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Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex and heterogeneous genetic etiology. While a proportion of ASD risk is attributable to common variants, rare copy-number variants (CNVs) and protein-disrupting single-nucleotide variants (SNVs) have been shown to significantly contribute to ASD etiology. We analyzed a homogeneous cohort of 127 ASD Italian families genotyped with the Illumina PsychArray, to perform an integrated analysis of CNVs and SNVs and to assess their contribution to ASD risk. We observed a higher burden of rare CNVs, especially deletions, in ASD individuals versus unaffected controls. Furthermore, we identified a significant enrichment of rare CNVs intersecting ASD candidate genes reported in the SFARI database. Family-based analysis of rare SNVs genotyped by the PsychArray also indicated an increased transmission of rare SNV variants from heterozygous parents to probands, supporting a multigenic model of ASD risk with significant contributions of both variant types. Moreover, our study reinforced the evidence for a significant role of VPS13B, WWOX, CNTNAP2, RBFOX1, MACROD2, APBA2, PARK2, GPHN , and RNF113A genes in ASD susceptibility. Finally, we showed that the PsychArray, besides providing useful genotyping data in psychiatric disorders, is a valuable and cost-efficient tool for genic CNV detection, down to 10 kb.

Early identification of Autism Spectrum Disorders (ASDs) can significantly improve outcomes. Deficits in joint attention (JA) abilities, considered a milestone in socio-communicative development, are among the earliest indicators of ASD. The purpose of this study is to examine if the ability to disengage visual attention (DA) at 12 months could predict joint attention abilities and socio-communicative development at 24 months in a population of infants at increased likelihood and reduced likelihood to develop ASD. Latency of DA at 12 months was analyzed through an eye-tracking paradigm in a group of 56 infants at increased (IL = 29) or reduced (RL = 27) likelihood to develop ASD. JA at 12 months was assessed through items from the Early Social Communication Scales. Diagnostic status was established at 24 months, with 10 children receiving a diagnosis of ASD. A higher DA latency at 12 months is correlated with a lower frequency of JA behaviors at 12 months and with poorer JA abilities at 24 months. Altered visual attention at 12 months was also correlated with socio-communicative development at 24 months and, together with lower JA abilities at 12 months, correlated with diagnostic status. Our findings point to the potential relevance of DA and JA skills as prognostic markers and intervention targets.

Background: Co-occurring conditions and psychiatric comorbidities are more frequently observed in autistic individuals than in typically developing populations. Objective: The present study aimed to investigate the agreement of parent- and self-reported psychopathological assessment using the Child Behavior Checklist (CBCL/6-18) and the Youth Self Report (YSR/11-18), respectively, in autistic adolescents without intellectual impairment. Methods: 54 autistic adolescents without intellectual impairment (11–18 years; M = 14.73; SD = 2.28) were assessed with a psychiatric and psychological evaluation conducted by expert clinicians also using self- and parent-reported scales and semi-structured interviews (K-SADS PL, CDI, MASC) including CBCL/6-18 and YSR/11-18. Results: According to clinical judgment, over 90% of participants had at least a comorbidity: anxiety (68.5%) and mood disorder (57.4%) were the most frequent. The results indicate significant discrepancies between parent- and self-reports across the three summary scales, which assess emotional and behavioral problems, as well as their combined presentation, often observed in youth with ASD. Specifically, differences were found in Internalizing (p < 0.001), Externalizing (p = 0.013), and Total Problems (p < 0.001) scales. Conclusions: The findings show the lack of agreement in parent- and self-reported scales in our sample. These results suggest the need for a cross- and multi-informant approach to support clinical judgment and understand psychopathological comorbidities of autistic adolescents without intellectual impairment.

Early diagnosis combined with an early intervention program, such as the Early Start Denver Model (ESDM), can positively influence the early natural history of autism spectrum disorders. This study evaluated the effectiveness of an early ESDM-inspired intervention, in a small group of toddlers, delivered at low intensity by the Italian Public Health System. Twenty-one toddlers at risk for autism spectrum disorders, aged 20-36 months, received 3 hours/wk of one-to-one ESDM-inspired intervention by trained therapists, combined with parents' and teachers' active engagement in ecological implementation of treatment. The mean duration of treatment was 15 months. Cognitive and communication skills, as well as severity of autism symptoms, were assessed by using standardized measures at pre-intervention (Time 0 [T0]; mean age =27 months) and post-intervention (Time 1 [T1]; mean age =42 months). Children made statistically significant improvements in the language and cognitive domains, as demonstrated by a series of nonparametric Wilcoxon tests for paired data. Regarding severity of autism symptoms, younger age at diagnosis was positively associated with greater improvement at post-assessment. Our results are consistent with the literature that underlines the importance of early diagnosis and early intervention, since prompt diagnosis can reduce the severity of autism symptoms and improve cognitive and language skills in younger children. Particularly in toddlers, it seems that an intervention model based on the ESDM principles, involving the active engagement of parents and nursery school teachers, may be effective even when the individual treatment is delivered at low intensity. Furthermore, our study supports the adaptation and the positive impact of the ESDM entirely sustained by the Italian Public Health System.

Standardized screening programs ensure that children are monitored for early signs of autism spectrum disorder (ASD) in order to promote earlier diagnosis and intervention. The aim of this study is to identify early signs of atypical development consistent with ASD or other developmental disorders in a population of 224 low-risk toddlers through a two-stage screening approach applied at 12 and 18 months of age. We adopted two screening tools combined: 1. the Communication and Symbolic Behavior Scales Developmental Profile (CSBS DP) Infant–Toddler Checklist (I-TC) and 2. The Quantitative Checklist for Autism in Toddlers (Q-CHAT). We assessed their sensitivity and specificity related to the diagnostic outcome at 36 months. The results showed that autistic signs can be detected as early as the first year even through a few questions extrapolated from both screeners and that our model could be used as a screening procedure in the Italian public health system.

The effects of environmental factors [including Socio-Economic Status, Cultural Capital, and Social Capital (Socio-Cultural Level) of both parents] on the Vineland-II adaptive behavior dimensions of toddlers with autism spectrum disorder (ASD), in addition to individual factors, was investigated in 148 Italian toddlers (82% males), aged 18 to 37 months with ASD. Toddlers’ age and Griffiths Mental Development Scales general development affected all of the adaptive behavior dimensions, with negative and positive associations, respectively. The Child Behavior Checklist comorbid conditions were negatively associated with some adaptive behavior dimensions while the ADOS-2 Social affect only with the communication dimension. Mothers’ and fathers’ specific Socio-Cultural Level dimensions were positively associated with toddlers’ specific adaptive behavior dimensions with the same magnitude as comorbid conditions.

Background: The literature suggests the existence of an association between autism spectrum disorders (ASDs) and subclinical electroencephalographic abnormalities (SEAs), which show a heterogeneous prevalence rate (12.5–60.7%) within the pediatric ASD population. The aim of this study was to investigate the EEG findings in a cohort of ASD preschoolers and their correlation with the phenotypic characteristics. Methods: We retrospectively reviewed data on 141 ASD preschoolers evaluated in a tertiary care university hospital over the period 2008–2018. All participants underwent at least one standard polygraphic electroencephalogram (EEG) and a clinical multidisciplinary assessment with standardized instruments. Results: 77 patients (55%) showed SEAs, which were mainly represented by epileptiform discharges (p < 0.00001), especially focal and multifocal (p = 0.010). Abnormal EEG (p = 0.035) and epileptiform discharges (p = 0.014) were associated with seizure onset and were predominant in sleep (p < 0.00001). Patients with abnormal tracing (p = 0.031) and slow abnormalities (p < 0.001) were significantly younger. ASD severity was not found to be correlated with EEG results, which showed a potential, albeit non-significant, association with some psychometric parameters. Very similar results were found when patients were divided according to sex. Conclusions: EEG abnormalities appear to correlate more with ASD internalizing, externalizing and emotional comorbidities, rather than with ASD core symptoms; larger samples are needed to further investigate this association.

The capacity of the Child Behavior Checklist 1½–5 (CBCL 1½–5) to identify children with autism spectrum disorder (ASD) at 18 months was tested on 37 children clinically referred for ASD and 46 children at elevated likelihood of developing ASD due to having an affected brother/sister. At 30 months the clinically referred children all received a confirmatory diagnosis, and 10 out of 46 siblings received a diagnosis of ASD. CBCL 1½-5 profiles were compared with a group of matched children with typical development (effect of cognitive level controlled for). The capacity of the CBCL 1½-5 DSM Oriented-Pervasive Developmental Problems scale to differentiate correctly between children diagnosed with ASD and children with typical development appeared dependent on group ascertainment methodology.

A massive asymptomatic creatine kinase elevation (MACKE) has been described during antipsychotic exposure in adult psychotic patients without signs of neuroleptic malignant syndrome (NMS), or other most frequent reasons for high creatine kinase (CK) serum level (intramuscular injections, restraints, intense physical activity, dystonic reactions). In this article, we review this clinical condition, and report three cases of MACKE in nonpsychotic, drug-naïve youth during treatment with second generation antipsychotics. The diagnosis of MACKE should be considered after ruling out other possible common reasons of CK increase. The finding of MACKE should indicate a need for weekly monitoring of the CK level only when there are reasons to believe elevated CK is toxic or harmful. Further investigations are recommended when signs and symptoms raise a suspicion of NMS or rhabdomyolysis, including flu-like syndrome, fever, weakness, alteration of consciousness, muscle rigidity, tachycardia, hyper-/hypotension, and dark urine. A drug discontinuation should be considered when possible signs of NMS or rhabdomyolysis are suspected, or in cases of very high and persisting CK levels. Empirical evidence indicates that there is not a “safe” antipsychotic medication; therefore, a switch to another antipsychotic with a different profile is not necessarily a safe option. The spontaneously remitting or intermittent course suggests that the “true” MACKE should be kept distinct from both rhabdomyolysis and NMS. Raising awareness with MACKE may reduce the need for unnecessary diagnosis of NMS or rhabdomyolysis, which may otherwise lead to an unnecessary discontinuation of an effective therapeutic agent.

Sex/gender (S/G) differences in ASD language profiles have been poorly investigated. The present study aims to explore whether male (M) and female (F) children with ASD and with normal non-verbal cognitive abilities differ in their linguistic profiles. A sample of 76 Italian children with ASD (range: 4.9–8 years), including 50 Ms and 26 Fs, was retrospectively recruited. Language profiles were analyzed using standardized tests for the evaluation of receptive and expressive vocabulary as well as grammar. Grammatical comprehension was the most impaired domain compared to the other language measures in both M and F children. Comparing language profiles between S/G, Fs showed significantly better scores than Ms in grammatical production (p = 0.002), and Ms showed better active negative sentence comprehension (p = 0.035). Moreover, comparing the language profiles between Ms and Fs with a receptive disorder, Fs had significantly worse grammatical comprehension and better grammatical production than Ms. Even among children without a receptive disorder, Fs had significantly higher grammatical production scores. The S/G differences in language profile, particularly better expressive language in Fs than Ms, can partially contribute to the delayed ASD diagnosis or underdiagnosis of Fs without intellectual disability. Finally, the results document the importance of accurately investigating both expressive and receptive abilities in children with ASD.