1. Chen MH, Tsai SJ, Bai YM, Huang KL, Su TP, Chen TJ, Hsu JW. Type 1 diabetes mellitus and risks of major psychiatric disorders: A nationwide population-based cohort study. Diabetes & metabolism. 2022; 48(1): 101319.

BACKGROUND: The temporal association between type 1 diabetes mellitus (T1DM) and major psychiatric disorders, including schizophrenia, major affective disorder, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD), remains elusive. METHODS: The specialized databases of catastrophic diseases and mental disorders and the longitudinal health insurance database of Taiwan National Health Insurance Research Database were used in current study. A total of 6,226 patients with T1DM and 62,260 age- and sex-matched controls were recruited between 2001 and 2010 and were followed until the end of 2011 for the identification of diagnoses of schizophrenia (International Classification of Clinical Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code: 295), bipolar disorder (ICD-9-CM codes: 296 except 296.2x, 296.3x, 296.9x, and 296.82), major depressive disorder (ICD-9-CM codes: 296.2x and 296.3x), ASD (ICD-9-CM code: 299), and ADHD (ICD-9-CM code: 314). RESULTS: Cox regression analysis revealed increased hazard ratios of schizophrenia (12.28), bipolar disorder (13.80), major depressive disorder (10.41), ASD (14.52), and ADHD (8.19) in patients with T1DM compared with controls. DISCUSSION: Our findings indicate the importance of clinicians closely monitoring the mental health condition of children, adolescents, and adults with T1DM. Additional studies should be conducted to elucidate the definite pathomechanisms of comorbidities between T1DM and major psychiatric disorders.

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2. Foy AMH, Hudock RL, Shanley R, Pierpont EI. Social behavior in RASopathies and idiopathic autism. Journal of neurodevelopmental disorders. 2022; 14(1): 5.

BACKGROUND: RASopathies are genetic syndromes that result from pathogenic variants in the RAS-MAPK cellular signaling pathway. These syndromes, which include neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, and Costello syndrome, are associated with a complex array of medical and behavioral health complications. Despite a heightened risk for social challenges and autism spectrum disorder (ASD), few studies have compared different aspects of social behavior across these conditions. It is also unknown whether the underlying neuropsychological characteristics that contribute to social competence and socially empathetic (« prosocial ») behaviors differ in children with RASopathies as compared to children with nonsyndromic (i.e., idiopathic) ASD. METHODS: In this cross-sectional, survey-based investigation, caregivers of preschool and school-aged children with RASopathies (n = 202) or with idiopathic ASD (n = 109) provided demographic, medical, and developmental information about their child, including psychiatric comorbidities. For children who were able to communicate verbally, caregivers also completed standardized rating scales to assess social competence and empathetic behavior as well as symptoms of hyperactivity/inattention and emotional problems. RESULTS: As compared to children with idiopathic ASD, children with RASopathies were rated as demonstrating more resilience in the domain of empathy relative to their overall social competence. Similarities and differences emerged in the psychological factors that predicted social behavior in these two groups. Stronger communication skills and fewer hyperactive-impulsive behaviors were associated with increased empathy and social competence for both groups. Greater emotional challenges were associated with lower social competence for children with RASopathies and stronger empathy for children with idiopathic ASD. Among children with RASopathy and a co-occurring ASD diagnosis, socially empathetic behaviors were observed more often as compared to children with idiopathic ASD. CONCLUSIONS: Findings suggest that the development of social behavior among children with RASopathies involves a distinct pattern of strengths and weaknesses as compared to a behaviorally defined disorder (idiopathic ASD). Identification of areas of resilience as well as behavioral and social challenges will support more targeted intervention.

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3. Glauser J, Wilkinson CL, Gabard-Durnam LJ, Choi B, Tager-Flusberg H, Nelson CA. Neural correlates of face processing associated with development of social communication in 12-month infants with familial risk of autism spectrum disorder. Journal of neurodevelopmental disorders. 2022; 14(1): 6.

BACKGROUND: Differences in face processing in individuals with ASD is hypothesized to impact the development of social communication skills. This study aimed to characterize the neural correlates of face processing in 12-month-old infants at familial risk of developing ASD by (1) comparing face-sensitive event-related potentials (ERP) (Nc, N290, P400) between high-familial-risk infants who develop ASD (HR-ASD), high-familial-risk infants without ASD (HR-NoASD), and low-familial-risk infants (LR), and (2) evaluating how face-sensitive ERP components are associated with development of social communication skills. METHODS: 12-month-old infants participated in a study in which they were presented with alternating images of their mother’s face and the face of a stranger (LR = 45, HR-NoASD = 41, HR-ASD = 24) as EEG data were collected. Parent-reported and laboratory-observed social communication measures were obtained at 12 and 18 months. Group differences in ERP responses were evaluated using ANOVA, and multiple linear regressions were conducted with maternal education and outcome groups as covariates to assess relationships between ERP and behavioral measures. RESULTS: For each of the ERP components (Nc [negative-central], N290, and P400), the amplitude difference between mother and stranger (Mother-Stranger) trials was not statistically different between the three outcome groups (Nc p = 0.72, N290 p = 0.88, P400 p = 0.91). Marginal effects analyses found that within the LR group, a greater Nc Mother-Stranger response was associated with better expressive language skills on the Mullen Scales of Early Learning, controlling for maternal education and outcome group effects (marginal effects dy/dx = 1.15; p < 0.01). No significant associations were observed between the Nc and language or social measures in HR-NoASD or HR-ASD groups. In contrast, specific to the HR-ASD group, amplitude difference between the Mother versus Stranger P400 response was positively associated with expressive (dy/dx = 2.1, p < 0.001) and receptive language skills at 12 months (dy/dx = 1.68, p < 0.005), and negatively associated with social affect scores on the Autism Diagnostic Observation Schedule (dy/dx = - 1.22, p < 0.001) at 18 months. CONCLUSIONS: In 12-month-old infant siblings with subsequent ASD, increased P400 response to Mother over Stranger faces is positively associated with concurrent language and future social skills.

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4. Krenn M, Kepa S, Kasprian G, Riedhammer KM, Wagner M, Goedl-Fleischhacker U, Milenkovic I. A de novo truncating variant in CSDE1 in an adult-onset neuropsychiatric phenotype without intellectual disability. European journal of medical genetics. 2022; 65(3): 104423.

Variants in CSDE1, a gene encoding a constrained RNA-binding protein, have recently been associated with a spectrum of neurodevelopmental conditions encompassing autism, seizures and ocular abnormalities. According to previously reported individuals, pathogenic variants in CSDE1 are typically associated with developmental delay and intellectual disability. Here, we report one individual with normal neurodevelopment and adult-onset neuropsychiatric features (i.e., acute psychosis) due to the novel de novo truncating variant c.2272C>T, p.(Gln758*) in CSDE1 (NM_001242891.1). Neuropsychological assessment confirmed deficits regarding verbal fluency, semantic memory, executive function and processing speed. Overall, our findings expand the phenotypic spectrum of CSDE1-related disorder towards the mild end.

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5. Li G, Song B, Wang C, Tang D, Li K, He X, Cao Y. Diet, microbe, and autism: Cause or consequence?. Cell host & microbe. 2022; 30(1): 5-7.

Numerous studies have shown the possible contributions of the gut microbiome to the pathogenesis of autism spectrum disorder (ASD). However, recently in Cell, Yap et al. found that autism-related dietary preferences may mediate the ASD-microbiome associations, while the direct associations between ASD and gut microbiota are negligible.

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6. Liu Y, Lv Y, Zarrei M, Dong R, Yang X, Higginbotham EJ, Li Y, Zhao D, Song F, Yang Y, Zhang H, Wang Y, Scherer SW, Gai Z. Chromosomal microarray analysis of 410 Han Chinese patients with autism spectrum disorder or unexplained intellectual disability and developmental delay. NPJ genomic medicine. 2022; 7(1): 1.

Copy number variants (CNVs) are recognized as a crucial genetic cause of neurodevelopmental disorders (NDDs). Chromosomal microarray analysis (CMA), the first-tier diagnostic test for individuals with NDDs, has been utilized to detect CNVs in clinical practice, but most reports are still from populations of European ancestry. To contribute more worldwide clinical genomics data, we investigated the genetic etiology of 410 Han Chinese patients with NDDs (151 with autism and 259 with unexplained intellectual disability (ID) and developmental delay (DD)) using CMA (Affymetrix) after G-banding karyotyping. Among all the NDD patients, 109 (26.6%) carried clinically relevant CNVs or uniparental disomies (UPDs), and 8 (2.0%) had aneuploidies (6 with trisomy 21 syndrome, 1 with 47,XXY, 1 with 47,XYY). In total, we found 129 clinically relevant CNVs and UPDs, including 32 CNVs in 30 ASD patients, and 92 CNVs and 5 UPDs in 79 ID/DD cases. When excluding the eight patients with aneuploidies, the diagnostic yield of pathogenic and likely pathogenic CNVs and UPDs was 20.9% for all NDDs (84/402), 3.3% in ASD (5/151), and 31.5% in ID/DD (79/251). When aneuploidies were included, the diagnostic yield increased to 22.4% for all NDDs (92/410), and 33.6% for ID/DD (87/259). We identified a de novo CNV in 14.9% (60/402) of subjects with NDDs. Interestingly, a higher diagnostic yield was observed in females (31.3%, 40/128) compared to males (16.1%, 44/274) for all NDDs (P = 4.8 × 10(-4)), suggesting that a female protective mechanism exists for deleterious CNVs and UPDs.

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7. Ly A, Leppert B, Rai D, Jones H, Dardani C, Stergiakouli E. Genetic liability to rheumatoid arthritis on autism and autistic traits: polygenic risk score and Mendelian randomization analyses. Translational psychiatry. 2022; 12(1): 18.

Higher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring’s own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73-1.07, p = 0.21; offspring’s own PRS on autism: RR 1.11, 95%CI 0.88-1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98-1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.

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8. Mashayekhi F, Shabani S, Sasani ST, Salehi Z. The association of stem cell factor and soluble c-Kit (s-cKit) receptor serum concentrations with the severity and risk prediction of autism spectrum disorders. Metabolic brain disease. 2022; 37(3): 619-24.

S tem cell factor (SCF) and its receptor (c-kit) signaling play important role in normal brain physiology including neurogenesis, synapse formation and spatial learning function of the hippocampal region of the brain. Autism spectrum disorder (ASD) is believed to result from abnormal development of neuronal networks and synaptic function. The aim of this study was to evaluate the SCF and its soluble receptor (s-ckit) serum concentrations in ASD. We also studied the serum SCF and s-ckit concentration with the severity of ASD (Levels 1-3; Mild, Moderate and severe, respectively). Ninety five patients with ASD (Mild; n=33, Moderate; n=32 and severe; n=30) and 82 normal controls age matched were included in this study. The serum concentration of SCF and s-ckit were measured by enzyme-linked immunosorbent assay (ELISA). The SCF serum concentration in control subjects was 3.45±1.06 ng/ml and in ASD was 3.41±0.92 ng/ml (P=0.88). The serum levels of s-ckit in control and ASD groups were 56.82±13.22 ng/ml and 67.11±12.00, respectively (P=001). We have also studied serum SCF and s-ckit concentrations with the severity of ASD. The serum concentration of SCF in mild, moderate and severe ASD groups was 3.45±0.93, 3.4±0.87 and 3.43±0.98 ng/ml, respectively (P>0.05) and for s-ckit was 48.77±9.28, 61.66±12.18 and 93.11±14.81ng/ml, respectively (P<0.05). The result of this study suggests that serum s-cKit concentrations may provide a reliable and practical indicator of ASD and positively correlated with disease severity. It is also concluded that s-cKit might be involved in the pathophysiology of ASD.

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9. Mirenda P, Colozzo P, Smith V, Kroc E, Kalynchuk K, Rogers SJ, Ungar WJ. A Randomized, Community-Based Feasibility Trial of Modified ESDM for Toddlers with Suspected Autism. Journal of autism and developmental disorders. 2022: 1-20.

A randomized feasibility trial of a parent coaching (PC) intervention was conducted across 16 community agencies in a Canadian province. Parents of toddlers with suspected autism were assigned to either a PC group (n = 24) or an enhanced community treatment (ECT) group (n = 25). PC participants received 24 weeks of coaching support from community service providers trained in the project. Children in both groups also received available community services and supplementary materials. PC children made significantly greater gains in word understanding and PC parents had significantly higher quality of life, satisfaction, and self-efficacy scores. Results are discussed in terms of the challenges of conducting feasibility studies in community settings and the lessons learned in the project.

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10. Mylonas D, Machado S, Larson O, Patel R, Cox R, Vangel M, Maski K, Stickgold R, Manoach DS. Dyscoordination of non-rapid eye movement sleep oscillations in autism spectrum disorder. Sleep. 2022; 45(3).

STUDY OBJECTIVES: Converging evidence from neuroimaging, sleep, and genetic studies suggest that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD. METHODS: Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9-17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep. RESULTS: ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but their relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite. CONCLUSIONS: The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.

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11. Narvekar N, Carter Leno V, Pasco G, Johnson MH, Jones EJ, Charman T. A prospective study of associations between early fearfulness and perceptual sensitivity and later restricted and repetitive behaviours in infants with typical and elevated likelihood of autism. Autism : the international journal of research and practice. 2022: 13623613211068932.

Restricted interests and repetitive behaviours are central to the diagnosis of autism and can have profound effects on daily activities and quality of life. These challenges are also linked to other co-occurring conditions such as anxiety and sensory sensitivities. Here, we looked at whether early emerging signs of anxiety and sensory problems appear before symptoms of autism by studying infants with a family history of autism, as these infants are more likely to develop autism themselves. Studying infant siblings provides an opportunity for researchers to focus on early developmental markers of autism as these infants can be followed from birth. This study found that early infant signs of anxiety (e.g. fear/shyness) predicted later perceptual sensitivity, and those infants who scored higher on fear/shyness and sensitivity were more likely to experience more persistent repetitive behaviours, but also social and communication difficulties in toddlerhood. Early signs of anxiety and perceptual sensitivity may thus relate to both later social difficulties and repetitive behaviours. These findings support the importance of further research exploring the causal links between these domains in relation to autism, resulting in increased understanding of children who go onto develop autism in the future and guiding early interventions and supports.

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12. Sheppard E, van Loon E, Ropar D. Dimensions of Self-Reported Driving Difficulty in Autistic and Non-Autistic Adults and their Relationship with Autistic Traits. Journal of autism and developmental disorders. 2022.

A survey asked autistic and non-autistic people about the driving difficulties they experience and their autistic traits. Principle components analysis was used to identify how reported difficulties clustered together in each group, and regression was used to determine which subscales of the Autism Spectrum Quotient predict these factors. For autistic drivers three factors of driving difficulty emerged: a Driving Executive factor, predicted by Attention Switching; a Driving Understanding factor, predicted by Communication; and a Driving Social Interaction factor, predicted by Attention Switching. For non-autistic drivers only one Driving General factor emerged, predicted by Communication. This suggests autistic people may experience at least three distinct domains of difficulty when driving which may relate to their particular profile of autistic features.

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13. Suhrheinrich J, Nahmias AS, Yu Y, Melgarejo M, Schetter P, Holt TC, Stahmer AC. Practice-driven research for statewide scale up: Implementation outcomes of the California Autism Professional Training and Information Network. Autism : the international journal of research and practice. 2022; 26(3): 727-36.

Supporting use of evidence-based practice in public service programs for autistic individuals is critical. The California Autism Professional Training and Information Network (CAPTAIN) brings together best practices from intervention and implementation research to support scale up of autism services. The current study was designed to evaluate the impact of CAPTAIN on provider-level outcomes including attitude toward, knowledge, fidelity, and use of autism EBPs and overall classroom quality. Overall, results indicated variability across measures, with some significant differences between CAPTAIN-trained and non-CAPTAIN-trained providers. These preliminary findings show promise for the efficacy of the CAPTAIN model to increase dissemination and implementation of EBP at the classroom level.

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14. Tzanoulinou S, Musardo S, Contestabile A, Bariselli S, Casarotto G, Magrinelli E, Jiang YH, Jabaudon D, Bellone C. Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism. Molecular psychiatry. 2022.

Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3(+/-) mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

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15. Wang SY, Lee WT, Shieh JY, Huang YH, Wong LC, Tsao CH, Chiu YL, Wu YT. Multidimensional Development and Adaptive Behavioral Functioning in Younger and Older Children With Rett Syndrome. Physical therapy. 2022; 102(4).

OBJECTIVE: The purpose of this study was to examine clinical severity, multidimensional development, and adaptive behavioral functioning in younger and older children with Rett syndrome (RTT) in the pseudostationary stage (stage III). METHODS: Fourteen younger (≤10 years of age) and 15 older (11-18 years of age) children with confirmed stage III RTT (assigned to young-RTT and old-RTT groups, respectively) participated in this study. Clinical severity was determined using the Clinical Severity Score (CSS) scale for RTT. The children’s cognitive, language, motor, and sociocommunicative development was assessed using the Mullen Scales of Early Learning (MSEL) and the Early Social Communication Scale (ESCS). Their adaptive behavioral and daily functional skills were assessed using the Vineland Adaptive Behavior Scales-Chinese version (VABS-C) and Pediatric Evaluation of Disability Inventory-Chinese version (PEDI-C). RESULTS: Compared with the young-RTT group, the old-RTT group had higher severity of scoliosis on the CSS scale, poorer fine motor scores on the MSEL, reduced eye contact, reduced alternating eye gaze, and reduced turn-taking during social interaction on the ESCS. However, none of the VABS-C or PEDI-C subscale scores differed significantly between the groups. Higher CSSs were significantly correlated with lower scores in several subscales of MSEL, ESCS, VABS-C, and PEDI-C, especially for gross motor, mobility, and socialization functioning in all children with RTT. CONCLUSION: Age-related differences in fine motor and sociocommunicative skills were observed between the young-RTT and old-RTT group, as measured using standardized assessments. Greater severity of RTT was correlated with poor motor, sociocommunicative, adaptive behavioral, and daily functional skills in stage III RTT. IMPACT: Practitioners should be aware of clinical severity and the differences of developmental and adaptive behavioral functioning between younger and older children in the pseudostationary stage of RTT to provide specific age-related treatments. LAY SUMMARY: With an understanding of severity and differences of developmental and adaptive behavioral functioning between younger and older children, clinical professionals can provide specific age-related treatments.

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16. Zhou ZD, Jankovic J, Ashizawa T, Tan EK. Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions. Nature reviews Neurology. 2022; 18(3): 145-57.

Non-coding CGG repeat expansions cause multiple neurodegenerative disorders, including fragile X-associated tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukodystrophy, and oculopharyngodistal myopathy. The underlying genetic causes of several of these diseases have been identified only in the past 2-3 years. These expansion disorders have substantial overlapping clinical, neuroimaging and histopathological features. The shared features suggest common mechanisms that could have implications for the development of therapies for this group of diseases – similar therapeutic strategies or drugs may be effective for various neurodegenerative disorders induced by non-coding CGG expansions. In this Review, we provide an overview of clinical and pathological features of these CGG repeat expansion diseases and consider the likely pathological mechanisms, including RNA toxicity, CGG repeat-associated non-AUG-initiated translation, protein aggregation and mitochondrial impairment. We then discuss future research needed to improve the identification and diagnosis of CGG repeat expansion diseases, to improve modelling of these diseases and to understand their pathogenesis. We also consider possible therapeutic strategies. Finally, we propose that CGG repeat expansion diseases may represent manifestations of a single underlying neuromyodegenerative syndrome in which different organs are affected to different extents depending on the gene location of the repeat expansion.

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