scores of ABC and the sub-score of sensory and stereotypic behavior (β = 5.122, 95% CI: 0.818, 9.426, P < 0.05; β = 1.104, 95% CI: 0.120, 2.089, P < 0.05; β = 1.388, 95% CI: 0.038, 2.737, P < 0.05), the SRS total scores and the sub-score of autistic mannerisms (β = 4.991, 95% CI: 0.494, 9.487, P < 0.05; β = 1.297, 95% CI: 0.140, 2.453, P < 0.05) of children in the regressive group were all higher than the non-regressive group. The total developmental quotient (DQ) of CNBS-R2016 and the DQ of gross motor, fine motor, adaptive behavior, language (β = -5.827, 95% CI: -11.529, -0.125, P < 0.05) and personal society in the regressive group were lower than the non-regressive group and the proportion of children with intelligent developmental impairment was higher the non-regressive group.

Regressive autism is mainly manifested as language and social regression. Children with regressive ASD have more severe core symptoms, lower neurodevelopmental level DQ, and more serious disease degree than children with non-regressive ASD, which requires further etiological examinations and more clinical attention.