1. Abbasi DA, Nguyen TTA, Hall DA, Robertson-Dick E, Berry-Kravis E, Cologna SM. Correction to: Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome. Cerebellum (London, England). 2022; 21(1): 99-100.

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2. Al-Soleiti M, Balaj K, Thom RP, McDougle CJ, Keary CJ. Brief Report: Suspected Cannabis-Induced Mania and Psychosis in Young Adult Males with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

There is increasing interest in investigating cannabis for behavioral symptoms in individuals with autism spectrum disorder (ASD). The potential role of dysregulated cannabinoid signaling contributing to the pathophysiology of ASD is an area of active investigation. Results from retrospective and uncontrolled trials of cannabis in subjects with ASD have been published, reporting both potential benefits and adverse effects. Here, we describe the clinical course of three young adult males with ASD who developed mania or psychosis after the consistent use of cannabidiol and delta-9-tetrahydrocannabinol. Caution should be utilized with cannabis use in individuals with ASD until large-scale, replicated randomized controlled trials demonstrating efficacy, safety and tolerability have been published.

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3. Casey S, Carter M, Looney AM, Livingstone V, Moloney G, O’Keeffe GW, Taylor RS, Kenny LC, McCarthy FP, McCowan LME, Thompson JMD, Murray DM. Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2021.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

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4. Cheslack-Postava K, Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Surcel HM, Brown AS. A biomarker-based study of prenatal smoking exposure and autism in a Finnish national birth cohort. Autism research : official journal of the International Society for Autism Research. 2021; 14(11): 2444-53.

Maternal exposure to tobacco smoke during pregnancy is a common and persistent exposure linked to adverse neurodevelopmental outcomes in the offspring. However, previous studies provide mixed evidence regarding the relationship between prenatal smoking and offspring autism. This study used cotinine level, a biomarker for nicotine, to investigate the relationship between prenatal smoking and autism. The authors conducted a population-based case-control study nested in a national cohort of all births in Finland from 1987 to 2005. Cases diagnosed with childhood autism (ICD-10/9 code F84.0/299.0) through 2007 were identified using data from linked national registers. Each case was matched with a control on date of birth (±30 days), sex, and place of birth (N = 962 pairs). Maternal serum cotinine levels were prospectively measured in first- to early second-trimester serum samples archived in a national biobank using a quantitative immunoassay. Data were analyzed using conditional logistic regression. Prenatal maternal levels of serum cotinine were not associated with the odds of autism, whether cotinine was classified continuously, by deciles, or using previously defined categories corresponding to probable maternal smoking status. After adjusting for maternal age, paternal age, previous births, and any history of parental psychiatric disorder, the odds ratio for categorical high versus low cotinine, using a 3-level exposure variable, was 0.98 (95% CI = 0.76, 1.26; p = 0.88). In conclusion, this national birth cohort-based study does not provide evidence for an association between maternal cotinine, a biomarker of maternal smoking, and risk of autism. LAY SUMMARY: This study explored whether prenatal exposure to tobacco smoke in mothers is related to the diagnosis of autism in their children, by measuring the levels of cotinine, a biomarker for tobacco exposure, in stored serum samples drawn from mothers during pregnancy. The levels of cotinine in the mothers of children diagnosed with autism were similar to those in the mothers of control children of similar age and gender distribution.

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5. Dell’Osso L, Cremone IM, Chiarantini I, Arone A, Massimetti G, Carmassi C, Carpita B. Autistic traits and camouflaging behaviors: a cross-sectional investigation in a University student population. CNS spectrums. 2021: 1-7.

BACKGROUND: Increasing research is stressing the importance of identifying autistic traits (ATs) in clinical and general populations. University students may be a group at higher risk for the presence of ATs. Recently, specific attention has been paid to camouflaging strategies used by subjects in the autism spectrum in order to cope with the social environment. The aim of this work was to evaluate the prevalence of ATs and camouflaging behaviors in a population of University students. METHODS: Subjects were requested to anonymously fill out through an online form the Adult Autism Subthreshold Spectrum and the Camouflaging AT Questionnaire. RESULTS: ATs were more represented among males and among students of specific fields of study. Camouflaging behaviors were significantly more frequent among subjects with more severe autism spectrum symptoms, without differences depending from sex. CONCLUSIONS: Our study confirms the strong association between ATs and camouflaging behaviors and the relationship between ATs, sex, and specific fields of study.

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6. Dhulkifle H, Agouni A, Zeidan A, Al-Kuwari MS, Parray A, Tolefat M, Korashy HM. Influence of the Aryl Hydrocarbon Receptor Activating Environmental Pollutants on Autism Spectrum Disorder. International journal of molecular sciences. 2021; 22(17).

Autism spectrum disorder (ASD) is an umbrella term that includes many different disorders that affect the development, communication, and behavior of an individual. Prevalence of ASD has risen exponentially in the past couple of decades. ASD has a complex etiology and traditionally recognized risk factors only account for a small percentage of incidence of the disorder. Recent studies have examined factors beyond the conventional risk factors (e.g., environmental pollution). There has been an increase in air pollution since the beginning of industrialization. Most environmental pollutants cause toxicities through activation of several cellular receptors, such as the aryl hydrocarbon receptor (AhR)/cytochrome P450 (CYPs) pathway. There is little research on the involvement of AhR in contributing to ASD. Although a few reviews have discussed and addressed the link between increased prevalence of ASD and exposure to environmental pollutants, the mechanism governing this effect, specifically the role of AhR in ASD development and the molecular mechanisms involved, have not been discussed or reviewed before. This article reviews the state of knowledge regarding the impact of the AhR/CYP pathway modulation upon exposure to environmental pollutants on ASD risk, incidence, and development. It also explores the molecular mechanisms involved, such as epigenesis and polymorphism. In addition, the review explores possible new AhR-mediated mechanisms of several drugs used for treatment of ASD, such as sulforaphane, resveratrol, haloperidol, and metformin.

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7. Ecker C, Pretzsch CM, Bletsch A, Mann C, Schaefer T, Ambrosino S, Tillmann J, Yousaf A, Chiocchetti A, Lombardo MV, Warrier V, Bast N, Moessnang C, Baumeister S, Dell’Acqua F, Floris DL, Zabihi M, Marquand A, Cliquet F, Leblond C, Moreau C, Puts N, Banaschewski T, Jones EJH, Mason L, Bölte S, Meyer-Lindenberg A, Persico AM, Durston S, Baron-Cohen S, Spooren W, Loth E, Freitag CM, Charman T, Dumas G, Bourgeron T, Beckmann CF, Buitelaar JK, Murphy DGM. Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder. The American journal of psychiatry. 2022; 179(3): 242-54.

OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in « core » ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals’ total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

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8. Gillespie-Smith K, Hendry G, Anduuru N, Laird T, Ballantyne C. Using social media to be ‘social’: Perceptions of social media benefits and risk by autistic young people, and parents. Research in developmental disabilities. 2021; 118: 104081.

Autistic individuals are reported to struggle with aspects of social interaction. Past research has shown that social media use can help to facilitate social functioning, however, the perceptions of risks and benefits when engaging on social media platforms remains unclear. The current study aimed to explore perceptions of social media participation in terms of online risk and online relationships in both autistic young people and parents. Eight autistic young people and six parents of autistic young people took part in semi-structured interviews, with the resultant data being transcribed and analysed using Braun and Clarke’s (2006) inductive thematic analysis. Two themes were identified in relation to the impact social media has on autistic young people’s relationships (Socialisation; Communication) and two themes were identified in relation to the perceived barriers and risks to engaging online (Abusive interactions; Talking to strangers). These findings show that social interaction is of particular value to young autistic people, in terms of affording them easier social interactions than there would be in ‘real life’. The findings also show that the autistic young people were aware of risks online, and considered ways in which they try to manage this risk. Future research is needed to understand if similar interactions and risk take place across all platforms and whether online communication is successful between matched or mixed autistic and non-autistic groups.

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9. Haweel R, Seada N, Ghoniemy S, Alghamdi NS, El-Baz A. A CNN Deep Local and Global ASD Classification Approach with Continuous Wavelet Transform Using Task-Based FMRI. Sensors (Basel, Switzerland). 2021; 21(17).

Autism spectrum disorder (ASD) is a neurodegenerative disorder characterized by lingual and social disabilities. The autism diagnostic observation schedule is the current gold standard for ASD diagnosis. Developing objective computer aided technologies for ASD diagnosis with the utilization of brain imaging modalities and machine learning is one of main tracks in current studies to understand autism. Task-based fMRI demonstrates the functional activation in the brain by measuring blood oxygen level-dependent (BOLD) variations in response to certain tasks. It is believed to hold discriminant features for autism. A novel computer aided diagnosis (CAD) framework is proposed to classify 50 ASD and 50 typically developed toddlers with the adoption of CNN deep networks. The CAD system includes both local and global diagnosis in a response to speech task. Spatial dimensionality reduction with region of interest selection and clustering has been utilized. In addition, the proposed framework performs discriminant feature extraction with continuous wavelet transform. Local diagnosis on cingulate gyri, superior temporal gyrus, primary auditory cortex and angular gyrus achieves accuracies ranging between 71% and 80% with a four-fold cross validation technique. The fused global diagnosis achieves an accuracy of 86% with 82% sensitivity, 92% specificity. A brain map indicating ASD severity level for each brain area is created, which contributes to personalized diagnosis and treatment plans.

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10. Hong SJ, Chae YK, Lee C, Choi SC, Nam OH. A Digital Fabrication of Dental Prosthesis for Preventing Self-Injurious Behavior Related to Autism Spectrum Disorder: A Case Report. International journal of environmental research and public health. 2021; 18(17).

This case report aimed to demonstrate the prosthetic solution of an autism patient with self-injurious behavior using digital dentistry. A 24-year-old male visited our clinic with chief complaints of severe gingival recession associated with self-injurious behavior. Bilateral fixed prosthesis with denture flange were delivered using a digital workflow for the protection of the gingiva. The patient showed healed gingival tissue, behavioral modification, and acceptable oral hygiene during the follow-up period. Also, his caregivers reported no recurrence of the self-injurious behavior. Autism patients usually show self-injurious behavior, which can damage their oral tissue. With adoption of this prosthesis, behavior modification as well as healing of oral tissue was achieved.

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11. Juarez-Martinez EL, Sprengers JJ, Cristian G, Oranje B, van Andel DM, Avramiea AE, Simpraga S, Houtman SJ, Hardstone R, Gerver C, Jan van der Wilt G, Mansvelder HD, Eijkemans MJC, Linkenkaer-Hansen K, Bruining H. Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder. Biological psychiatry Cognitive neuroscience and neuroimaging. 2021.

BACKGROUND: Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning-based predictions of meaningful clinical improvement. METHODS: Using modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7-15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes. RESULTS: We observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively. CONCLUSIONS: Bumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.

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12. Kamp-Becker I, Tauscher J, Wolff N, Küpper C, Poustka L, Roepke S, Roessner V, Heider D, Stroth S. Is the Combination of ADOS and ADI-R Necessary to Classify ASD? Rethinking the « Gold Standard » in Diagnosing ASD. Frontiers in psychiatry. 2021; 12: 727308.

Diagnosing autism spectrum disorder (ASD) requires extensive clinical expertise and training as well as a focus on differential diagnoses. The diagnostic process is particularly complex given symptom overlap with other mental disorders and high rates of co-occurring physical and mental health concerns. The aim of this study was to conduct a data-driven selection of the most relevant diagnostic information collected from a behavior observation and an anamnestic interview in two clinical samples of children/younger adolescents and adolescents/adults with suspected ASD. Via random forests, the present study discovered patterns of symptoms in the diagnostic data of 2310 participants (46% ASD, 54% non-ASD, age range 4-72 years) using data from the combined Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) and ADOS data alone. Classifiers built on reduced subsets of diagnostic features yield satisfactory sensitivity and specificity values. For adolescents/adults specificity values were lower compared to those for children/younger adolescents. The models including ADOS and ADI-R data were mainly built on ADOS items and in the adolescent/adult sample the classifier including only ADOS items performed even better than the classifier including information from both instruments. Results suggest that reduced subsets of ADOS and ADI-R items may suffice to effectively differentiate ASD from other mental disorders. The imbalance of ADOS and ADI-R items included in the models leads to the assumption that, particularly in adolescents and adults, the ADI-R may play a lesser role than current behavior observations.

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13. Karba BE, Lemay JF, McLeod SA. The Clinical Dilemma of Autism Spectrum Disorder Diagnosis in a Child with 9p Deletion. Journal of pediatric genetics. 2021; 10(3): 250-2.

We reported on a 3-year-old girl child patient with the presence of trigonocephaly, broad nasal bridge, flattened occiput, and midface hypoplasia. Formal assessment of her development profile demonstrated expressive and receptive language delays, fine and gross motor delays, and no imaginative or symbolic representative play. Investigation of the etiology of her developmental delays revealed a genetic diagnosis of a 9p24 deletion by chromosomal microarray analysis. The possibility of an additional co-occurring disorder of autism spectrum disorder (ASD) was also raised by a referring clinician. This case report highlighted the clinical dilemma of diagnosing ASD in those with existing genetic syndromes.

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14. Keating CT. Participatory Autism Research: How Consultation Benefits Everyone. Frontiers in psychology. 2021; 12: 713982.

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15. Libsack EJ, Keenan EG, Freden CE, Mirmina J, Iskhakov N, Krishnathasan D, Lerner MD. A Systematic Review of Passing as Non-autistic in Autism Spectrum Disorder. Clinical child and family psychology review. 2021; 24(4): 783-812.

While long described in anecdotal accounts of the lived experiences of autistic individuals, the phenomenon of behaving in ways that appear inconsistent with the presence of autism (or passing as non-autistic; PAN) has recently seen a dramatic increase in scrutiny in the published scientific literature. Increased research attention has coincided with a proliferation of methods, definitions, measures, and population assumptions associated with PAN. To date, however, no review has sought to systematically identify and synthesize the literature on PAN. This systematic review reflects the state of the PAN literature as of May 2020. Ninety articles were screened, 66 were identified for evaluation, and 46 met inclusion criteria and were reliably coded for study characteristics and participant characteristics. Results reveal that the PAN literature includes a relatively even mix of qualitative, quantitative, and mixed-method studies, and that a variety of terms are used for PAN (with masking and camouflage being the most frequent). Sample sizes varied widely (from one to 832 participants), with 63.06% of participants being categorized as autistic. Nearly all studies reported methods for confirming autism diagnoses, with community and clinical diagnoses being most common. The majority of studies reported participant gender, with slightly more females included than males on average, but fewer than half of all studies compared PAN across genders. Nearly all studies reported participant age, demonstrating a wide range of 2 to 79 years, with a mean age of 23.85. Conversely, only 23.91% of studies provided participant race or ethnicity data. Nearly all studies formally or informally excluded participants with intellectual disability. Finally, measures of internalizing symptoms, which are often thought to be linked to PAN, were reported in only 17.4% of studies. Implications for gaps in understanding of PAN and future directions for the field are discussed.

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16. Mao Y, Evans EE, Mishra V, Balch L, Eberhardt A, Zauderer M, Gold WA. Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model. International journal of molecular sciences. 2021; 22(17).

Rett syndrome is a neurodevelopmental disorder caused by mutations of the methyl-CpG binding protein 2 gene. Abnormal physiological functions of glial cells contribute to pathogenesis of Rett syndrome. Semaphorin 4D (SEMA4D) regulates processes central to neuroinflammation and neurodegeneration including cytoskeletal structures required for process extension, communication, and migration of glial cells. Blocking SEMA4D-induced gliosis may preserve normal glial and neuronal function and rescue neurological dysfunction in Rett syndrome. We evaluated the pre-clinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody in the Rett syndrome Mecp2T158A transgenic mouse model and investigated the contribution of glial cells as a proposed mechanism of action in treated mice and in primary glial cultures isolated from Mecp2T158A/y mutant mice. SEMA4D is upregulated in neurons while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1-positive cells are upregulated in Mecp2T158A/y mice. Anti-SEMA4D treatment ameliorates Rett syndrome-specific symptoms and improves behavioural functions in both pre-symptomatic and symptomatic cohorts of hemizygous Mecp2T158A/y male mice. Anti-SEMA4D also reduces astrocyte and microglia activation in vivo. In vitro experiments demonstrate an abnormal cytoskeletal structure in mutant astrocytes in the presence of SEMA4D, while anti-SEMA4D antibody treatment blocks SEMA4D-Plexin B1 signaling and mitigates these abnormalities. These results suggest that anti-SEMA4D immunotherapy may be an effective treatment option to alleviate symptoms and improve cognitive and motor function in Rett syndrome.

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17. Parellada M, San José Cáceres A, Palmer M, Delorme R, Jones EJH, Parr JR, Anagnostou E, Murphy DGM, Loth E, Wang PP, Charman T, Strydom A, Arango C. A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Arbaclofen Administered for the Treatment of Social Function in Children and Adolescents With Autism Spectrum Disorders: Study Protocol for AIMS-2-TRIALS-CT1. Frontiers in psychiatry. 2021; 12: 701729.

Background: Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families’ quality of life. Currently no pharmacological interventions have been shown to be effective for improving social communication in autism. Previous trials have indicated the potential of arbaclofen for improving social function among autistic children and adolescents with fluent speech. The AIMS2TRIALS-Clinical Trial 1 (AIMS-CT1) will examine whether arbaclofen is superior to placebo in improving social function and other secondary outcomes over 16 weeks, along with safety and tolerability profiles. Methods: AIMS-CT1 is an international, multi-site, double-blind, parallel group Phase II randomized clinical trial. It will include 130 males and females aged 5:0-17:11 years, with a diagnosis of ASD and fluent speech. Eligible participants will be randomized on a ratio of 1:1 for a 16-week treatment period. Medication will be titrated over 5 weeks. The primary outcome is the effect on social function from weeks 0 to 16 measured on the Socialization domain of the Vineland Adaptive Behavior Scales, 3rd edition(TM). Secondary outcome measures include the CGI-S (Clinical Global Impression-Severity), CGI-I (Clinical Global Impression-Improvement), other areas of adaptive function, social communication and other autism symptoms, co-occurring behavior problems and health-related quality of life. Genetic and electrophysiological markers will be examined as potential stratifiers for treatment response. Exploratory novel digital technologies will also be used to measure change, examining simultaneously the validity of digital biomarkers in natural environments. The safety and tolerability of the drug will also be examined. Our protocol is very closely aligned with a parallel Canadian trial of 90 participants (ARBA Study, US NCT number: NCT03887676) to allow for secondary combined analyses. Outcomes will be compared using both an Intent-to-reat and Per Protocol approach. Discussion: The outcomes of this trial, combined with the parallel Canadian trial, will contribute to the evidence base for medications used to help social difficulties among young autistic individuals; demonstrate the capabilities of the AIMS-2-TRIALS network of academic centers to deliver clinical trials; and support future drug development. Clinical Trial Registration: EudraCT number: 2018-000942-21 and ClinicalTrials.gov registry number: NCT03682978. Currently under protocol v.7.2, dated 20.11.2020.

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18. Pascual-Alonso A, Martínez-Monseny AF, Xiol C, Armstrong J. MECP2-Related Disorders in Males. International journal of molecular sciences. 2021; 22(17).

Methyl CpG binding protein 2 (MECP2) is located at Xq28 and is a multifunctional gene with ubiquitous expression. Loss-of-function mutations in MECP2 are associated with Rett syndrome (RTT), which is a well-characterized disorder that affects mainly females. In boys, however, mutations in MECP2 can generate a wide spectrum of clinical presentations that range from mild intellectual impairment to severe neonatal encephalopathy and premature death. Thus, males can be more difficult to classify and diagnose than classical RTT females. In addition, there are some variants of unknown significance in MECP2, which further complicate the diagnosis of these children. Conversely, the entire duplication of the MECP2 gene is related to MECP2 duplication syndrome (MDS). Unlike in RTT, in MDS, males are predominantly affected. Usually, the duplication is inherited from an apparently asymptomatic carrier mother. Both syndromes share some characteristics, but also differ in some aspects regarding the clinical picture and evolution. In the following review, we present a thorough description of the different types of MECP2 variants and alterations that can be found in males, and explore several genotype-phenotype correlations, although there is still a lot to understand.

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19. Petruzzelli MG, Matera E, Giambersio D, Marzulli L, Gabellone A, Legrottaglie AR, Margari A, Margari L. Subjective and Electroencephalographic Sleep Parameters in Children and Adolescents with Autism Spectrum Disorder: A Systematic Review. Journal of clinical medicine. 2021; 10(17).

BACKGROUND: Sleep problems have commonly manifested in children and adolescents with autism spectrum disorder (ASD) with a complex and multifactorial interaction between clinical and etiological components. These disorders are associated with functional impairment, and provoke significant physical and mental affliction. The purpose of this study is to update the existing literature about objective and subjective sleep parameters in children and adolescents with ASD, extrapolating information from polysomnography or sleep electroencephalography, and sleep related questionnaires. METHODS: We have conducted a systematic review of case-control studies on this topic, performing a web-based search on PubMed, Scopus and the Web of Science databases according to the Preferred Reporting items for Systematic Review and Meta-analyses (PRISMA) guidelines. RESULTS: Data collected from 20 survey result reports showed that children and adolescents with ASD experienced a higher rate of sleep abnormalities than in typically developing children. The macrostructural sleep parameters that were consistent with subjective parent reported measures unveil a greater percentage of nighttime signs of insomnia. Sleep microstructure patterns, in addition, pointed towards the bidirectional relationship between brain dysfunctions and sleep problems in children with ASD. CONCLUSIONS: Today’s literature acknowledges that objective and subjective sleep difficulties are more often recognized in individuals with ASD, so clinicians should assess sleep quality in the ASD clinical population, taking into consideration the potential implications on treatment strategies. It would be worthwhile in future studies to examine how factors, such as age, cognitive level or ASD severity could be related to ASD sleep abnormalities. Future research should directly assess whether sleep alterations could represent a specific marker for atypical brain development in ASD.

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20. Petruzzi M, Stella A, Capra V, Contaldo M, Della Vella F. Oro-Dental Manifestations in a Pediatric Patient Affected by Helsmoortel-Van der Aa Syndrome. International journal of environmental research and public health. 2021; 18(17).

Aim: Aim of this case report is to describe oro-facial abnormalities in a patient affected by Helsmoortel-Van der Aa syndrome, a rare autism syndrome, with not well described dental and cranial malformations. Case Report: Helsmoortel-Van der Aa Syndrome is a rare autosomal genetic syndrome causing mental impairment and autism, craniofacial dysmorphism, chest deformity and multiple organs dysfunction. Oro-facial involvement in Helsmoortel-Van der Aa syndrome has not been thoroughly described yet. The present article reports a case of a 9 years old male patient affected by Helsmoortel-Van der Aa Syndrome, presenting with oral breathing typical facies, high arched palate, II class and dental crowding. The patient teething was adequate to his age. The enamel of incisors and molars showed demineralization areas and dark spots, a clinical picture consistent with molar incisor hypomineralization syndrome. These hypo-mineralized areas are more susceptible to cavities, in fact the patient’s 4.6 tooth was decayed. The child was brought to our attention due to a mucocele on the lower lip, confirmed by histopathologic examination. Available data on oro-dental manifestation of this syndrome are rather poor and inconsistent, also due to the rarity of the disease. The finding of enamel abnormalities in the presented case could suggest a potential genetic etiopathogenesis linked to the same genes causing Helsmoortel-Van der Aa syndrome.

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21. Rees E, Creeth HDJ, Hwu HG, Chen WJ, Tsuang M, Glatt SJ, Rey R, Kirov G, Walters JTR, Holmans P, Owen MJ, O’Donovan MC. Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations. Nature communications. 2021; 12(1): 5353.

People with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10(-6)). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.

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22. Rivard M, Patrick C, Mello C, Morin D, Morin M. The diagnostic trajectory in autism and intellectual disability in Quebec: pathways and parents’ perspective. BMC pediatrics. 2021; 21(1): 393.

BACKGROUND: This paper aimed to describe the diagnostic service trajectory of families of children with autism or intellectual disability in the province of Québec and identify predictors of parents’ perceptions of its quality. METHODS: The Evaluation of the services Trajectory in Autism by Parents instrument was completed by 259 parents at an assessment clinic. Children’s clinical records were also examined. RESULTS: On average 26 months elapsed between their first concerns and their child’s diagnosis, a period during which few (25%) received support. Parents’ evaluations were generally positive but were lower for the accessibility of the pre-assessment phase and the flexibility of the assessment process. Longer delays and a greater number of professionals consulted were associated with lower quality ratings. Some language-, immigration status-, and income-related differences in families’ appraisals were noted. CONCLUSION: The diagnostic trajectory for neurodevelopmental disorders within public services in Québec presents some efficiency and accessibility challenges. Possible improvements are proposed to facilitate screening and to support families throughout this phase of their trajectory.

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23. Russo GI, Sholklapper TN, Cocci A, Broggi G, Caltabiano R, Smith AB, Lotan Y, Morgia G, Kamat AM, Witjes JA, Daneshmand S, Desai MM, Gill IS, Cacciamani GE. Performance of Narrow Band Imaging (NBI) and Photodynamic Diagnosis (PDD) Fluorescence Imaging Compared to White Light Cystoscopy (WLC) in Detecting Non-Muscle Invasive Bladder Cancer: A Systematic Review and Lesion-Level Diagnostic Meta-Analysis. Cancers. 2021; 13(17).

Despite early detection and regular surveillance of non-muscle invasive bladder cancer (NMIBC), recurrence and progression rates remain exceedingly high for this highly prevalent malignancy. Limited visualization of malignant lesions with standard cystoscopy and associated false-negative biopsy rates have been the driving force for investigating alternative and adjunctive technologies for improved cystoscopy. The aim of our systematic review and meta-analysis was to compare the sensitivity, specificity, and oncologic outcomes of photodynamic diagnosis (PDD) fluorescence, narrow band imaging (NBI), and conventional white light cystoscopy (WLC) in detecting NMIBC. Out of 1,087 studies reviewed, 17 prospective non-randomized and randomized controlled trials met inclusion criteria for the study. We demonstrated that tumor resection with either PDD and NBI exhibited lower recurrence rates and greater diagnostic sensitivity compared to WLC alone. NBI demonstrated superior disease sensitivity and specificity as compared to WLC and an overall greater hierarchical summary receiver operative characteristic. Our findings are consistent with emerging guidelines and underscore the value of integrating these enhanced technologies as a part of the standard care for patients with suspected or confirmed NMIBC.

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24. Tierney E, Remaley AT, Thurm A, Jager LR, Wassif CA, Kratz LE, Bailey-Wilson JE, Bukelis I, Sarphare G, Jung ES, Brand B, Noah KK, Porter FD. Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits. Translational psychiatry. 2021; 11(1): 471.

An improved understanding of sterol and lipid abnormalities in individuals with autism spectrum disorder (ASD) could lead to personalized treatment approaches. Toward this end, in blood, we identified reduced synthesis of cholesterol in families with ≥2 children with ASD participating with the Autism Genetic Resource Exchange (AGRE), as well as reduced amounts of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), with 19.9% of the subjects presenting with apolipoprotein patterns similar to hypolipidemic clinical syndromes and 30% with either or both ApoA1 and ApoB less than the fifth centile. Subjects with levels less than the fifth centile of HDL or ApoA1 or ApoA1 + ApoB had lower adaptive functioning than other individuals with ASD, and hypocholesterolemic subjects had apolipoprotein deficits significantly divergent from either typically developing individuals participating in National Institutes of Health or the National Health and Nutrition Examination Survey III.

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25. Wang J, Napoli E, Kim K, McLennan YA, Hagerman RJ, Giulivi C. Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS. International journal of molecular sciences. 2021; 22(17).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5’UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH(2)-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH(2)-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings-and the lack of correlations with FXTAS diagnosis/stages-may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.

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26. Zhao X, Usdin K. (Dys)function Follows Form: Nucleic Acid Structure, Repeat Expansion, and Disease Pathology in FMR1 Disorders. International journal of molecular sciences. 2021; 22(17).

Fragile X-related disorders (FXDs), also known as FMR1 disorders, are examples of repeat expansion diseases (REDs), clinical conditions that arise from an increase in the number of repeats in a disease-specific microsatellite. In the case of FXDs, the repeat unit is CGG/CCG and the repeat tract is located in the 5′ UTR of the X-linked FMR1 gene. Expansion can result in neurodegeneration, ovarian dysfunction, or intellectual disability depending on the number of repeats in the expanded allele. A growing body of evidence suggests that the mutational mechanisms responsible for many REDs share several common features. It is also increasingly apparent that in some of these diseases the pathologic consequences of expansion may arise in similar ways. It has long been known that many of the disease-associated repeats form unusual DNA and RNA structures. This review will focus on what is known about these structures, the proteins with which they interact, and how they may be related to the causative mutation and disease pathology in the FMR1 disorders.

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