1. Abbasi DA, Nguyen TTA, Hall DA, Robertson-Dick E, Berry-Kravis E, Cologna SM. Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome. Cerebellum (London, England). 2022; 21(1): 86-98.

Fragile X-associated tremor/ataxia syndrome (FXTAS), first described in 2001, is a neurodegenerative and movement disorder, caused by a premutation in the fragile X mental retardation 1 (FMR1) gene. To date, the biological mechanisms causing this condition are still not well understood, as not all premutation carriers develop FXTAS. To further understand this syndrome, we quantitatively compared the cerebrospinal fluid (CSF) proteome of FXTAS patients with age-matched controls using mass spectrometry. We identified 415 proteins of which 97 were altered in FXTAS patients. These proteins suggest changes in acute phase response signaling, liver X receptor/ retinoid X receptor (LXR/RXR) activation, and farnesoid X receptor (FXR)/RXR activation, which are the main pathways found to be affected. Additionally, we detected changes in many other proteins including amyloid-like protein 2, contactin-1, afamin, cell adhesion molecule 4, NPC intracellular cholesterol transporter 2, and cathepsin B, that had been previously noted to hold important roles in other movement disorders. Specific to RXR pathways, several apolipoproteins (APOA1, APOA2, APOA4, APOC2, and APOD) showed significant changes in the CSF of FXTAS patients. Lastly, CSF parameters were analyzed to investigate abnormalities in blood brain barrier function. Correlations were observed between patient albumin quotient values, a measure of permeability, and CGG repeat length as well as FXTAS rating scale scores.

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2. Abdul F, Sreenivas N, Kommu JVS, Banerjee M, Berk M, Maes M, Leboyer M, Debnath M. Disruption of circadian rhythm and risk of autism spectrum disorder: role of immune-inflammatory, oxidative stress, metabolic and neurotransmitter pathways. Reviews in the neurosciences. 2022; 33(1): 93-109.

Circadian rhythms in most living organisms are regulated by light and synchronized to an endogenous biological clock. The circadian clock machinery is also critically involved in regulating and fine-tuning neurodevelopmental processes. Circadian disruption during embryonic development can impair crucial phases of neurodevelopment. This can contribute to neurodevelopmental disorders like autism spectrum disorder (ASD) in the offspring. Increasing evidence from studies showing abnormalities in sleep and melatonin as well as genetic and epigenetic changes in the core elements of the circadian pathway indicate a pivotal role of circadian disruption in ASD. However, the underlying mechanistic basis through which the circadian pathways influence the risk and progression of ASD are yet to be fully discerned. Well-recognized mechanistic pathways in ASD include altered immune-inflammatory, nitro oxidative stress, neurotransmission and synaptic plasticity, and metabolic pathways. Notably, all these pathways are under the control of the circadian clock. It is thus likely that a disrupted circadian clock will affect the functioning of these pathways. Herein, we highlight the possible mechanisms through which aberrations in the circadian clock might affect immune-inflammatory, nitro-oxidative, metabolic pathways, and neurotransmission, thereby driving the neurobiological sequelae leading to ASD.

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3. Alemany S, Avella-García C, Liew Z, García-Esteban R, Inoue K, Cadman T, López-Vicente M, González L, Riaño Galán I, Andiarena A, Casas M, Margetaki K, Strandberg-Larsen K, Lawlor DA, El Marroun H, Tiemeier H, Iñiguez C, Tardón A, Santa-Marina L, Júlvez J, Porta D, Chatzi L, Sunyer J. Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts. European journal of epidemiology. 2021; 36(10): 993-1004.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.

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4. Bonsu NEM, Mire SS, Sahni LC, Berry LN, Dowell LR, Minard CG, Cunningham RM, Boom JA, Voigt RG, Goin-Kochel RP. Understanding Vaccine Hesitancy Among Parents of Children With Autism Spectrum Disorder and Parents of Children With Non-Autism Developmental Delays. Journal of child neurology. 2021; 36(10): 911-8.

Parents of children with autism spectrum disorder (ASD) may be at greater risk for developing antivaccine beliefs that lead to vaccine delays and/or refusals for their children. We investigated current parental vaccine hesitancy, parents’ beliefs about causes of children’s developmental delays, and children’s vaccination histories among parents of children with ASD or non-ASD developmental delays. Data were analyzed from 89/511 parents (17.4%) who completed the Parent Attitudes About Childhood Vaccines questionnaire and the Revised Illness Perception Questionnaire; 46.1% had childhood vaccination records available. Overall, 21/89 (23.6%, 95% confidence interval [CI]: 15.0-34.0) of parents were vaccine hesitant (ASD n = 19/21 [90.5%], non-ASD n = 2/21 [9.5%]). Parents of children with ASD were significantly more likely to agree with « toxins in vaccines » as a cause of their child’s developmental delays (28.4% vs 5.0%, P = .034). The odds of being vaccine hesitant were 11.9 times (95% CI 2.9-48.0) greater among parents who agreed versus disagreed that toxins in vaccines caused their children’s developmental delays. Rates of prior vaccine receipt did not differ between hesitant and nonhesitant groups.

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5. Burns NK, Grissett K, Macaluso M, Raza M, Gracious B. Excited Catatonia in Autism Spectrum Disorder: A Case Series. Frontiers in psychiatry. 2021; 12: 674335.

Introduction: Autistic catatonia is an under-recognized debilitating syndrome with long-lasting negative effects for families, healthcare workers, and high-cost to the healthcare system. In this report, we describe two cases of excited catatonia in young men diagnosed with autism. Both endured a delay to diagnosis and difficulty to obtain appropriate treatment. Main concern: Each patient had a change in behavior from their baseline but with differences in severity and onset. The diagnosis in the first patient was made after only 3 months as the change was dramatic and sudden. Yet, despite a confirmed diagnosis, it was difficult to treat as the importance of M-ECT was not recognized by the clinicians. The second patient had been suffering for more than 5 years with a slow progression of worsening aggressive symptoms. The aggression was so uncontrollable that the patient required sedation, intubation and daily ECT. Both suffered from agitation, unprovoked aggression, urinary incontinence, stereotypic, and OCD behaviors and compulsive masturbation. Primary Diagnosis, intervention/outcomes: Both patients were diagnosed with autism, one high-functioning, attending high school and working a part-time job, the second low-functioning, nearly non-verbal, isolated to home and ABA school. The first patient’s diagnosis of catatonia was only suspected after five psychiatric admissions and more than 20 medication trials. Lorazepam challenge was effective, he was treated with a short series of ECT but each time the treatments were tapered, the aggression returned. Ultimately, stabilized on weekly ECT. The second patient’s behavior was escalating over a 5 month period, to the point, the aggression was uncontrollable. He presented to the ED under involuntary hold and the behavior could not be stabilized to the point that emergent ECT was initiated. Conclusion: Two cases of autistic catatonia diagnosed and treated within a year time span at a small community hospital indicates that this diagnosis is more common than previously recognized. We propose screening all patients with neurodevelopmental disorders with the Bush-Francis and Kanner scales to diagnose and treat them appropriately.

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6. Fukui T, Chakrabarty M, Sano M, Tanaka A, Suzuki M, Kim S, Agarie H, Fukatsu R, Nishimaki K, Nakajima Y, Wada M. Enhanced use of gaze cue in a face-following task after brief trial experience in individuals with autism spectrum disorder. Scientific reports. 2021; 11(1): 11240.

Eye movements toward sequentially presented face images with or without gaze cues were recorded to investigate whether those with ASD, in comparison to their typically developing (TD) peers, could prospectively perform the task according to gaze cues. Line-drawn face images were sequentially presented for one second each on a laptop PC display, and the face images shifted from side-to-side and up-and-down. In the gaze cue condition, the gaze of the face image was directed to the position where the next face would be presented. Although the participants with ASD looked less at the eye area of the face image than their TD peers, they could perform comparable smooth gaze shift to the gaze cue of the face image in the gaze cue condition. This appropriate gaze shift in the ASD group was more evident in the second half of trials in than in the first half, as revealed by the mean proportion of fixation time in the eye area to valid gaze data in the early phase (during face image presentation) and the time to first fixation on the eye area. These results suggest that individuals with ASD may benefit from the short-period trial experiment by enhancing the usage of gaze cue.

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7. Giesinger RE, El Shahed AI, Castaldo MP, Bischoff AR, Chau V, Whyte HEA, El-Khuffash AF, Mertens L, McNamara PJ. Neurodevelopmental outcome following hypoxic ischaemic encephalopathy and therapeutic hypothermia is related to right ventricular performance at 24-hour postnatal age. Archives of disease in childhood Fetal and neonatal edition. 2022; 107(1): 70-5.

OBJECTIVE: Our aim was to determine whether right ventricular (RV) dysfunction at 24-hour postnatal age predicts adverse developmental outcome among patients with hypoxic ischaemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). DESIGN: Neonates≥35 weeks with HIE/TH were enrolled in a physiological study in the neonatal period (n=46) and either died or underwent neurodevelopmental follow-up at 18 months (n=43). The primary outcome was a composite of death, diagnosis of cerebral palsy or any component of the Bayley Scores of Infant Development III<70. We hypothesised that tricuspid annulus plane systolic excursion (TAPSE) <6 mm and/or RV fractional area change (RV-FAC) <0.29 would predict adverse outcome. RESULTS: Nine patients died and 34 patients were followed up at a mean age of 18.9±1.4 months. Both indices of RV systolic performance were abnormal in 15 (35%) patients, TAPSE <6 mm only was abnormal in 4 (9%) patients and RV-FAC <0.29 only was abnormal in 5 (12%) patients (19 had with normal RV function). Although similar at admission, neonates with RV dysfunction had higher cardiovascular and neurological illness severity by 24 hours than those without and severe MRI abnormalities (70% vs 53%, p=0.01) were more common. On logistic regression, TAPSE <6 mm (OR 3.6, 95% CI 1.2 to 10.1; p=0.017) and abnormal brain MRI [OR 21.7, 95% CI 1.4 to 336; p=0.028) were independently associated with adverse outcome. TAPSE <6 mm predicted outcome with a 91% sensitivity and 81% specificity. CONCLUSIONS: The role of postnatal cardiovascular function on neurological outcomes among patients with HIE who receive TH merits further study. Quantitative measurement of RV function at 24 hours may provide an additional neurological prognostic tool.

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8. Keating CT, Fraser DS, Sowden S, Cook JL. Differences Between Autistic and Non-Autistic Adults in the Recognition of Anger from Facial Motion Remain after Controlling for Alexithymia. Journal of autism and developmental disorders. 2022; 52(4): 1855-71.

To date, studies have not established whether autistic and non-autistic individuals differ in emotion recognition from facial motion cues when matched in terms of alexithymia. Here, autistic and non-autistic adults (N = 60) matched on age, gender, non-verbal reasoning ability and alexithymia, completed an emotion recognition task, which employed dynamic point light displays of emotional facial expressions manipulated in terms of speed and spatial exaggeration. Autistic participants exhibited significantly lower accuracy for angry, but not happy or sad, facial motion with unmanipulated speed and spatial exaggeration. Autistic, and not alexithymic, traits were predictive of accuracy for angry facial motion with unmanipulated speed and spatial exaggeration. Alexithymic traits, in contrast, were predictive of the magnitude of both correct and incorrect emotion ratings.

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9. Köse S, Yılmaz Kafalı H, Erkan İdris ZG, Şentürk Pilan B, Özbaran B, Erermiş S. The prevalence and risk factors for overweight/obesity among Turkish children with neurodevelopmental disorders. Research in developmental disabilities. 2021; 114: 103992.

OBJECTIVE: To compare the prevalence and correlates of overweight (OW) and obesity (OB) between autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit-hyperactivity disorder (ADHD) and to investigate which variables significantly contribute to OW/OB in each group. METHODS: Of 267 cases (96 with ASD, 80 with ID, and 91 with ADHD) aged 2-18 years, body mass index (BMI) percentiles, birth weight, food reward usage, weekly screen and physical activity time, and psychotropics used were recorded. RESULTS: OB (OB + OW) prevalence was 22.9 % (36.4 %) in ASD; 22.5 % (40 %) in ID; and 17.6 % (27.5 %) in ADHD. Although the ADHD group had the highest rate of stimulant usage (χ2 = 69.605, p < 0.001), physical activity attendance (χ2 = 49.751, p < 0.001), and the lowest anti-psychotic (χ2 = 69.142, p < 0.001), and anti-depressant usage (χ2 = 7.219, p < 0.001) than ID/DD or ASD, BMI percentile of the participants did not differ between the groups (H(2) = 1.652, p = 0.43). In hierarchical logistic regression analysis, in ASD, food reward (OR = 4.65, 95 %Cl = 1.25-17.19) and the number of psychotropics used (OR = 2.168, 95 %Cl = 1.07-4.36) were significantly related to the risk of OW/OB. In ADHD, each drugs administered and a 1-kilogram elevation in birth weight was associated with a 4.09 and 2.82 increased risk for OW/OB. CONCLUSION: OW/OB is prevalent in children with neurodevelopmental disorders regardless of their diagnosis. Our findings showed that food rewards put a higher risk for OW/OB in ASD than administering a psychotropic. It could be better to use other positive reinforcements other than edible ones to prevent OW/OB in these children.

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10. Li Q, Liang J, Fu N, Han Y, Qin J. A Ketogenic Diet and the Treatment of Autism Spectrum Disorder. Frontiers in pediatrics. 2021; 9: 650624.

Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interaction. There are no curative treatments for children with ASD. The ketogenic diet (KD) is a high-fat, appropriate-protein, and low-carbohydrate diet that mimics the fasting state of the body and is proven beneficial in drug-resistant epilepsy and some other brain diseases. An increasing number of studies demonstrated that a KD improved autistic behavior, but the underlying mechanisms are not known. We reviewed the neuroprotective role of a KD in ASD, which is likely mediated via improvements in energy metabolism, reductions in antioxidative stress levels, control of neurotransmitters, inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, and modulation of the gut microbiota. A KD is likely a safe and effective treatment for ASD.

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11. Licinio J, Wong ML. Advances in autism research, 2021: continuing to decipher the secrets of autism. Molecular psychiatry. 2021; 26(5): 1426-8.

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12. Ma H, Su L, Xia W, Wang W, Tan G, Jiao J. MacroH2A1.2 deficiency leads to neural stem cell differentiation defects and autism-like behaviors. EMBO reports. 2021; 22(7): e52150.

The development of the nervous system requires precise regulation. Any disturbance in the regulation process can lead to neurological developmental diseases, such as autism and schizophrenia. Histone variants are important components of epigenetic regulation. The function and mechanisms of the macroH2A (mH2A) histone variant during brain development are unknown. Here, we show that deletion of the mH2A isoform mH2A1.2 interferes with neural stem cell differentiation in mice. Deletion of mH2A1.2 affects neurodevelopment, enhances neural progenitor cell (NPC) proliferation, and reduces NPC differentiation in the developing mouse brain. mH2A1.2-deficient mice exhibit autism-like behaviors, such as deficits in social behavior and exploratory abilities. We identify NKX2.2 as an important downstream effector gene and show that NKX2.2 expression is reduced after mH2A1.2 deletion and that overexpression of NKX2.2 rescues neuronal abnormalities caused by mH2A1.2 loss. Our study reveals that mH2A1.2 reduces the proliferation of neural progenitors and enhances neuronal differentiation during embryonic neurogenesis and that these effects are at least in part mediated by NKX2.2. These findings provide a basis for studying the relationship between mH2A1.2 and neurological disorders.

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13. Ma Y, Zhou H, Li C, Zou X, Luo X, Wu L, Li T, Chen X, Mao M, Huang Y, Li E, An Y, Zhang L, Wang T, Xu X, Yan W, Jiang Y, Wang Y. Differential Metabolites in Chinese Autistic Children: A Multi-Center Study Based on Urinary (1)H-NMR Metabolomics Analysis. Frontiers in psychiatry. 2021; 12: 624767.

Background: Autism spectrum disorder (ASD) is a group of early-onset neurodevelopmental disorders. However, there is no valuable biomarker for the early diagnosis of ASD. Our large-scale and multi-center study aims to identify metabolic variations between ASD and healthy children and to investigate differential metabolites and associated pathogenic mechanisms. Methods: One hundred and seventeen autistic children and 119 healthy children were recruited from research centers of 7 cities. Urine samples were assayed by (1)H-NMR metabolomics analysis to detect metabolic variations. Multivariate statistical analysis, including principal component analysis (PCA), and orthogonal projection to latent structure discriminant analysis (OPLS-DA), as well as univariate analysis were used to assess differential metabolites between the ASD and control groups. The differential metabolites were further analyzed by receiver operating characteristics (ROC) curve analysis and metabolic pathways analysis. Results: Compared with the control group, the ASD group showed higher levels of glycine, guanidinoacetic acid, creatine, hydroxyphenylacetylglycine, phenylacetylglycine, and formate and lower levels of 3-aminoisobutanoic acid, alanine, taurine, creatinine, hypoxanthine, and N-methylnicotinamide. ROC curve showed relatively significant diagnostic values for hypoxanthine [area under the curve (AUC) = 0.657, 95% CI 0.588 to 0.726], creatinine (AUC = 0.639, 95% CI 0.569 to 0.709), creatine (AUC = 0.623, 95% CI 0.552 to 0.694), N-methylnicotinamide (AUC = 0.595, 95% CI 0.523 to 0.668), and guanidinoacetic acid (AUC = 0.574, 95% CI 0.501 to 0.647) in the ASD group. Combining the metabolites creatine, creatinine and hypoxanthine, the AUC of the ROC curve reached 0.720 (95% CI 0.659 to 0.777). Significantly altered metabolite pathways associated with differential metabolites were glycine, serine and threonine metabolism, arginine and proline metabolism, and taurine and hypotaurine metabolism. Conclusions: Urinary amino acid metabolites were significantly altered in children with ASD. Amino acid metabolic pathways might play important roles in the pathogenic mechanisms of ASD.

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14. Macdonald D, Luk G, Quintin EM. Early Reading Comprehension Intervention for Preschoolers with Autism Spectrum Disorder and Hyperlexia. Journal of autism and developmental disorders. 2022; 52(4): 1652-72.

Children with autism spectrum disorder (ASD) and hyperlexia (HPL) have both advanced word reading skills and a reading comprehension disorder, alongside impaired oral language. We developed a unique, parent-supported, tablet-based intervention aiming to improve oral and reading comprehension at the word-, phrase- and sentence-level, for preschoolers with ASD and hyperlexia (ASD + HPL). English-speaking preschoolers (N = 30) with ASD + HPL (N = 8), ASD without HPL (N = 7) and typical development (N = 15) underwent a 6-week no-intervention period followed by a 6-week intervention period. Findings revealed a significant increase in reading comprehension scores for the group with ASD + HPL as compared to the TD group (p = .023). Gains were also found for receptive but not expressive language for all groups. Implications for early intervention for preschoolers with ASD + HPL are discussed.

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15. Marballi K, MacDonald JL. Proteomic and transcriptional changes associated with MeCP2 dysfunction reveal nodes for therapeutic intervention in Rett syndrome. Neurochemistry international. 2021; 148: 105076.

Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly impacting females. MECP2 is an epigenetic transcriptional regulator acting mainly to repress gene expression, though it plays multiple gene regulatory roles and has distinct molecular targets across different cell types and specific developmental stages. In this review, we summarize MECP2 loss-of-function associated transcriptome and proteome disruptions, delving deeper into the latter which have been comparatively severely understudied. These disruptions converge on multiple biochemical and cellular pathways, including those involved in synaptic function and neurodevelopment, NF-κB signaling and inflammation, and the vitamin D pathway. RTT is a complex neurological disorder characterized by myriad physiological disruptions, in both the central nervous system and peripheral systems. Thus, treating RTT will likely require a combinatorial approach, targeting multiple nodes within the interactomes of these cellular pathways. To this end, we discuss the use of dietary supplements and factors, namely, vitamin D and polyunsaturated fatty acids (PUFAs), as possible partial therapeutic agents given their demonstrated benefit in RTT and their ability to restore homeostasis to multiple disrupted cellular pathways simultaneously. Further unravelling the complex molecular alterations induced by MECP2 loss-of-function, and contextualizing them at the level of proteome homeostasis, will identify new therapeutic avenues for this complex disorder.

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16. Reetzke R, Pfeiffer D, Kalb LG, Holingue C, Zetlmeisl C, Hong JS, Landa R. Informant (Dis)Agreement on Ratings of Challenging Behaviors and Social Communication in Preschool Children With Autism Spectrum Disorder. Journal of speech, language, and hearing research : JSLHR. 2021; 64(7): 2766-75.

Purpose Cross-informant ratings are considered best practice for assessing children with autism spectrum disorder (ASD). However, informant disagreement often occurs, which can pose significant challenges to various aspects of clinical services. This study explored the degree of parent and speech-language pathologist (SLP) agreement on ratings of challenging behaviors and social communication skills in preschool children with ASD. Method Fifty-eight informant ratings of challenging behaviors and social communication skills were collected from parents and SLPs on the same 29 preschool children with ASD (M = 49.93 months, SD = 11.67 months) using the Pervasive Developmental Disorder Behavior Inventory. Parent versus SLP group rating comparisons were assessed with paired t tests and Cohen’s d effect sizes. Intraclass correlation coefficients were calculated to examine interrater reliability between individual parent and SLP ratings. Bland-Altman plots were generated to evaluate informant agreement across the entire range of Pervasive Developmental Disorder Behavior Inventory composite scores. Results Group comparisons indicated that parents rated arousal regulation problems as more severe than SLPs, with no other group differences observed. Parents and SLPs exhibited poor agreement on ratings of challenging behaviors; however, moderate to good agreement was observed for social communication ratings. Conclusions These results highlight the importance of including parents in the assessment and treatment planning process for preschool children with ASD, as parents may report key behavioral concerns that clinicians may not otherwise observe. Understanding behaviors that may be more prone to informant disagreement has implications for promoting a shared understanding of behavioral concerns and treatment targets between parents and clinicians.

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17. Reis LM, Sorokina EA, Dudakova L, Moravikova J, Skalicka P, Malinka F, Seese SE, Thompson S, Bardakjian T, Capasso J, Allen W, Glaser T, Levin AV, Schneider A, Khan A, Liskova P, Semina EV. Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders. Human molecular genetics. 2021; 30(17): 1591-606.

The forkhead transcription factor FOXE3 is critical for vertebrate eye development. Recessive and dominant variants cause human ocular disease but the full range of phenotypes and mechanisms of action for the two classes of variants are unknown. We identified FOXE3 variants in individuals with congenital eye malformations and carried out in vitro functional analysis on selected alleles. Sixteen new recessive and dominant families, including six novel variants, were identified. Analysis of new and previously reported genetic and clinical data demonstrated a broad phenotypic range with an overlap between recessive and dominant disease. Most families with recessive alleles, composed of truncating and forkhead-domain missense variants, had severe corneal opacity (90%; sclerocornea in 47%), aphakia (83%) and microphthalmia (80%), but some had milder features including isolated cataract. The phenotype was most variable for recessive missense variants, suggesting that the functional consequences may be highly dependent on the type of amino acid substitution and its position. When assessed, aniridia or iris hypoplasia were noted in 89% and optic nerve anomalies in 60% of recessive cases, indicating that these defects are also common and may be underrecognized. In dominant pedigrees, caused by extension variants, normal eye size (96%), cataracts (99%) and variable anterior segment anomalies were seen in most, but some individuals had microphthalmia, aphakia or sclerocornea, more typical of recessive disease. Functional studies identified variable effects on the protein stability, DNA binding, nuclear localization and transcriptional activity for recessive FOXE3 variants, whereas dominant alleles showed severe impairment in all areas and dominant-negative characteristics.

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18. Rosencrans M, Arango P, Sabat C, Buck A, Brown C, Tenorio M, Witwer A. The impact of the COVID-19 pandemic on the health, wellbeing, and access to services of people with intellectual and developmental disabilities. Research in developmental disabilities. 2021; 114: 103985.

BACKGROUND: Individuals with intellectual and developmental disabilities (IDD) may be especially vulnerable to changes associated with the COVID-19 pandemic given an increased likelihood of health concerns, low socioeconomic status, and difficulty accessing services. AIMS: The purpose of this study was to explore mental health problems and services in individuals with IDD during the pandemic. We explored whether number of mental health problems differed by disability, age, gender, living situation, physical health, and access to services. METHODS AND PROCEDURES: An online survey about experiences during the pandemic was administered to adults with IDD and their caregivers in the United States and in Chile. OUTCOMES AND RESULTS: In both Chile and the United States, few people endorsed increased health problems. Half of the sample in Chile and 41 % of the sample in the United States endorsed increased mental health problems. Approximately 15 % of the sample in the US reported no longer receiving state developmental disability services. CONCLUSIONS AND IMPLICATIONS: Healthcare and disability-specific agencies should consider strategies to tailor supports to improve mental health functioning and access to community.

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19. Stickley A, Shirama A, Kitamura S, Kamio Y, Takahashi H, Saito A, Haraguchi H, Kumazaki H, Mishima K, Sumiyoshi T. Attention-deficit/hyperactivity disorder symptoms and sleep problems in preschool children: the role of autistic traits. Sleep medicine. 2021; 83: 214-21.

BACKGROUND: Sleep problems are elevated in children with attention-deficit/hyperactivity disorder (ADHD). However, until now there has been comparatively little research on the role of autistic traits in this association. The current study examined the association between ADHD symptoms and sleep problems in Japanese preschool children and whether autistic traits might also be important for this relationship. METHODS: Data were analyzed from 1053 children (average age 64.14 months, range 58-71; 50.3% male) that were drawn from the Tama Children’s Survey (TCS). Parent-reported information was obtained on ADHD symptoms using the Strengths and Difficulties Questionnaire (SDQ) and autistic traits with the Social Responsiveness Scale Second Edition (SRS-2). Parents also provided information on three different categories of sleep problems experienced by their children – parasomnias, sleep disordered breathing and awakening/daytime problems. Ordinal logistic regression analysis was used to examine the associations. RESULTS: In analyses adjusted for sociodemographic factors, the mother’s mental health and child’s emotional problems, compared to children with no ADHD symptoms or autistic traits, children with only ADHD symptoms had significantly increased odds for only one of 11 individual sleep problems – waking in a negative mood. In contrast, children with comorbid ADHD symptoms and autistic traits had elevated odds for five sleep problems with odds ratios ranging from 2.10 (takes time to become alert in the morning) to 3.46 (excessive body movement while sleeping). CONCLUSIONS: Sleep problems may be especially elevated in children with comorbid ADHD symptoms and autistic traits.

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20. Tsuji T, Mizutani R, Minami K, Furuhara K, Fujisaku T, Pinyue F, Jing Z, Tsuji C. Oxytocin administration modulates the complex type of ultrasonic vocalisation of mice pups prenatally exposed to valproic acid. Neuroscience letters. 2021; 758: 135985.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by communication disability with no curative treatment. Maternal separation-induced ultrasonic vocalisation (USV) was widely used to assess communication disability between pups and dams. Particularly, USV calls in many genetically modified ASD model mice were altered. Previously, we demonstrated that mice pups exposed to valproic acid in utero (VPA pups) showed decreased number of USV calls on postnatal day 11 and were rescued by subcutaneous injection of oxytocin. However, the qualitative change of USV calls by oxytocin has not been evaluated in VPA pups. In the present study, we examined the duration of oxytocin effect and analysed the altered pattern of USV calls using VPA pups. The oxytocin administration increased the total number of USV calls and the effect persisted up to 120 min in VPA pups. The pattern analysis revealed that the increase in the number of complex calls also persisted up to 120 min. These results suggested that oxytocin had a prolonged effect on USV calls, mainly on complex calls, in VPA pup, showing that oxytocin could recover their social modality to respond to maternal separation.

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21. Uljarević M, Jo B, Frazier TW, Scahill L, Youngstrom EA, Hardan AY. Using the big data approach to clarify the structure of restricted and repetitive behaviors across the most commonly used autism spectrum disorder measures. Molecular autism. 2021; 12(1): 39.

BACKGROUND: Restricted and repetitive behaviors (RRB) in autism spectrum disorder (ASD) encompass several distinct domains. However, commonly used general ASD measures provide broad RRB scores rather than assessing separate RRB domains. The main objective of the current investigation was to conduct a psychometric evaluation of the ability of the Social Responsiveness Scale (SRS-2), the Social Communication Questionnaire (SCQ), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to capture different RRB constructs. METHODS: Exploratory Structural Equation Modeling (ESEM) was conducted using individual item-level data from the SRS-2, SCQ, ADI-R and the ADOS. Data were obtained from five existing publicly available databases. For the SRS-2, the final sample consisted of N = 16,761 individuals (M(age) = 9.43, SD = 3.73; 18.5% female); for the SCQ, of N = 15,840 (M(age) = 7.99, SD = 4.06; 18.1% female); for the ADI-R, of N = 8985 (M(age) = 8.86, SD = 4.68; 19.4% female); and for the ADOS, of N = 6314 (M(age) = 12.29, SD = 6.79; 17.7% female). RESULTS: The three-factor structure provided the most optimal and interpretable fit to data for all measures (comparative fit index ≥ .983, Tucker Lewis index ≥ .966, root mean square error of approximation ≤ .028). Repetitive-motor behaviors, insistence on sameness and unusual or circumscribed interests factors emerged across all instruments. No acceptable fit was identified for the ADOS. LIMITATIONS: The five datasets used here afforded a large as well as wide distribution of the RRB item scores. However, measures used for establishing convergent and divergent validity were only available for a portion of the sample. CONCLUSIONS: Reported findings offer promise for capturing important RRB domains using general ASD measures and highlight the need for measurement development.

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22. Wang W, Tang J, Zhong M, Chen J, Li T, Dai Y. HIF-1 α may play a role in late pregnancy hypoxia-induced autism-like behaviors in offspring rats. Behavioural brain research. 2021; 411: 113373.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can be caused by various factors. The present study aimed to determine whether prenatal hypoxia can lead to ASD and the role of hypoxia-inducible factor-1α (HIF-1α) in this process. We constructed a prenatal hypoxia model of pregnant rats by piping nitrogen and oxygen mixed gas, with an oxygen concentration of 10 ± 0.5 %, into the self-made hypoxia chamber. Rats were subjected to different extents of hypoxia treatments at different points during pregnancy. The results showed that hypoxia for 6 h on the 17th gestation day is most likely to lead to autistic behavior in offspring rats, including social deficits, repetitive behaviors, and impaired learning and memory. The mRNA expression level of TNF-α also increased in hypoxia-induced autism group and valproic acid (VPA) group. Western blotting analysis showed increased levels of hypoxia inducible factor 1 alpha (HIF-1α) and decreased levels of phosphatase and tensin homolog (PTEN) in the hypoxic-induced autism group. Meanwhile, N-methyl d-aspartate receptor subtype 2 (NR2A) and glutamate ionotropic receptor AMPA type subunit 2 (GluR2) were upregulated in the hypoxic-induced autism group. HIF-1α might play a role in hypoxia-caused autism-like behavior and its regulatory effect is likely to be achieved by regulating synaptic plasticity.

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23. Washington-Nortey PM, Serpell Z. Parental expectations for children with intellectual disability or autism in Ghana and Zambia: A concept mapping study. Research in developmental disabilities. 2021; 114: 103989.

INTRODUCTION: Parent expectations have an important impact on children’s outcomes. Despite a wealth of research on the familial experience of children with disabilities in African countries, very few studies have examined expectations these children’s parents hold for them. AIMS: This study explores parental expectations for children with intellectual disability, or autism and assesses their perceived importance and likelihood of attainment. METHODS AND PROCEDURES: Concept mapping methodology with focus groups comprised of parents of children with intellectual disability or autism were employed. OUTCOMES AND RESULTS: Results revealed several expectation themes: independence, acceptance and inclusion, public awareness, education, governmental assistance, resources, and healthcare. Whereas some expectations were congruent with themes in the broader literature, nuances within themes reflected cultural and societal conditions. Themes unique to each country also emerged, and importance and likelihood ratings revealed some cultural variation across the two countries. Expectations and the value placed on them differ across countries. IMPLICATIONS: This study represents an important first step in efforts to understand the developmental contexts of children with disabilities on the African continent. Findings inform future research and potential strategies for policy and practice.

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24. Zhang J, Li X, Shen L, Khan NU, Zhang X, Chen L, Zhao H, Luo P. Trace elements in children with autism spectrum disorder: A meta-analysis based on case-control studies. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2021; 67: 126782.

Autism spectrum disorder (ASD) is a common childhood neurodevelopmental disorder that may be related to trace elements. However, reports on the relationship between them are still inconsistent. In this article, we conducted a meta-analysis on this issue. We searched the PubMed, EMBASE, and Cochrane databases as of November 15, 2019. A random-effects model was used, and subgroups of studies were analyzed using samples of different measurements. Twenty-two original articles were identified (18 trace elements, including a total of 1014 children with ASD and 999 healthy controls). In autistic children, the overall levels of barium (Ba), mercury (Hg), lithium (Li), and lead (Pb) were higher. There were significant differences in the levels of copper (Cu) in the hair and serum between autistic children and the control group. The levels of Hg, Li, Pb and selenium (Se) in the hair of autistic children were higher than those of healthy children, while the levels of zinc (Zn) in the blood were lower. Excessive exposure to toxic heavy metals and inadequate intake of essential metal elements may be associated with ASD. Preventing excessive exposure to toxic metals and correcting poor dietary behaviors may be beneficial for the prevention and treatment of the disease.

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