ASD-associated gene: SHANK3

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3-deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3-deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS.DOI: http://dx.doi.org/10.7554/eLife.18904.001

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice.

Association of schizophrenia spectrum and autism spectrum disorder (ASD) symptoms in children with ASD and clinic controls

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders that affect social communication, behavior, and sensory processing, in which PUFAs are considered important. This mini-review article aims to investigate the current evidence regarding the use of essential fatty acids (EFAs) in the treatment of autism spectrum disorders (ASDs). The study examines various research studies, related to EFAs, their benefits, and their role in ASD treatment. The article focuses on exploring the potential mechanisms underlying the effects of EFAs on ASDs, including their anti-inflammatory, antioxidant, and neuroprotective properties. Furthermore, the study discusses limitations and challenges associated with the use of EFAs in ASD treatment, including variability in dosage and duration of treatment. The results of this review indicate that while some studies suggest a positive effect of EFAs on ASD symptoms, there is currently insufficient evidence to support their routine use as a stand-alone treatment for ASD. The need for further research to better understand the potential benefits and limitations of EFAs in ASD treatment is highlighted.

Introduction Autism Spectrum Disorder (ASD) is a group of disorders that are manifested primarily by difficulties in interpersonal contact. Moreover, children with ASD have specific food habits, which can disturb their proper development. Nowadays, it is suggested that appropriate dietary interventions could help in the treatment of ASD. We will consider how effective a diet could be in this role. Aim This review aims to estimate the effectiveness of dietary interventions used in children with ASD based on scientific research. Material and method This article was created on the basis of a systematic review. Articles were searched using PubMed. The applied terms were: ‘diet in ASD’, ‘dietary interventions in Autism Spectrum Disorder’, ‘Autism Spectrum Disorder’, ‘therapies in ASD’. We searched for studies that were published in less than the last 5 years, but older references were also obtained from analyzed articles. Results We received a total of 227 results. After selection, It was decided to use 21 studies with dietetic interventions. Conclusions The most commonly performed interventions are the ketogenic diet, the gluten-free caseinfree diet, and probiotic supplementation. Most studies do not have enough evidence that would allow drawing definite conclusions. Currently, modifying the diet does not appear to have a significant impact on ASD symptoms.

BackgroundRestricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs in FXS could represent various underlying known co-occurring conditions in FXS such as anxiety or autism spectrum disorder (ASD), yet this distinction has not been investigated. Further, delineating whether RRBs are more indicative of anxiety or ASD in FXS may clarify phenotypic profiles within FXS and improve differential assessment.MethodsWe longitudinally examined the potentially independent or multiplicative effect of ASD and anxiety symptom severity on RRBs in 60 children with FXS. Anxiety was measured using the Child Behavior Checklist (CBCL), ASD severity was measured using the Childhood Autism Rating Scale (CARS), and RRBs were measured using the Repetitive Behavior Scale – Revised (RBS-R). We estimated a series of moderated regression models with anxiety and ASD symptoms at the initial assessment (Time 1) as predictors of RRBs at the outcome assessment two years later (Time 2), along with an anxiety-by-ASD interaction term to determine the potential multiplicative effect of these co-occurring conditions on RRBs.ResultsResults identified a significant interaction between ASD and anxiety symptom severity at the initial assessment that predicted elevated sensory-motor RRBs two years later. Increased sensory-motor RRBs were predicted by elevated ASD symptoms only when anxiety symptom severity was low. Likewise, increased sensory-motor RRBs were predicted by elevated anxiety symptoms only when ASD symptom severity was low. Interestingly, this relationship was isolated to Sensory-Motor RRBs, with evidence that it could also apply to total RRBs.ConclusionsFindings suggest that ASD and anxiety exert independent and differential effects on Sensory-Motor RRBs when at high severity levels and a multiplicative effect when at moderate levels, which has important implications for early and targeted interventions.

Parents of children with autism spectrum disorder (ASD) must identify, select, and even implement treatments. Child age, cognitive functioning, ASD symptoms, family income, parent education, and cultural background, all may influence treatment selection. Parents’ perceptions about ASD also may contribute. We explored whether parents’ perceptions of ASD, along with family- and child-specific characteristics, predicted use of various ASD treatment categories. Sixty-eight families from the Simons Simplex Collection completed the Revised Illness Perception Questionnaire (IPQ-R). Logistic regression results indicated that when parent perceptions predicted use of a treatment category, relative contribution of perceptions was somewhat stronger than child- and family-specific factors (i.e., demographics, functioning). Moreover, predictive factors differed between treatment categories. Overall, treatment category use was influenced by parents’ perceptions of control over ASD treatment, behaviors perceived to be related to ASD, and beliefs about chronicity of the diagnosis. These findings may contribute to broader understanding of parents’ ASD treatment selection and enhance professionals’ ability to guide families’ decision-making.

Objectives: 
\nThere has been a significant increase in the incidence rates and public awareness of autism spectrum disorder (ASD) in recent years. The DSM-5’s latest modification of diagnostic criteria for ASD has also stimulated considerable debate. Despite the rising concerns, few studies have been conducted in the Chinese population of Hong Kong, especially among youth and adolescents. This study investigates the clinical profile of ASD in adolescents in Hong Kong. In addition to using screening instruments commonly used to assess specific ASD characteristics, other psychometric measures for internalizing and externalizing problems are employed to examine their associations with the ASD symptoms. It also assesses the extent to which different ASD symptoms and their associated features predict parenting stress.
\nMethods:
\nA total of 143 adolescents aged between 11 and 17 (M = 14.17; SD = 1.76) completed this study with their parents, including 71 adolescents with ASD and 72 typically developing adolescents. Adolescents completed two self-report measures of emotional symptoms: the Spence Children’s Anxiety Scale (SCAS) and Children’s Depression Inventory (CDI). Their parents completed the Autism Spectrum Screening Questionnaire (ASSQ), Child Behaviour Checklist (CBCL), and Spence Children’s Anxiety Scale – Parent version (SCAS-P) for evaluating their child’s characteristics. Parents also completed the Depression, Anxiety, and Stress Scale-21 (DASS-21) and Parenting Stress Index-Short Form (PSI-SF) for measuring their own parenting stress.
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\nResults:
\nAll measures showed good to excellent internal consistency. They were as reliable and internally consistent as the original English versions. Parent reports in the ASD group were significantly higher than in the control group on all measures. Mean ASSQ scores in the ASD group fell within the clinical range. Optimal ASSQ cutoff scores were estimated using receiver operating characteristics analysis. ASD symptoms, as well as internalizing and externalizing problems, were found to be significant discriminators between the ASD group and the controls. In addition, parents reported that their child’s emotional and behaviour problems were more distressing than the ASD symptoms.
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\nDiscussion:
\nThis study highlights the importance of evaluating specific ASD characteristics and their associated symptoms of emotional and behavioural disturbances. This study suggests an optimal cutoff score of 9 for the ASSQ in Hong Kong. However, there is a need to assess its generalizability using large-scale community samples and other childhood clinical conditions. Although the findings appear to support the revised DSM-5 taxonomy of ASD, they must be interpreted with caution. Future treatments should provide parents with adequate professional support for reducing parenting stress and helping them cope with their child’s social, emotional, and behavioural impairments. 
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\nConclusions:
\nThis study documents preliminary norms for a broad range of measures for adolescents with ASD in Hong Kong. It also provides a useful empirical basis for future investigations of the interplay between specific ASD characteristics and their associated features. Regarding treatment planning, this study postulates a comprehensive treatment model for adolescents with ASD to guide treatment research.

To review current studies on the effectiveness of neurofeedback as a method of treatment of the core symptoms of autism spectrum disorders (ASD). Studies were selected based on searches in PubMed, Ovid MEDLINE, EMBASE, ERIC, and CINAHL using combinations of the following keywords: 'Neurofeedback' OR 'EEG Biofeedback' OR 'Neurotherapy' OR 'Mu-Rhythm' OR 'SMR' AND 'Autism' OR 'Autism Spectrum Disorder' OR 'Pervasive Developmental Disorder'. The existing evidence does not support the use of neurofeedback in the treatment of ASD. Studies with outcomes in favour of neurofeedback might be showing an improvement in comorbid attention-deficit-hyperactivity disorder symptoms rather than a true improvement in core ASD symptoms. Limitations of this review are those inherent in the studies available, including small sample size, short duration, variable diagnostic criteria, and insufficient control interventions, all causing a lack of generalizability.

Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations

Chapter 4.7 - SHANK2 and SHANK3 Mutations Implicate Glutamate Signaling Abnormalities in Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) presents distinct diagnostic and treatment challenges, particularly in understanding gender differences in symptom presentation and intervention effectiveness. The male-to-female ASD diagnosis ratio, often cited as 4:1, is increasingly questioned due to the subtler symptom presentation in females, contributing to significant underdiagnosis. This systematic review followed PRISMA guidelines to analyze data from 47 studies, examining gender differences in ASD diagnosis, symptom expression, and intervention effectiveness. Females with ASD more frequently exhibit internalizing symptoms like anxiety, social withdrawal, and emotional regulation difficulties, in contrast to the externalized behaviors typical of males. Analysis of over 1,000 individuals reveals that 75 % of males exhibit hallmark traits like repetitive behaviors and speech delays, compared to only 40 % of females. Conversely, over 60 % of females demonstrate social camouflaging behaviors, masking their symptoms and complicating their diagnosis. Additionally, this research investigates gender differences in response to intervention, finding that while 70 % of males benefit from traditional interventions like Applied Behavior Analysis (ABA) and Cognitive Behavioral Therapy (CBT), only 45 % of females show comparable progress. Females with ASD benefit more from therapies that focus on emotional regulation, social communication, and adaptive behaviors, underscoring the need for gender-sensitive approaches. Based on these findings, the study advocates for the development of diagnostic tools that account for gender-specific ASD traits, urging healthcare professionals to be more vigilant in identifying subtler ASD symptoms in females. Furthermore, intervention programs should be restructured to integrate social and emotional components that address the unique profiles of females with ASD. Families and caregivers must also be educated to recognize these gender-based differences, enabling earlier identification and more personalized care. Addressing these diagnostic and intervention disparities will significantly improve long-term outcomes for females with ASD.

IntroductionAvoidant/Restrictive Food Intake Disorder (ARFID) was introduced as a diagnostic category in DSM-5 to describe individuals with restrictive eating behaviors without fear of weight gain, differentiating it from Anorexia Nervosa (American Psychiatric Association, DSM-5, 2013). Although prevalent in children with Autism Spectrum Disorder (ASD), ARFID’s co-occurrence with ASD and its prevalence in parents of children with ASD, particularly regarding the Broad Autism Phenotype (BAP), remains underexplored. This study investigates the prevalence of ARFID in both children diagnosed with ASD and their parents, focusing on BAP features in parents and their relationship with ARFID symptoms.ObjectivesTo determine the prevalence of ARFID in parents of children diagnosed with ASD.To explore the relationship between ARFID symptoms and ASD symptoms in both parents and children, examining the role of BAP in parents.MethodsA cross-sectional study was conducted at Başkent University Psychiatry Clinic. The sample consisted of 69 children aged 2-18 diagnosed with ASD and 115 parents. ARFID diagnosis was determined using structured clinical interviews and the Nine-Item ARFID Screen (NIAS), while autism symptoms were assessed using the Childhood Autism Rating Scale (CARS) for children and the Autism Spectrum Quotient (AQ) for parents. Psychosocial, anthropometric, and clinical assessments were performed, including body mass index (BMI), nutritional status, and vitamin deficiencies. Statistical analysis included t-tests, chi-square tests, and correlation analyses (SPSS 24).ResultsThe study found that 34.8% of children with ASD (n=24) and 13% of parents (n=15) were diagnosed with ARFID, significantly higher than general population estimates (3.5%, p<0.001) (Thomas et al. Curr Psychiatry Rep 2017; 19: 54). Children with ARFID scored higher on the CARS (mean=38.58, SD=7.92) compared to non-ARFID children (mean=33.73, SD=5.59), with a statistically significant difference (t=-2.878, p=0.005). Furthermore, positive correlations were found between ARFID symptoms and autism-related features in both children and parents, particularly in the AQ imagination subscale (r=0.358, p<0.01).ConclusionsThis study highlights a significantly higher prevalence of ARFID in children with ASD and their parents compared to the general population. The strong correlation between ARFID and ASD symptoms, particularly BAP features in parents, suggests shared neurodevelopmental pathways. These findings underscore the need for increased clinical awareness of ARFID in both ASD children and their families, as well as the importance of incorporating ARFID assessments into ASD treatment plans. Future research should focus on the genetic and developmental mechanisms linking ARFID and ASD.Disclosure of InterestNone Declared

This study examined whether disruptions in connectivity involving regions critical for learning, planning, and executing movements are relevant to core autism symptoms. Spatially constrained ICA was performed using resting-state fMRI from 419 children (autism spectrum disorder (ASD) = 105; typically developing (TD) = 314) to identify functional motor subdivisions. Comparing the spatial organization of each subdivision between groups, we found voxels that contributed significantly less to the right posterior cerebellar component in children with ASD versus TD (P <0.001). Next, we examined the effect of diagnosis on right posterior cerebellar connectivity with all other motor subdivisions. The model was significant (P = 0.014) revealing that right posterior cerebellar connectivity with bilateral dorsomedial primary motor cortex was, on average, stronger in children with ASD, while right posterior cerebellar connectivity with left-inferior parietal lobule (IPL), bilateral dorsolateral premotor cortex, and supplementary motor area was stronger in TD children (all P ≤0.02). We observed a diagnosis-by-connectivity interaction such that for children with ASD, elevated social-communicative and excessive repetitive-behavior symptom severity were both associated with right posterior cerebellar-left-IPL hypoconnectivity (P ≤0.001). Right posterior cerebellar and left-IPL are strongly implicated in visuomotor processing with dysfunction in this circuit possibly leading to anomalous development of skills, such as motor imitation, that are crucial for effective social-communication. LAY SUMMARY: This study examines whether communication between various brain regions involved in the control of movement are disrupted in children with autism spectrum disorder (ASD). We show communication between the right posterior cerebellum and left IPL, a circuit important for efficient visual-motor integration, is disrupted in children with ASD and associated with the severity of ASD symptoms. These results may explain observations of visual-motor integration impairments in children with ASD that are associated with ASD symptom severity.

Many children with autism spectrum disorder have problems with managing their emotions (emotion regulation) and anxiety. In this study, over 1000 parents completed an online survey which showed that emotion regulation and anxiety are closely linked. Although emotion regulation and anxiety are inter-connected, the results also show that autism symptoms play an important role in anxiety in autism spectrum disorder. Emotion regulation problems may be an important target for the treatment of anxiety in autism.