Cranio-Facial Characteristics in Autism Spectrum Disorder: A Scoping Review.

Autism spectrum disorders (ASD) consist of a complex group of neurodevelopmental disorders characterised by qualitative impairments of social interactions, communication abilities, and a limited, stereotyped, and repetitive selection of interests and activities. In light of the imperative to identify a possible biomarker for ASD, it has been determined that craniofacial anomalies serve as significant risk factors for neurodevelopmental disorders. The aim of this scoping review is to deepen the knowledge of the scientific literature related to cranio-facial characteristics in individuals with ASD, with a particular focus on recent research advancements. The review was performed by employing the search strings (("Autism Spectrum Disorder" OR autism OR ASD OR "Autism Spectrum") AND ("facial morphology" OR "facial phenotype")) on the databases PubMed/MEDLINE, Scopus, and ERIC as of March 9, 2023. The review comprised seven studies whose findings were obtained through quantitative analysis of Euclidean distances between anatomical landmarks. The examination of facial abnormalities represents a possible reliable diagnostic biomarker that could aid in the timely identification of ASD. Phenotypic characteristics that may serve as predictive indicators of the severity of autistic symptoms can be observed in certain individuals with ASD by applying anthropometric and instrumental measurements. The presence of a phenotype characterised by an increased intercanthal distance and a reduced facial midline height appears to be associated with a higher degree of severity in autistic symptoms. In addition, it is worth noting that facial asymmetry and facial masculinity can be considered reliable indicators for predicting a more severe manifestation of symptoms.

Metabotropic Glutamate Receptor Subtype 5 Positron-Emission-Tomography Radioligands as a Tool for Central Nervous System Drug Development: Between Progress and Setbacks.

The metabotropic glutamate receptor subtype 5 (mGluR5) is a class C G-protein-coupled receptor (GPCR) that has been implicated in various neuronal processes and, consequently, in several neuropsychiatric or neurodevelopmental disorders. Over the past few decades, mGluR5 has become a major focus for pharmaceutical companies, as an attractive target for drug development, particularly through the therapeutic potential of its modulators. In particular, allosteric binding sites have been targeted for better specificity and efficacy. In this context, Positron Emission Tomography (PET) appears as a useful tool for making decisions along a drug candidate's development process, saving time and money. Thus, PET provides quantitative information about a potential drug candidate and its target at the molecular level. However, in this area, particular attention has to be given to the interpretation of the PET signal and its conclusions. Indeed, the complex pharmacology of both mGluR5 and radioligands, allosterism, the influence of endogenous glutamate and the choice of pharmacokinetic model are all factors that may influence the PET signal. This review focuses on mGluR5 PET radioligands used at several stages of central nervous system drug development, highlighting advances and setbacks related to the complex pharmacology of these radiotracers.

Skin type and nerve effects on cortical tactile processing: a somatosensory evoked potentials study.

Somatosensory evoked potential (SEP) studies typically characterize short-latency components following median nerve stimulations of the wrist. However, these studies rarely considered 1) skin type (glabrous/hairy) at the stimulation site, 2) nerve being stimulated, and 3) middle-latency (>30 ms) components. Our aim was to investigate middle-latency SEPs following simple mechanical stimulation of two skin types innervated by two different nerves. Eighteen adults received 400 mechanical stimulations over four territories of the right hand (two nerves: radial/median; two skin types: hairy/glabrous skin) while their EEG was recorded. Four middle-latency components were identified: P50, N80, N130, and P200. As expected, significantly shorter latencies and larger amplitudes were found over the contralateral hemisphere for all components. A skin type effect was found for the N80; glabrous skin stimulations induced larger amplitude than hairy skin stimulations. Regarding nerve effects, median stimulations induced larger P50 and N80. Latency of the N80 was longer after median nerve stimulation compared with radial nerve stimulation. This study showed that skin type and stimulated nerve influence middle-latency SEPs, highlighting the importance of considering these parameters in future studies. These modulations could reflect differences in cutaneous receptors and somatotopy. Middle-latency SEPs can be used to evaluate the different steps of tactile information cortical processing. Modulation of SEP components before 100 ms possibly reflects somatotopy and differential processing in primary somatosensory cortex.NEW & NOTEWORTHY The current paper highlights the influences of stimulated skin type (glabrous/hairy) and nerve (median/radial) on cortical somatosensory evoked potentials. Mechanical stimulations were applied over four territories of the right hand in 18 adults. Four middle-latency components were identified: P50, N80, N130, and P200. A larger N80 was found after glabrous skin stimulations than after hairy skin ones, regardless of the nerve being stimulated. P50 and N80 were larger after median than radial nerve stimulations.

Glutamate levels of the right and left anterior cingulate cortex in autistics adults.

BACKGROUND: The neurobiology of Autism Spectrum Disorder (ASD) is still unknown. Alteration in glutamate metabolism might translate into an imbalance of the excitation/inhibition equilibrium of cortical networks that in turn are related to autistic symptoms, but previous studies using voxel located in bilateral anterior cingulate cortex (ACC) failed to show abnormalities in total glutamate level. Due to the functional differences in the right and left ACC, we sought to determine whether a difference between right and left ACC glutamate levels could be found when comparing ASD patients and control subjects. METHODS: Using single-voxel proton magnetic resonance spectroscopy (1H-MRS), we analyzed the glutamate + glutamine (Glx) concentrations in the left and right ACC of 19 ASD patients with normal IQs and 25 matched control subjects. RESULTS: No overall group differences in Glx were shown, in the left ACC (p = 0.24) or in the right ACC (p = 0.11). CONCLUSIONS: No significant alterations in Glx levels were detected in the left and right ACC in high-functioning autistic adults. In the excitatory/inhibitory imbalance framework, our data reinforce the critical need to analyze the GABAergic pathway, for better understanding of basic neuropathology in autism.

Sounds Pleasantness Ratings in Autism: Interaction Between Social Information and Acoustical Noise Level.

A lack of response to voices, and a great interest for music are part of the behavioral expressions, commonly (self-)reported in Autism Spectrum Disorder (ASD). These atypical interests for vocal and musical sounds could be attributable to different levels of acoustical noise, quantified in the harmonic-to-noise ratio (HNR). No previous study has investigated explicit auditory pleasantness in ASD comparing vocal and non-vocal sounds, in relation to acoustic noise level. The aim of this study is to objectively evaluate auditory pleasantness. 16 adults on the autism spectrum and 16 neuro-typical (NT) matched adults rated the likeability of vocal and non-vocal sounds, with varying harmonic-to-noise ratio levels. A group by category interaction in pleasantness judgements revealed that participants on the autism spectrum judged vocal sounds as less pleasant than non-vocal sounds; an effect not found for NT participants. A category by HNR level interaction revealed that participants of both groups rated sounds with a high HNR as more pleasant for non-vocal sounds. A significant group by HNR interaction revealed that people on the autism spectrum tended to judge as less pleasant sounds with high HNR and more pleasant those with low HNR than NT participants. Acoustical noise level of sounds alone does not appear to explain atypical interest for voices and greater interest in music in ASD.

Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Atypical Response to Affective Touch in Children with Autism: Multi-Parametric Exploration of the Autonomic System.

This study aimed at evaluating the autonomic response to pleasant affective touch in children with Autism Spectrum Disorders (ASD) and age-matched typically developing (TD) peers, thanks to multiple autonomic nervous system (ANS) parameters and by contrasting CT (C-tactile fibers) high- vs. low-density territory stimulations. We measured pupil diameter, skin conductance, and heart rate during gentle stroking of two skin territories (CT high- and low-density, respectively, forearm and palm of the hand) in thirty 6-12-year-old TD children and twenty ASD children. TD children showed an increase in pupil diameter and skin conductance associated with a heart rate deceleration in response to tactile stimulations at the two locations. Only the pupil was influenced by the stimulated location, with a later dilation peak following CT low-density territory stimulation. Globally, ASD children exhibited reduced autonomic responses, as well as different ANS baseline values compared to TD children. These atypical ANS responses to pleasant touch in ASD children were not specific to CT-fiber stimulation. Overall, these results point towards both basal autonomic dysregulation and lower tactile autonomic evoked responses in ASD, possibly reflecting lower arousal and related to social disengagement.

Autonomic tone in children and adults: Pupillary, electrodermal and cardiac activity at rest.

Considering the suspected involvement of the autonomic nervous system (ANS) in several neurodevelopmental disorders, a description of its tonus in typical populations and of its maturation between childhood and adulthood is necessary. We aimed to arrive at a better understanding of the maturation of the sympathetic (SNS) and parasympathetic (PNS) tonus by comparing children and adults at rest, via recordings of multiple ANS indices. We recorded simultaneously pupil diameter, electrodermal activity (EDA) and cardiac activity (RR interval and HRV: heart rate variability) in 29 children (6-12 years old) and 30 adults (20-42 years old) during a 5-min rest period. Children exhibited lower RR intervals, higher LF peak frequencies, and lower LF/HF (low frequency/high frequency) ratios compared to adults. Children also produced more spontaneous EDA peaks, reflected in a larger EDA AUC (area under the curve), in comparison with adults. Finally, children displayed a larger median pupil diameter and a higher pupillary hippus frequency than adults. Our results converged towards higher SNS and PNS tones in children compared to adults. Childhood would thus be characterized by a high autonomic tone, possibly reflecting a physiological state compatible with developmental acquisitions.

Autism spectrum disorder during French COVID-19 lockdown: The importance of individualized support.

AIM: This observational and repeated measures study assesses the impact of the first, most restrictive, COVID-19 lockdown in France on children with autism spectrum disorder (ASD) and their families. METHOD: During the first COVID-19 lockdown, families of ASD children enrolled in the day-care centre of the child and adolescent psychiatry department of the Tours University Hospital were contacted weekly. A total of 95 parents took part in this study between the 18th of March and the 8th of May 2020. Advice and personalized support materials were provided by professionals involved in children's care. Questions regarding clinical outcomes were addressed to parents, and their assessments were reported on a 5-point Likert scale. Two time points were considered: the first 3 weeks and the three last weeks of the lockdown period. RESULTS: No difference was highlighted between clinical scores collected at the beginning and at the end of the lockdown. No effect of intellectual disability, accommodation type (house or apartment) or parental status was observed. The reasons for the relatively minor impact of the COVID-19 lockdown observed in this study are discussed. CONCLUSIONS: Individualized and regular support provided by caregivers, familiar with ASD children's clinical specificities, in the context of a trusted relationship with parents may have contributed to the stability of this population. This 'tailor-made' approach should be promoted, in order to help support families of ASD children in this challenging period.

A Preliminary Study on Photic Driving in the Electroencephalogram of Children with Autism across a Wide Cognitive and Behavioral Range.

Intermittent photic stimulation (IPS) is a useful technique in electroencephalography (EEG) to investigate the neurophysiological anomalies of brain activity. Although not an active task, IPS has also been explored in ASD; it is thought to capture local potential oscillators at specific frequencies and perhaps tap into rhythmic activity in a way that general resting-state recordings cannot. Previous studies suggest that individuals with ASD showed photic driving reactivity predominantly at lower frequencies of stimulation. In our study we used IPS to measure rhythmic oscillatory activity in a sample of 81 ASD children. We found a significant correlation linking ASD children with photic driving activation only at low frequencies (δθ band) and increased severity of "restricted behavior". This suggests that ASD children with higher severity of restricted behaviors could have a hypersynchronous θ power and an impaired resonance synchronization at middle-ranged frequencies (α). Furthermore, we found some evidence of hemispherical oscillatory asymmetry linked particularly to behavioral impairments. This result is in line with the EEG pattern model indicating a "U-shaped profile" of electrophysiological power alterations with excess power in low- and high-frequency bands and a reduction of power in the middle-ranged frequencies. IPS technique in electroencephalography is confirmed to reveal EEG biomarkers in autistic children, with a focus on spectral power, coherence, and hemisphere asymmetries.

Neural repetition suppression to vocal and non-vocal sounds.

Adaptation to the sensory environment is essential in everyday life, to anticipate future events and quickly detect and respond to changes; and to distinguish vocal variations in congeners, for communication. The aim of the current study was to explore the effects of the nature (vocal/non-vocal) of the information to be encoded, on the establishment of auditory regularities. In electrophysiology, neural adaptation is measured by the 'Repetition Positivity' (RP), which refers to an increase in positive potential, with the increasing number of repetitions of a same stimulus. The RP results from the combined variation of several ERP components; the P1, the first positivity (∼100 ms) may reflect the onset of repetition effects. We recorded auditory evoked potentials during a roving paradigm in which trains of 4, 8 or 16 repetitions of the same stimulus were presented. Sequences of vocal and non-vocal complex stimuli were delivered, to study the influence of the type of stimulation on the characteristics of the brain responses. The P1 to each train length, and the RP responses were recorded between 90 and 200 ms, reflecting adaptation for both vocal and non-vocal stimuli. RP was not different between vocal and non-vocal sequences (in latency, amplitude and spatial organization) and was found to be similar to that found in previous studies using pure tones, suggesting that the repetition suppression phenomena is somehow independent of the nature of the stimulus. However, results showed faster stabilization of the P1 amplitude for non-vocal stimuli than for vocal stimuli, which require more repetitions. This revealed different dynamics for the establishment of regularity encoding for non-vocal and vocal stimuli, indicating that the richness of vocal sounds may require further processing before full neural adaptation occurs.

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin.

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild. Fetal hemoglobin (HbF) fraction was elevated 2.2%-11.2% (reference value <2% in individuals > 6 months) in four of the five individuals for whom results were available. Ten of twelve individuals had undergone surgery at least once for lymphoid hypertrophy limited to the pharynx. In the most severely affected individual (individual 1), airway obstruction resulted in 17 surgical procedures before the age of 13 years. Sleep apnea was present in 8 of 10 individuals. In the nine unrelated individuals, ZBTB7A variants were novel and de novo. The six frameshift/nonsense and four missense variants were spread throughout the gene. This is the first report of a cohort of individuals with this novel syndromic neurodevelopmental disorder.

Adult attention-deficit/hyperactivity disorder among alcohol use disorder inpatients is associated with food addiction and binge eating, but not BMI.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is associated with binge eating (BE), food addiction (FA), and obesity/higher BMI in individuals without alcohol use disorder (AUD). ADHD is highly prevalent in patients with AUD, but it is unknown whether the presence of comorbid AUD might change the nature of the association between ADHD, BE, FA and BMI (food and alcohol may either compete for the same brain neurocircuitry or share vulnerability risk factors). Here, we filled this gap by testing the association between ADHD and FA/BE in adult patients hospitalized for AUD, with the strength of simultaneously assessing childhood and adult ADHD. We also investigated the association between ADHD and BMI, and the other factors associated with BMI (FA/BE, AUD severity). METHODS: We included 149 AUD inpatients between November 2018 and April 2019. We assessed both childhood and adulthood ADHD (Wender Utah Render Scale and Adult ADHD Self-Report Scale), FA (modified Yale Food Addiction Scale 2.0), BE (Binge Eating Scale), and BMI and AUD (clinical assessment). RESULTS: In multivariable analyses adjusted for age, adult ADHD was associated with higher BE scores (p = .048), but not significant BE (9% vs. 7%; p = .70). ADHD was also associated with FA diagnosis and the number or FA symptoms, with larger effect size for adult (ORs: 9.45[95%CI: 2.82-31.74] and 1.38[1.13-1.69], respectively) than childhood ADHD (ORs: 4.45[1.37-14.46] and 1.40[1.13-1.75], respectively). In multivariable analysis, BMI was associated with both significant BE (p < .001) and FA diagnosis (p = .014), but not adult ADHD nor AUD severity. CONCLUSION: In patients hospitalized for AUD, self-reported adult ADHD was associated with FA and BE, but not BMI. Our results set the groundwork for longitudinal research on the link between ADHD, FA, BE, and BMI in AUD inpatients.

Does Phonological Complexity Provide a Good Index of Language Disorder in Children With Cochlear Implants?

Purpose Phonological complexity is known to be a good index of developmental language disorder (DLD) in normal-hearing children, who have major difficulties on some complex structures. Some deaf children with cochlear implants (CIs) present a profile that evokes DLD, with persistent linguistic difficulties despite good audiological and environmental conditions. However, teasing apart what is related to auditory deficit or to language disorder remains complex. Method We compared the performance of three groups of school-age children, 33 children with CI, 22 with DLD, and 24 with typical development, on a nonword repetition (NWR) task based on phonological complexity. Children with CI were studied regarding their linguistic profile, categorized in four subgroups ranging from excellent to very poor performance. Influence of syllable length and phonological structures on the results of all the children were explored. Results The NWR task correctly distinguished children with DLD from typically developing children, and also children with CI with the poorest linguistic performance from other children with CI. However, most complex phonological structures did not reliably identify children with CI displaying a profile similar to that of children with DLD because these structures were difficult for all of the children with CI. The simplest phonological structures were better at detecting persistent language difficulties in children with CI, as they were challenging only for the children with the poorest language outcomes. Conclusions The most complex phonological structures are not good indices of language disorder in children with CI. Phonological complexity represents a gradient of difficulty that affects normal-hearing and deaf children differently.

When Alterations in Social Cognition Meet Subjective Complaints in Autism Spectrum Disorder: Evaluation With the "ClaCoS" Battery.

Background: Deficit in social communication is a core feature in Autism Spectrum Disorder but remains poorly assessed in classical clinical practice, especially in adult populations. This gap between needs and practice is partly due to a lack of standardized evaluation tools. The multicentric Research group in psychiatry GDR3557 (Institut de Psychiatrie) developed a new battery for social cognitive evaluation named "ClaCoS," which allows testing the main components of social cognition: Emotion Recognition, Theory of Mind, Attributional Style, and Social Perception and Knowledge. It further provides an assessment of subjective complaints in social cognition. Methods: We compared the social cognition abilities of 45 adults with Autism Spectrum Disorder without intellectual disability and 45 neurotypically developed volunteers using the "ClaCoS" battery, in order to determine its relevance in the evaluation of social cognition impairments in autism. A correlational approach allowed us to test the links between subjective complaints and objectively measured impairments for the different components of social cognition. Results: As expected, the Autism Spectrum Disorder group showed deficits in all four components of social cognition. Moreover, they reported greater subjective complaints than controls regarding their social abilities, correlated to the neuropsychological assessments. Conclusion: The "ClaCoS" battery is an interesting tool allowing to assess social impairments in autism and to specify the altered components, for a better adjustment of tailored social cognition training programs. Our results further suggest that people with Autism Spectrum Disorder have a good social cognitive insight, i.e., awareness into social cognitive functioning, and may thus benefit from social cognitive training tools.

Local Processing Bias Impacts Implicit and Explicit Memory in Autism.

Autism spectrum disorder (ASD) is characterized by atypical perception, including processing that is biased toward local details rather than global configurations. This bias may impact on memory. The present study examined the effect of this perception on both implicit (Experiment 1) and explicit (Experiment 2) memory in conditions that promote either local or global processing. The first experiment consisted of an object identification priming task using two distinct encoding conditions: one favoring local processing (Local condition) and the other favoring global processing (Global condition) of drawings. The second experiment focused on episodic (explicit) memory with two different cartoon recognition tasks that favored either local (i.e., processing specific details) or a global processing (i.e., processing each cartoon as a whole). In addition, all the participants underwent a general clinical cognitive assessment aimed at documenting their cognitive profile and enabling correlational analyses with experimental memory tasks. Seventeen participants with ASD and 17 typically developing (TD) controls aged from 10 to 16 years participated to the first experiment and 13 ASD matched with 13 TD participants were included for the second experiment. Experiment 1 confirmed the preservation of priming effects in ASD but, unlike the Comparison group, the ASD group did not increase his performance as controls after a globally oriented processing. Experiment 2 revealed that local processing led to difficulties in discriminating lures from targets in a recognition task when both lures and targets shared common details. The correlation analysis revealed that these difficulties were associated with processing speed and inhibition. These preliminary results suggest that natural perceptual processes oriented toward local information in ASD may impact upon their implicit memory by preventing globally oriented processing in time-limited conditions and induce confusion between explicit memories that share common details.

Phase-IIa randomized, double-blind, sham-controlled, parallel group trial on anodal transcranial direct current stimulation (tDCS) over the left and right tempo-parietal junction in autism spectrum disorder-StimAT: study protocol for a clinical trial.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction, and stereotyped, repetitive behaviour and sensory interests. To date, there is no effective medication that can improve social communication and interaction in ASD, and effect sizes of behaviour-based psychotherapy remain in the low to medium range. Consequently, there is a clear need for new treatment options. ASD is associated with altered activation and connectivity patterns in brain areas which process social information. Transcranial direct current stimulation (tDCS) is a technique that applies a weak electrical current to the brain in order to modulate neural excitability and alter connectivity. Combined with specific cognitive tasks, it allows to facilitate and consolidate the respective training effects. Therefore, application of tDCS in brain areas relevant to social cognition in combination with a specific cognitive training is a promising treatment approach for ASD. METHODS: A phase-IIa pilot randomized, double-blind, sham-controlled, parallel-group clinical study is presented, which aims at investigating if 10 days of 20-min multi-channel tDCS stimulation of the bilateral tempo-parietal junction (TPJ) at 2.0 mA in combination with a computer-based cognitive training on perspective taking, intention and emotion understanding, can improve social cognitive abilities in children and adolescents with ASD. The main objectives are to describe the change in parent-rated social responsiveness from baseline (within 1 week before first stimulation) to post-intervention (within 7 days after last stimulation) and to monitor safety and tolerability of the intervention. Secondary objectives include the evaluation of change in parent-rated social responsiveness at follow-up (4 weeks after end of intervention), change in other ASD core symptoms and psychopathology, social cognitive abilities and neural functioning post-intervention and at follow-up in order to explore underlying neural and cognitive mechanisms. DISCUSSION: If shown, positive results regarding change in parent-rated social cognition and favourable safety and tolerability of the intervention will confirm tDCS as a promising treatment for ASD core-symptoms. This may be a first step in establishing a new and cost-efficient intervention for individuals with ASD. TRIAL REGISTRATION: The trial is registered with the German Clinical Trials Register (DRKS), DRKS00014732 . Registered on 15 August 2018. PROTOCOL VERSION: This study protocol refers to protocol version 1.2 from 24 May 2019.

Early Intervention in Severe Autism: Positive Outcome Using Exchange and Development Therapy.

Early intervention programs positively affect key behaviors for children with autism spectrum disorder (ASD). However, most of these programs do not target children with severe autistic symptomatology associated with intellectual disability (ID). This study aimed to investigate the psychological and clinical outcomes of children with severe autism and ID enrolled in the Tailored and Inclusive Program for Autism-Tours (TIPA-T). The first step of the TIPA-T is the Exchange and Development Therapy (EDT): an individual neurofunctional intervention consisting of one-to-one exchanges between a child and a therapist taking place in a pared-down environment. It aims to rehabilitate psychophysiological abilities at the roots of social communication through structured sequences of "social play." Cognitive and socio-emotional skills and general development were evaluated with the Social Cognitive Evaluation Battery scale and the Brunet-Lézine Scale-Revised, respectively, before and after 9 months of intervention in 32 children with ASD and ID. Autistic symptomatology was evaluated with the Behavior Summarized Evaluation-Revised scale at five time-points in a subset of 14 children, both in individual and group settings. Statistically significant post-intervention improvements were found in cognitive and socio-emotional skills. All but one child showed improvements in at least one social domain, and 78% of children gained one level in at least four social domains. Twenty-nine children improved in cognitive domains, with 66% of children improving in at least three cognitive domains. Autistic symptomatology evaluated in one-to-one settings significantly decreased with therapy; this reduction was observed in more than 85% of children. In group settings, autistic symptomatology also decreased in more than 60% of children. Global developmental age significantly increased by 3.8 months. The TIPA-T, including EDT in particular, improves socio-emotional skills of most children with ASD and reduces autistic symptomatology, yet with heterogeneous outcomes profiles, in line with the strong heterogeneity of profiles observed in ASD. At the group level, this study highlights the benefits of the TIPA-T for children with severe autism and associated ID. Assessment of autistic core symptoms showed an improvement of social interaction, both in one-to-one and group evaluations, demonstrating the generalizability of the skills learned during the EDT.

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction.

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.