TLDc Domain-Containing Genes in Autism Spectrum Disorder: New Players in the Oxidative Stress Response.

Oxidative stress (OS) plays a key role in autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by deficits in social communication, restricted interests, and repetitive behaviors. Recent evidence suggests that the TLDc [Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic] domain is a highly conserved motif present in proteins that are important players in the OS response and in neuroprotection. Human proteins sharing the TLDc domain include OXR1, TLDC1, NCOA7, TBC1D24, and C20ORF118. This study was aimed at understanding whether TLDc domain-containing mRNAs together with specific microRNAs (200b-3p and 32-5p) and long noncoding RNAs (TUG1), known to target TLDc proteins, contributed to regulate the OS response in ASD. Data showed a significant increase in the levels of OXR1 and TLDC1 mRNAs in peripheral blood mononuclear cells (PBMCs) of ASD children compared to their neurotypically developing (NTD) counterparts, along with an increase in TUG1 mRNA expression levels, suggesting its possible role in the regulation of TLDc proteins. A positive correlation between the expression of some TLDc mRNAs and the Childhood Autism Rating Scale (CARS) global score as well as inflammatory gene expression was found. In conclusion, our data suggest a novel biological pathway in the OS response of ASD subjects that deserves further exploration.

An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%-30%) presenting a rare large-effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD-associated susceptibility variants. From chromosomal microarrays analysis of 104 ASD individuals, we identified an inherited NRXN1 deletion in a trio family. We carried out whole-exome sequencing and deep sequencing of mitochondrial DNA (mtDNA) in this family, to evaluate the burden of rare variants which may contribute to the phenotypic outcome in NRXN1 deletion carriers. We identified an increased burden of exonic rare variants in the ASD child compared to the unaffected NRXN1 deletion-transmitting mother, which remains significant if we restrict the analysis to potentially deleterious rare variants only (P = 6.07 × 10-5 ). We also detected significant interaction enrichment among genes with damaging variants in the proband, suggesting that additional rare variants in interacting genes collectively contribute to cross the liability threshold for ASD. Finally, the proband's mtDNA presented five low-level heteroplasmic mtDNA variants that were absent in the mother, and two maternally inherited variants with increased heteroplasmic load. This study underlines the importance of a comprehensive assessment of the genomic background in carriers of large-effect variants, as penetrance modulation by additional interacting rare variants to might represent a widespread mechanism in neurodevelopmental disorders.

Long-term follow-up of cognitive functions in patients with continuous spike-waves during sleep (CSWS).

Continuous spike-waves during sleep (CSWS) are associated with several cognitive, neurological, and psychiatric disorders, which sometimes persist after CSWS disappearance. The purpose of this retrospective study was to investigate the correlation between general (clinical and instrumental) and neuropsychological findings in CSWS, to identify variables that predispose patients to a poorer long-term neuropsychological outcome. Patients with spikes and waves during sleep with a frequency ≥25/min (spikes and waves frequency index - SWFI) were enrolled. There were patients presenting abnormal EEG activity corresponding to the classic CSWS and patients with paroxysmal abnormalities during sleep <85% with SWFI ≥25/min that was defined as excessive spike-waves during sleep (ESWS). Clinical and instrumental features and neuropsychological findings during and after the spike and wave active phase period were considered. A statistical analysis was performed utilizing the Spearman correlation test and multivariate analysis. The study included 61 patients; the mean follow-up (i.e., the period between SWFI ≥25 first recording and last observation) was 7years and 4months. The SWFI correlated inversely with full and performance IQ during CSWS/ESWS. Longer-lasting SWFI ≥25 was related to worse results in verbal IQ and performance IQ after CSWS/ESWS disappearance. Other variables may influence the neuropsychological outcome, like age at SWFI ≥25 first recording, perinatal distress, pathologic neurologic examination, and antiepileptic drug resistance. This confirms that CSWS/ESWS are a complex pathology and that many variables contribute to its outcome. The SWFI value above all during CSWS/ESWS and long-lasting SWFI ≥25 after CSWS/ESWS disappearance are the most significant indexes that appear mostly to determine cognitive evolution. This finding underscores the importance of EEG recordings during sleep in children with a developmental disorder, even if seizures are not reported, as well as the importance of using therapy with an early efficacy.

Prognostic factors of drug-resistant epilepsy in childhood: An Italian study.

BACKGROUND: Epilepsy is drug resistant in 30-40% of cases. We studied, retrospectively, the prognostic factors of drug resistance (DR) during a 15 year period, in an Italian sample of patients with childhood epilepsy. METHODS: A total of 117 patients were divided into two groups: one with DR, and the other without DR. The two groups were compared at the following time points: epilepsy onset (T0), and at 2, 5, 8 and 10 years after seizure onset (T2, T5, T8 and T10, respectively) using Fisher's exact test and randomization test. Multiple logistic regression analysis was then used to identify the most reliable predictive model of DR. RESULTS: Positive neurological examination at onset, symptomatic/probable symptomatic etiology, lack of response to the first drug, seizure clustering during follow up, intelligence quotient ≤ 70, altered neuropsychological examination at onset, and presence of cerebral lesions were predominant in cases of DR. The most reliable combinations of predictors of DR included partial or no response to the first drug, presence of seizure clustering during follow up, altered neurological examination at onset, and long latency between epilepsy onset and first drug at T2; partial or absent response to the first drug and positive magnetic resonance imaging (MRI) at T5; positive MRI and absence of generalized seizures at T8; and positive MRI at T10. DR also sometimes appeared after discontinuation of an effective therapy. CONCLUSIONS: Predictive factors of DR can be recognized in a large number of patients with epilepsy at disease onset, although the current possibility of predicting epilepsy outcome remains limited. In the long term, evidence of cerebral lesions appears to become the most significant prognostic factor.

Continuous Spike-Waves during Slow Sleep Today: An Update.

In the context of childhood epilepsy, the concept of continuous spike-waves during slow sleep (CSWS) includes several childhood-onset heterogeneous conditions that share electroencephalograms (EEGs) characterized by a high frequency of paroxysmal abnormalities during sleep, which have negative effects on the cognitive development and behavior of the child. These negative effects may have the characteristics of a clear regression or of a slowdown in development. Seizures are very often present, but not constantly. The above makes it clear why CSWS have been included in epileptic encephalopathies, in which, by definition, frequent EEG paroxysmal abnormalities have an unfavorable impact on cognitive functions, including socio-communicative skills, causing autistic features, even regardless of the presence of clinically overt seizures. Although several decades have passed since the original descriptions of the electroclinical condition of CSWS, there are still many areas that are little-known and deserve to be further studied, including the EEG diagnostic criteria, the most effective electrophysiological parameter for monitoring the role of the thalamus in CSWS pathogenesis, its long-term evolution, the nosographic location of Landau-Kleffner syndrome, standardized neuropsychological and behavioral assessments, and pharmacological and non-pharmacological therapies.

Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in the cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 8 severe de novo pdSNVs in genes not previously implicated in ASD (AGPAT3, IRX5, MGAT5B, RAB8B, RAP1A, RASAL2, SLC9A1, YME1L1) highlighted promising candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, although this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in ASD/NDD candidate genes not yet established. In conclusion, our study highlights promising ASD candidate genes and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

Autism Spectrum Disorder in 2023: A Challenge Still Open.

In this paper, we provide an update on autism spectrum disorder (ASD), including epidemiology, etiopathogenesis, clinical presentation, instrumental investigations, early signs, onset patterns, neuropsychological hypotheses, treatments, and long-term outcome. The prevalence of this condition has increased enormously over the last few decades. This increase prompted a search for possible environmental factors whose effects would add up to a genetic predisposition leading to the development of autism. But the genetic and environmental variables involved are extremely numerous, and conclusive data regarding the etiopathogenesis are still far away. Assuming that a well-defined etiology is still found today only in a minority of cases, numerous pathogenetic mechanisms have been hypothesized. Among these, we mention oxidative stress, mitochondrial dysfunction, alteration of the intestinal microbiota, immune dysregulation, and neuroinflammation. These pathogenetic mechanisms could alter epigenetic status and gene expression, finally leading to ASD. Inherent in the term spectrum is the great clinical heterogeneity of this condition, mainly due to the frequent comorbidity that characterizes it. The earlier the diagnosis is made and the earlier psychoeducational treatment begins, the better the prognosis. In this sense, the role of pediatricians can be decisive in making children with signs suggestive of autism undergo a specialist diagnostic course. The development of increasingly advanced cognitive-behavioral educational techniques has considerably improved the prognosis of affected individuals, even though only a small minority of them come off the autistic spectrum. Pharmacological therapies are used to treat comorbidities. During childhood, the most important prognostic factor for long-term outcome seems to be intellectual functioning.

Whole genome analysis of rare deleterious variants adds further evidence to BRSK2 and other risk genes in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component in which rare variants contribute significantly to risk. We have performed whole genome and/or exome sequencing (WGS and WES) and SNP-array analysis to identify both rare sequence and copy number variants (SNVs and CNVs) in 435 individuals from 116 ASD families. We identified 37 rare potentially damaging de novo SNVs (pdSNVs) in cases (n = 144). Interestingly, two of them (one stop-gain and one missense variant) occurred in the same gene, BRSK2. Moreover, the identification of 9 severe de novo pdSNVs in genes not previously implicated in ASD (RASAL2, RAP1A, IRX5, SLC9A1, AGPAT3, MGAT3, RAB8B, MGAT5B, YME1L1), highlighted novel candidates. Potentially damaging CNVs (pdCNVs) provided support to the involvement of inherited variants in PHF3, NEGR1, TIAM1 and HOMER1 in neurodevelopmental disorders (NDD), although mostly acting as susceptibility factors with incomplete penetrance. Interpretation of identified pdSNVs/pdCNVs according to the ACMG guidelines led to a molecular diagnosis in 19/144 cases, but this figure represents a lower limit and is expected to increase thanks to further clarification of the role of likely pathogenic variants in new ASD/NDD candidates. In conclusion, our study strengthens the role of BRSK2 and other neurodevelopmental genes in ASD risk, highlights novel candidates and contributes to characterize the allelic diversity, mode of inheritance and phenotypic impact of de novo and inherited risk variants in ASD/NDD genes.

Early Motor Signs in Autism Spectrum Disorder.

A growing number of literature data suggest the presence of early impairments in the motor development of children with autism spectrum disorder, which could be often recognized even before the appearance of the classical social communication deficits of autism. In this narrative review, we aimed at performing an update about the available data on the early motor function in children with autism spectrum disorder. Early motor impairment in these children can manifest itself both as a mere delay of motor development and as the presence of atypicalities of motor function, such as a higher rate and a larger inventory, of stereotyped movements both with and without objects. In the perspective of a timely diagnosis, the presence of early motor signs can be an important clue, especially in an individual considered at high risk for autism. Motor and communication (both verbal and non-verbal) skills are connected and a pathogenetic role of early motor dysfunctions in the development of autism can be hypothesized. From this, derives the importance of an early enabling intervention aimed at improving motor skills, which could also have favorable effects on other aspects of development.

Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility.

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.

Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder.

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%-5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers' germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.

Update about "minimally verbal" children with autism spectrum disorder.

OBJECTIVE: To review clinical and neurobiological features of minimally verbal children with autism spectrum disorder. DATA SOURCE: We carried out a narrative review using the PubMed database. We considered the following search terms combined through the Boolean operator "AND": "autism spectrum disorder"; "minimally verbal." DATA SYNTHESIS: To date, there is no shared definition of minimally verbal children with autism spectrum disorder. The heterogeneity in intellectual functioning and in linguistic abilities among these individuals suggests there is no single mechanism underlying their difficulties in learning to speak. However, the reasons why these children do not speak and the biological markers that can identify them are still unknown. Language impairment in these children can lead to several unfavorable consequences, including behavior problems (such as self-aggression, hetero-aggression, and property destruction), poorer daily living and social skills. Psychiatric comorbidities (including attention deficit/hyperactivity disorder, specific phobias, and compulsions) consist in a serious problem related to the lack of verbal language in individuals with autism spectrum disorder. Although in the literature there are very few evidence-based results, several findings suggest that an alternative and augmentative communication intervention, creating an extra-verbal communication channel, may be effective in these individuals. CONCLUSIONS: The exact definition, clinical characteristics, associated disorders, etiology, and treatment of minimally verbal subjects with autism spectrum disorder must still be further studied and understood.

Case Report: Burden of Illness in Narcolepsy Type 1: Hikikomori in a Teenage Girl.

Narcolepsy type 1 (NT1) deeply impacts on quality of life, especially during adolescence, with NT1 children and adolescents that frequently report difficulties in integration with peers and decreased participation in after-school activities. Here we describe the case of NT1 teenager girl presenting with severe physical and social withdrawal, fulfilling the proposed diagnostic criteria for hikikomori, together with the classic NT1 symptoms. Social withdrawal is an overlooked phenomenon among NT1 children and adolescents that, if present, require a multidisciplinary approach and personalized interventions, but patients can benefit from NT1 pharmacological treatment.

Syndromic Autism Spectrum Disorder: Let Us Not Forget about Succinic Semialdehyde Dehydrogenase Deficiency. A Case Report with Literature Review.

We describe a girl with syndromic autism spectrum disorder (ASD), who at the end of the medical workup proved affected by a succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare autosomal-recessive disorder of degradation of the γ-aminobutyric acid (GABA), that is, the most important central nervous system inhibitory neurotransmitter. The diagnosis of SSADH deficiency was made using a next-generation sequencing (NGS) multigene panel for neurological disorders and was confirmed by urinary organic acid analysis. Compared to the classic description of SSADH deficiency, our patient presented a less severe picture. In fact, she had no epilepsy, and her neuromotor signs were soft, and over time they became less evident. This case report emphasizes the importance of considering in a patient with syndromic ASD, the possible diagnosis of SSADH deficiency, even when all its typical signs are not present. Nowadays, the use of NGS multigene panels could facilitate the etiological diagnosis in individuals with syndromic ASD.

Neuro-Behavioral Phenotype in 16p11.2 Duplication: A Case Series.

Duplications of chromosome 16p11.2, even though rare in the general population, are one of the most frequent known genetic causes of autism spectrum disorder and of other neurodevelopmental disorders. However, data about the neuro-behavioral phenotype of these patients are few. We described a sample of children with duplication of chromosome 16p11.2 focusing on the neuro-behavioral phenotype. The five patients reported presented with very heterogeneous conditions as for characteristics and severity, ranging from a learning disorder in a child with normal intelligence quotient to an autism spectrum disorder associated with an intellectual disability. Our case report underlines the wide heterogeneity of the neuropsychiatric phenotypes associated with a duplication of chromosome 16p11.2. Similarly to other copy number variations that are considered pathogenic, the wide variability of phenotype of chromosome 16p11.2 duplication is probably related to additional risk factors, both genetic and not genetic, often difficult to identify and most likely different from case to case.

Whatever happened to multiple complex developmental disorder?

Multiple complex developmental disorder is characterized by early-onset combined impairment in the regulation of affective states, in the social behavior, and in the thought processes. First described in the Eighties, so far multiple complex developmental disorder has so far not found recognition as an autonomous nosographic entity in international classifiers. In the past, the most common diagnosis for patients presenting with this clinical picture was that of 'pervasive developmental disorder not otherwise specified,' due to the early-onset impairment in various development areas, including the social functioning, with pervasive characteristics. Over recent years, based on literature data, the interest in multiple complex developmental disorder has seemed to decline. Yet, several clinical and neurobiological findings emerging from the literature seem to support the nosographic autonomy of multiple complex developmental disorder. The correct recognition of this clinical picture appears to be of considerable importance because children who are affected seem to be predisposed to develop a schizophrenia spectrum disorder during their lifetime. Multiple complex developmental disorder could be a very interesting entity, being a possible kind of "bridge" condition between autism spectrum disorder and childhood-onset schizophrenia. However, there is a lack of findings of the real recurrence, neurobiologic background, and course of this clinical picture.

Is it autism? Some suggestions for pediatricians.

An early diagnosis of autism spectrum disorder, leading to a timely enabling intervention, is associated with a better long-term prognosis and allows the early detection of any medical comorbidities that are sometimes found in individuals with autism. It is, therefore, an important challenge to begin the diagnostic procedure of these children as soon as possible. Nowadays, much progress has been made in this respect compared with the past, but considerable work remains. A fundamental role in starting a correct and timely diagnostic procedure is obviously played by the pediatrician. Today, many tools are available for the early screening of autism in the general population, but unfortunately, their real effectiveness has yet to be established. In this narrative review, we address the topic of the early diagnosis of autism spectrum disorder, emphasizing, in particular, those that are now considered the first warning signs. We list a few of the most important signs to consider when a child aged around 18 months presents to a pediatrician, subdivided into three subgroups: social-communication skills; patterns of behavior, interests, or activities; and sensory behaviors and reactivity/temperament. We deal separately with the possible presence of slight motor signs, which can also go unnoticed, but probably they should be considered as very early signs appearing even before social-communication deficits.

Sleep Problems in Children with Autism Spectrum Disorder.

Sleep disorders are one of the most frequent comorbidities in children with autism spectrum disorder (ASD). Heterogeneous sleep problems in children with ASD have been reported, and insomnia has a prevalence in children with ASD ranging from 60% to 86%. Poor sleep can cause harmful effects on cognitive functions, fostering the appearance of aggression, irritability, inattention, and hyperactivity in children with ASD. Sleep disorders can also be related to the severity of the core symptoms of ASD, including social cognition and communication, stereotypic behavior, and hypersensitivity to the environment. The etiology of sleep disorders in children with ASD is multifactorial, related to complex interactions between biological factors and psychological, socio-environmental, and family factors. From the therapeutic perspective, interventions should only be considered after any medical conditions potentially contributing to sleep disorders have been carefully evaluated. [Pediatr Ann. 2020;49(6):e278-e282.].

Autism Spectrum Disorder and Narcolepsy: A Possible Connection That Deserves to Be Investigated.

Narcolepsy in childhood-adolescence is characterized by a high occurrence of psychiatric comorbidities. The most frequent psychiatric disorders reported in these patients are attention deficit/hyperactivity disorder, depression, anxiety disorder, and schizophrenia. However, narcolepsy can be associated also with introversion, sorrowfulness, feelings of inferiority, impaired affectivity modulation, emotional lability, irritability, aggressiveness, and poor attention, that have been pooled by some authors under a definition of "narcoleptic personality." Some aspects of this "narcoleptic personality," and in particular introversion, impaired affectivity modulation, irritability, and poor attention, partially overlap with the clinical features of the individuals with autism spectrum disorder, considering also those that are not regarded as core autism symptoms. Till now, in literature the number of cases affected by both narcolepsy and autism spectrum disorder (seven patients) has been clearly too small to demonstrate the presence of a pathogenetic link between these two conditions, but this possible connection has not yet been adequately investigated, despite the presence of several points in common. The finding of a connection between narcolepsy and autism spectrum disorder could boost the study of possible etiopathogenetic mechanisms shared between these two apparently so distant disorders. Basing on the literature data summarized in this paper, in the diagnostic work-up of a child with narcolepsy it is essential to evaluate also the social-communicative behavior using standardized tools in order to detect the real recurrence of clinical features suggesting an autism spectrum disorder. At the same time, it appears necessary to screen in the individuals with autism spectrum disorder for the possible presence of evoking symptoms of narcolepsy.

Brain Magnetic Resonance Findings in 117 Children with Autism Spectrum Disorder under 5 Years Old.

We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of neuroradiologic findings in routine magnetic resonance imaging (MRI) scans of a group of 117 ASD children younger than 5 years old. These data were compared to those reported in typically developing (TD) children. MRI findings in children with ASD were analyzed in relation to their cognitive level, severity of autistic symptoms, and the presence of electroencephalogram (EEG) abnormalities. The MRI was rated abnormal in 55% of children with ASD with a significant prevalence in the high-functioning subgroup compared to TD children. We report significant incidental findings of mega cisterna magna, ventricular anomalies and abnormal white matter signal intensity in ASD without significant associations between these MRI findings and EEG features. Based on these results we discuss the role that brain MRI may play in the diagnostic procedure of ASD.