1. Ahlberg R, Garcia-Argibay M, Hirvikoski T, Boman M, Chen Q, Taylor MJ, Frans E, Bölte S, Larsson H. Shared familial risk factors between autism spectrum disorder and obesity – a register-based familial coaggregation cohort study. Journal of child psychology and psychiatry, and allied disciplines. 2021.

BACKGROUND: Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined. METHOD: We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD. RESULTS: Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID. CONCLUSIONS: Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

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2. Barcelos AM, Kargas N, Packham C, Mills DS. Understanding the impact of dog ownership on autistic adults: implications for mental health and suicide prevention. Scientific reports. 2021; 11(1): 23655.

Mental health problems and suicide are more frequent in autistic adults than general population. Dog ownership can improve human well-being. This study aimed to generate a framework of well-being outcomes for dog-related activities in autistic adults and compare it to the framework generated for a general adult population. Thirty-six autistic dog owners (18-74 years old, 18 males) from diverse UK regions were interviewed and transcripts thematically analysed. 16.7% reported that their dogs prevented them from taking their own lives, mainly due to the dog’s affection and the need to care for the animal. Close dog-owner interactions (e.g., cuddling, walking, dog’s presence) were the most frequent activities improving emotions/moods and life functioning, whereas routine-like activities (e.g., feeding the animal) particularly enhanced life functioning. Well-being worsening was mainly linked to dog behaviour problems, dog poor health/death and obligations to the dog. Despite some negatives associated with ownership, having a dog could improve the well-being of many autistic adults and assist suicide prevention strategies in this high-risk group. The framework was consistent with that generated previously, indicating its robustness and the potential opportunity to focus on dog-related activities rather than the vague concept of « ownership » when considering the impact of ownership on well-being.

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3. Boyce N. Alex Plank: building bridges. Lancet (London, England). 2022; 399(10321): 229.

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4. Ford CL, Young LJ. Refining oxytocin therapy for autism: context is key. Nature reviews Neurology. 2022; 18(2): 67-8.

A recent clinical trial found no effect of chronic intranasal oxytocin on social behaviour in children with autism spectrum disorders. The result is not surprising, as oxytocin facilitates social learning but does not directly cause prosocial behaviour. In future trials, oxytocin should be paired with behavioural therapy to enhance learning and improve social behaviour.

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5. Frankish H, Horton R. A way forward to improve the lives of autistic people. Lancet (London, England). 2022; 399(10321): 215-7.

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6. Gilmore D, Krantz M, Weaver L, Hand BN. Healthcare service use patterns among autistic adults: A systematic review with narrative synthesis. Autism : the international journal of research and practice. 2022; 26(2): 317-31.

Autistic adults often have complex healthcare needs due to factors like having other health conditions, sensory sensitivities, and limited access to healthcare providers who are trained to provide care for them. All these factors may influence the healthcare services that autistic adults use. In this review, we searched six electronic research databases to gather the most recent evidence about how often autistic adults use five important healthcare services (the emergency department, hospitalization, outpatient mental health, preventive services, and primary care) compared to populations of non-autistic adults. A total of 16 articles were ultimately included in this review. Most articles found that autistic adults had equal or higher use of healthcare services than non-autistic adults. Autistic adults frequently used the emergency department and hospital. This may indicate that routine outpatient care in the community is not meeting their needs. Our findings show the importance of improving care at this level for autistic adults to reduce overuse of the emergency department (in this article referred to as ED) and hospital.

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7. Han E, Scior K, Avramides K, Crane L. A systematic review on autistic people’s experiences of stigma and coping strategies. Autism research : official journal of the International Society for Autism Research. 2022; 15(1): 12-26.

Autism can be understood as a concealable stigmatized identity. This is the first systematic review to synthesize the literature on autistic people’s experiences of stigma and coping strategies. 2877 studies were screened and 27 were included in this review. The reviewed literature demonstrates that autistic individuals are acutely aware of being stereotyped, judged, and discriminated by others. Autistic people also show signs of internalizing stigma, rendering them more vulnerable to low self-worth and poorer mental health. To manage the impact of stigma, the included studies suggest that autistic individuals may use these strategies: concealment and camouflaging, selective disclosure and self-advocacy, as well as positive reframing and reconstructing identity. However, the evidence is limited and mixed in terms of how helpful and effective these strategies are. Future studies should include autistic populations with a wider range of intellectual abilities and explore interventions that can support autistic people in managing stigma to supplement interventions that seek to reduce stigma towards autistic people. The power of language in perpetuating and challenging stigma also has important implications for research and practice, underscoring the need for researchers and practitioners to reflect carefully on the messages they are communicating about autism.

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8. Imai J, Sasayama D, Kuge R, Honda H, Washizuka S. Hyperactive/impulsive symptoms and autistic trait in institutionalized children with maltreatment experience. New directions for child and adolescent development. 2021; 2021(179): 29-39.

The present study examined how maltreatment experience was associated with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) symptoms in children under institutional care. The key caregivers of children and adolescents aged 6 to 18 years who were under institutional care in Nagano prefecture, Japan were asked to answer the background questionnaire, ADHD-Rating Scale, and the Japanese children’s version of the Autism-Spectrum Quotient. A total of 378 valid responses were obtained, of which 222 reported maltreatment experience prior to institutionalization. Both hyperactive/impulsive and inattentive scores were significantly higher in the maltreated group. Maltreatment experience was significantly associated with the presence of hyperactive/impulsive symptoms (p = 0.003) and inattentive symptoms (p = 0.027). Particularly, those who had experienced physical abuse were significantly more likely to have hyperactive/impulsive symptoms (p = 0.012) and autistic trait (p = 0.002). Thorough assessment of neurodevelopmental symptoms should be performed when placing children with maltreatment experience into institutional care.

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9. Kakooza-Mwesige A, Bakare M, Gaddour N, Juneja M. The need to improve autism services in lower-resource settings. Lancet (London, England). 2022; 399(10321): 217-20.

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10. Lane R. Catherine Lord: pre-eminent autism clinician-researcher. Lancet (London, England). 2022; 399(10321): 228.

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11. Lipina T, Blundell M. From atypical senses to autism: towards new therapeutic targets and improved diagnostics. Pharmacology, biochemistry, and behavior. 2022; 212: 173312.

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12. Lord C, Charman T, Havdahl A, Carbone P, Anagnostou E, Boyd B, Carr T, de Vries PJ, Dissanayake C, Divan G, Freitag CM, Gotelli MM, Kasari C, Knapp M, Mundy P, Plank A, Scahill L, Servili C, Shattuck P, Simonoff E, Singer AT, Slonims V, Wang PP, Ysrraelit MC, Jellett R, Pickles A, Cusack J, Howlin P, Szatmari P, Holbrook A, Toolan C, McCauley JB. The Lancet Commission on the future of care and clinical research in autism. Lancet (London, England). 2022; 399(10321): 271-334.

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13. Martin K, McConnell A, Elsea SH. Assessing Prevalence and Carrier Frequency of Succinic Semialdehyde Dehydrogenase Deficiency. Journal of child neurology. 2021; 36(13-14): 1218-22.

Pathogenic variants in ALDH5A1 cause succinic semialdehyde dehydrogenase (SSADH) deficiency, with >180 cases reported worldwide. However, a nonspecific neurologic presentation and inconsistent variant nomenclature have limited diagnoses. In this study, pathogenic variants in ALDH5A1 were curated and variant prevalence assessed in the Genome Aggregation Database (gnomAD) to determine a minimum carrier frequency and to estimate disease prevalence. Stringent population variant analysis, including 98 reported disease-associated ALDH5A1 variants, indicates a pan-ethnic carrier frequency of ∼1/340, supporting a prevalence of SSADH deficiency of ∼1/460 000 worldwide, with highest carrier frequencies observed in East Asian and South Asian populations. Because heterozygous loss of function alleles are rare in gnomAD and >60% of reported disease-causing variants were missense changes that were not present in gnomAD, the pan-ethnic carrier frequency for SSADH deficiency is likely not fully represented in this study. Additional analyses to investigate the potential impact of more common ALDH5A1 variants with reduced but not deficient enzyme activity, including analysis in diverse populations, are needed to fully assess the prevalence of this ultra-rare disease.

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14. Okada NJ, Liu J, Tsang T, Nosco E, McDonald NM, Cummings KK, Jung J, Patterson G, Bookheimer SY, Green SA, Jeste SS, Dapretto M. Atypical cerebellar functional connectivity at 9 months of age predicts delayed socio-communicative profiles in infants at high and low risk for autism. Journal of child psychology and psychiatry, and allied disciplines. 2021.

BACKGROUND: While the cerebellum is traditionally known for its role in sensorimotor control, emerging research shows that particular subregions, such as right Crus I (RCrusI), support language and social processing. Indeed, cerebellar atypicalities are commonly reported in autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by socio-communicative impairments. However, the cerebellum’s contribution to early socio-communicative development remains virtually unknown. METHODS: Here, we characterized functional connectivity within cerebro-cerebellar networks implicated in language/social functions in 9-month-old infants who exhibit distinct 3-year socio-communicative developmental profiles. We employed a data-driven clustering approach to stratify our sample of infants at high (n = 82) and low (n = 37) familial risk for ASD into three cohorts-Delayed, Late-Blooming, and Typical-who showed unique socio-communicative trajectories. We then compared the cohorts on indices of language and social development. Seed-based functional connectivity analyses with RCrusI were conducted on infants with fMRI data (n = 66). Cohorts were compared on connectivity estimates from a-priori regions, selected on the basis of reported coactivation with RCrusI during language/social tasks. RESULTS: The three trajectory-based cohorts broadly differed in social communication development, as evidenced by robust differences on numerous indices of language and social skills. Importantly, at 9 months, the cohorts showed striking differences in cerebro-cerebellar circuits implicated in language/social functions. For all regions examined, the Delayed cohort exhibited significantly weaker RCrusI connectivity compared to both the Late-Blooming and Typical cohorts, with no significant differences between the latter cohorts. CONCLUSIONS: We show that hypoconnectivity within distinct cerebro-cerebellar networks in infancy predicts altered socio-communicative development before delays overtly manifest, which may be relevant for early detection and intervention. As the cerebellum is implicated in prediction, our findings point to probabilistic learning as a potential intermediary mechanism that may be disrupted in infancy, cascading into alterations in social communication.

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15. Postema MC, van Rooij D, Anagnostou E, Arango C, Auzias G, Behrmann M, Filho GB, Calderoni S, Calvo R, Daly E, Deruelle C, Di Martino A, Dinstein I, Duran FLS, Durston S, Ecker C, Ehrlich S, Fair D, Fedor J, Feng X, Fitzgerald J, Floris DL, Freitag CM, Gallagher L, Glahn DC, Gori I, Haar S, Hoekstra L, Jahanshad N, Jalbrzikowski M, Janssen J, King JA, Kong XZ, Lazaro L, Lerch JP, Luna B, Martinho MM, McGrath J, Medland SE, Muratori F, Murphy CM, Murphy DGM, O’Hearn K, Oranje B, Parellada M, Puig O, Retico A, Rosa P, Rubia K, Shook D, Taylor MJ, Tosetti M, Wallace GL, Zhou F, Thompson PM, Fisher SE, Buitelaar JK, Francks C. Author Correction: Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets. Nature communications. 2021; 12(1): 7260.

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16. Putra PU, Shima K, Alvarez SA, Shimatani K. Publisher Correction: Identifying autism spectrum disorder symptoms using response and gaze behavior during the Go/NoGo game CatChicken. Scientific reports. 2021; 11(1): 23937.

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17. Shekel I, Giladi S, Raykin E, Weiner M, Chalifa-Caspi V, Lederman D, Kofman O, Golan HM. Isolation-Induced Ultrasonic Vocalization in Environmental and Genetic Mice Models of Autism. Frontiers in neuroscience. 2021; 15: 769670.

Studies in rodent models suggest that calls emitted by isolated pups serve as an early behavioral manifestation of communication deficits and autistic like behavior. Previous studies in our labs showed that gestational exposure to the pesticide chlorpyrifos (CPF) and the Mthfr-knock-out mice are associated with impaired social preference and restricted or repetitive behavior. To extend these studies, we examine how pup communication via ultrasonic vocalizations is altered in these ASD models. We implemented an unsupervised hierarchical clustering method based on the spectral properties of the syllables in order to exploit syllable classification to homogeneous categories while avoiding over-categorization. Comparative exploration of the spectral and temporal aspects of syllables emitted by pups in two ASD models point to the following: (1) Most clusters showed a significant effect of the ASD factor on the start and end frequencies and bandwidth and (2) The highest percent change due to the ASD factor was on the bandwidth and duration. In addition, we found sex differences in the spectral and temporal properties of the calls in both control groups as well as an interaction between sex and the gene/environment factor. Considering the basal differences in the characteristics of syllables emitted by pups of the C57Bl/6 and Balb/c strains used as a background in the two models, we suggest that the above spectral-temporal parameters start frequency, bandwidth, and duration are the most sensitive USV features that may represent developmental changes in ASD models.

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18. Zarantonello G, Arnoldi M, Filosi M, Tebaldi T, Spirito G, Barbieri A, Gustincich S, Sanges R, Domenici E, Di Leva F, Biagioli M. Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase. Frontiers in genetics. 2021; 12: 745229.

CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of CHD8 suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following CHD8 knock down (KD), we first identified RAB11B-AS1 as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by CHD8 suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment.

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