1. Bamgboye MA, Herold KG, Vieira DCO, Traficante MK, Rogers PJ, Ben-Johny M, Dick IE. CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms. The Journal of general physiology. 2022; 154(11).

The first pathogenic mutation in CaV1.2 was identified in 2004 and was shown to cause a severe multisystem disorder known as Timothy syndrome (TS). The mutation was localized to the distal S6 region of the channel, a region known to play a major role in channel activation. TS patients suffer from life-threatening cardiac symptoms as well as significant neurodevelopmental deficits, including autism spectrum disorder (ASD). Since this discovery, the number and variety of mutations identified in CaV1.2 have grown tremendously, and the distal S6 regions remain a frequent locus for many of these mutations. While the majority of patients harboring these mutations exhibit cardiac symptoms that can be well explained by known pathogenic mechanisms, the same cannot be said for the ASD or neurodevelopmental phenotypes seen in some patients, indicating a gap in our understanding of the pathogenesis of CaV1.2 channelopathies. Here, we use whole-cell patch clamp, quantitative Ca2+ imaging, and single channel recordings to expand the known mechanisms underlying the pathogenesis of CaV1.2 channelopathies. Specifically, we find that mutations within the S6 region can exert independent and separable effects on activation, voltage-dependent inactivation (VDI), and Ca2+-dependent inactivation (CDI). Moreover, the mechanisms underlying the CDI effects of these mutations are varied and include altered channel opening and possible disruption of CDI transduction. Overall, these results provide a structure-function framework to conceptualize the role of S6 mutations in pathophysiology and offer insight into the biophysical defects associated with distinct clinical manifestations.

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2. Caporali L, Fiorini C, Palombo F, Romagnoli M, Baccari F, Zenesini C, Visconti P, Posar A, Scaduto MC, Ormanbekova D, Battaglia A, Tancredi R, Cameli C, Viggiano M, Olivieri A, Torroni A, Maestrini E, Rochat MJ, Bacchelli E, Carelli V, Maresca A. Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder. Frontiers in genetics. 2022; 13: 953762.

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%-5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers’ germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.

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3. Clements CC, Ascunce K, Nelson CA. In Context: A Developmental Model of Reward Processing, With Implications for Autism and Sensitive Periods. Journal of the American Academy of Child and Adolescent Psychiatry. 2022.

OBJECTIVE: Differences in reward processing have been associated with numerous psychiatric disorders, including autism and ADHD. Many attempts to understand reward processing characterize differences in clinical populations after disorder onset; however, divergence may begin much earlier. In fact, the typical developmental progression of reward processing in infancy and early childhood is poorly understood. We reconceptualize classic infant developmental constructs such as preferential looking into a Six-Component Developmental Model of Reward Processing: an infant- and young child-focused framework to guide research and assessment of reward processing across development. METHOD: The extant developmental literature including recent textbooks, systematic reviews, and meta-analyses was reviewed to build a conceptual framework. We describe experimental paradigms to assess each developmental component of reward processing longitudinally from infancy. A timeline of each component’s emergence was estimated. RESULTS: Six components of reward processing were identified – association, discrimination, preference/valuation, effort, anticipation, and response. Selected evidence suggests emergence between birth and six months. Application of this model to autism led to a reinterpretation of existing disparate results, and illuminated a path to study the developmental processes underlying a popular hypothesis of autism, the motivation hypothesis. Current evidence further suggests a sensitive period may exist for the emergence of reward processing. CONCLUSION: The proposed framework offers a useful reconceptualization of the extant literature. Future longitudinal work using the suggested experimental paradigms with high-risk populations could elucidate the developmental trajectory of the six components and timing of potential sensitive period(s) for each component.

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4. Estes A, Munson J, St John T, Finlayson R, Pandey J, Gottlieb B, Herrington J, Schultz RT. Sleep problems in autism: Sex differences in the school-age population. Autism research : official journal of the International Society for Autism Research. 2022.

Clinically significant sleep problems affect up to 86% of the autistic population in school-age. Sleep problems can have negative impacts on child cognition, behavior, and health. However, sex differences in the prevalence and types of sleep problems are not well understood in autism. To evaluate sex differences in sleep problems in the school-age autistic population, we obtained parent-report of sleep problems on the Children’s Sleep Habits Questionnaire and conducted direct assessments to establish diagnosis and intellectual ability in 6-12-year-old children (autism n = 250; typical development [TD] n = 114). Almost 85% of autistic females demonstrated sleep problems compared to 65.8% of autistic males, 44.8% of TD females, and 42.4% of TD males; a statistically significant increase for autistic females. Autistic females demonstrated increased bedtime resistance, sleep anxiety, and sleepiness, and decreased sleep duration, but did not differ in sleep onset delay, night wakings, parasomnias, or disordered breathing compared with autistic males. Intellectual ability was not related to increased sleep problems. Higher anxiety scores were associated with more sleep problems for males but not females. In one of the first studies to evaluate sex differences in sleep in the school-age, autistic population, autistic females demonstrated increased sleep problems compared to autistic males, TD females, and TD males. Current autism assessment and intervention practices may benefit from increased attention to sleep problems in autistic school-age females and to anxiety in autistic males to enhance well-being and behavioral and health outcomes.

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5. Ferron L, Zamponi GW. The road to the brain in Timothy syndrome is paved with enhanced CaV1.2 activation gating. The Journal of general physiology. 2022; 154(11).

Specific gating effects of Timothy syndrome Ca(V)1.2 channel mutations determine cardiovascular versus nervous system deficits.

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6. Gardner L, Cederberg C, Hangauer J, Campbell JM. Law enforcement officers’ interactions with autistic individuals: Commonly reported incidents and use of force. Research in developmental disabilities. 2022; 131: 104371.

Little research exists examining interactions between law enforcement officers (LEOs) and autistic individuals. The present study includes responses from 130 LEOs who participated in autism-specific training and completed surveys assessing professional experiences responding to calls that involved individuals with known autism spectrum disorder (ASD) diagnosis. The purpose of the present study was to determine the types of incidents LEOs respond to involving autistic people, and the level of force used in response to the incident. Analysis revealed four categories captured the majority of reported incidents: disruptive behavior, suspected abuse/neglect, elopement, and noncriminal behavior. The most commonly reported responses by LEOs included providing support and extreme controlling behaviors, with female officers more likely to report utilizing supportive behaviors and less force compared to male counterparts.

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7. Martinez ME, Stohn JP, Mutina EM, Whitten RJ, Hernandez A. Thyroid hormone elicits intergenerational epigenetic effects on adult social behavior and fetal brain expression of autism susceptibility genes. Frontiers in neuroscience. 2022; 16: 1055116.

Genetic mutations identified in genome-wide association studies can only explain a small percentage of the cases of complex, highly heritable human conditions, including neurological and neurodevelopmental disorders. This suggests that intergenerational epigenetic effects, possibly triggered by environmental circumstances, may contribute to their etiology. We previously described altered DNA methylation signatures in the sperm of mice that experienced developmental overexposure to thyroid hormones as a result of a genetic defect in hormone clearance (DIO3 deficiency). Here we studied fetal brain gene expression and adult social behavior in genetically normal F2 generation descendants of overexposed mice. The brain of F2 generation E13.5 fetuses exhibited abnormal expression of genes associated with autism in humans, including Auts2, Disc1, Ldlr, Per2, Shank3, Oxtr, Igf1, Foxg1, Cd38, Grid2, Nrxn3, and Reln. These abnormal gene expression profiles differed depending on the sex of the exposed ancestor. In the three-chamber social box test, adult F2 generation males manifested significantly decreased interest in social interaction and social novelty, as revealed by decrease total time, distance traveled and time immobile in the area of interaction with novel strangers. F1 generation mice, compared to appropriate controls also exhibited altered profiles in fetal brain gene expression, although these profiles were substantially different to those in the F2 generation. Likewise adult F1 generation mice showed some abnormalities in social behavior that were sexually dimorphic and milder than those in F2 generation mice. Our results indicate that developmental overexposure to thyroid hormone causes intergenerational epigenetic effects impacting social behavior and the expression of autism-related genes during early brain development. Our results open the possibility that altered thyroid hormone states, by eliciting changes in the epigenetic information of the germ line, contribute to the susceptibility and the missing-but heriTables-etiology of complex neurodevelopmental conditions characterized by social deficits, including autism and schizophrenia.

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8. Miller HL, Templin TN, Fears NE, Sherrod GM, Patterson RM, Bugnariu NL. Movement smoothness during dynamic postural control to a static target differs between autistic and neurotypical children. Gait & posture. 2022; 99: 76-82.

BACKGROUND: Autistic children and adults have known differences in motor performance, including postural instability and atypical gross motor control. Few studies have specifically tested dynamic postural control. This is the first study to quantify movement smoothness and its relationship to task performance during lateral dynamic postural control tasks in autism. RESEARCH QUESTION: We sought to test the hypothesis that autistic children would have less smooth movements to lateral static targets compared to neurotypical children, and that this difference would relate to specific movement strategies. METHODS: We used camera-based motion-capture to measure spatiotemporal characteristics of lateral movement of a marker placed on the C7 vertebrae, and of markers comprising trunk and pelvis segments during a dynamic postural movements to near and far targets administered in an immersive virtual environment. We tested a sample of 15 autistic children and 11 age-matched neurotypical children. We quantified movement smoothness using log dimensionless jerk. RESULTS: Autistic children exhibited more medial-lateral pelvic position range of motion compared to neurotypical children, and used a stepping strategy more often compared to neurotypical children. Autistic children also had higher log dimensionless jerk than neurotypical children for motion of the C7 marker. All participants had higher log dimensionless jerk for far targets than for near targets. Autistic children had longer trial durations than neurotypical children, and younger children had longer trial durations than older children across diagnostic groups. SIGNIFICANCE: The stepping strategy observed more often in the autistic group likely contributed to log dimensionless jerk and reduced movement smoothness. This strategy is indicative of either an attempt to prevent an impending loss of balance, or an attempt to compensate for and recover from a loss of balance once it is detected.

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9. Mukherjee D, Bhavnani S, Lockwood Estrin G, Rao V, Dasgupta J, Irfan H, Chakrabarti B, Patel V, Belmonte MK. Digital tools for direct assessment of autism risk during early childhood: A systematic review. Autism : the international journal of research and practice. 2022: 13623613221133176.

The challenge of finding autistic children, and finding them early enough to make a difference for them and their families, becomes all the greater in parts of the world where human and material resources are in short supply. Poverty of resources delays interventions, translating into a poverty of outcomes. Digital tools carry potential to lessen this delay because they can be administered by non-specialists in children’s homes, schools or other everyday environments, they can measure a wide range of autistic behaviours objectively and they can automate analysis without requiring an expert in computers or statistics. This literature review aimed to identify and describe digital tools for screening children who may be at risk for autism. These tools are predominantly at the ‘proof-of-concept’ stage. Both portable (laptops, mobile phones, smart toys) and fixed (desktop computers, virtual-reality platforms) technologies are used to present computerised games, or to record children’s behaviours or speech. Computerised analysis of children’s interactions with these technologies differentiates children with and without autism, with promising results. Tasks assessing social responses and hand and body movements are the most reliable in distinguishing autistic from typically developing children. Such digital tools hold immense potential for early identification of autism spectrum disorder risk at a large scale. Next steps should be to further validate these tools and to evaluate their applicability in a variety of settings. Crucially, stakeholders from underserved communities globally must be involved in this research, lest it fail to capture the issues that these stakeholders are facing.

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10. Nic Ghiolla Phadraig A, Smyth S. Sleep mediates the relationship between having an autistic child and poor family functioning. Sleep medicine. 2022; 101: 190-6.

Sleep is an important biological necessity, a lack of which can have many cognitive, psychological, social, and physical impacts. Children with autism are known to present with sleep difficulties more frequently than their typically developing peers but despite this, there is relatively little research looking at the impact of sleep on the family. To investigate the effect of sleep on families of autistic and typically developing (TD) children, we conducted a study of sleep disturbances among children, sleep quality of their parents in association with their family function. In our study, 239 parents of autistic children and 227 parents of TD children participated. These parents completed a survey about their child’s sleep disturbances, their own sleep quality, and their family function, along with a series of demographic questions. Analyses indicated that autistic children experience more sleep difficulties than TD peers, that children’s sleep disturbances are associated with parental sleep quality and that parents of autistic children report decreased sleep quality compared to parents of TD children. Parental sleep quality, and child sleep quality were both found to partially mediate the relationship between autism diagnosis and family function.

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11. Norelius R. Juvenile Benign Diseases of the Breast. The Surgical clinics of North America. 2022; 102(6): 1065-75.

The developmental phases of the breast are fluid and spread throughout prenatal, postnatal, and adolescent life. Developmental derangement during each phase can lead to disease formation. Before reaching adulthood, most abnormalities of the breast are benign in nature and can be characterized as congenital disorders, developmental disorders, or acquired disorders. Surgical intervention early in life is rarely warranted.

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12. Williams EG, Smith MJ, Boyd B. Perspective: The role of diversity advisory boards in autism research. Autism : the international journal of research and practice. 2022: 13623613221133633.

This article argues that using groups of individuals that specifically focus on addressing issues with diversity in autism research and autism intervention development are key in ensuring that a greater amount of racial, ethnic, and gender diverse autistic individuals are included in the research and that the research is addressing the needs of these individuals and groups. We call these groups a diversity advisory board. A diversity advisory board will help improve diversity in autism research and intervention development by making sure that autism researchers (1) are intentional about addressing issues of diversity in their research and (2) are able to recruit a greater number of autistic individuals with diverse identities, and (3) by giving greater consideration to the context of diverse autistic individuals which will help autism-focused interventions work better in community settings. We give a short description of these arguments and ideas for how to form and use a diversity advisory board.

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13. Zhong NH, Grimm RP, Kanne SM, Mazurek MO. Measurement invariance of the Autism Impact Measure (AIM) across sex in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2022.

Measurement invariance, or the degree to which an instrument measures constructs consistently across subgroups, is critical for appropriate interpretations of measures. Given sex differences in the phenotypic and clinical presentation of autism spectrum disorder (ASD), it is particularly important to examine measurement invariance in autism instruments to ensure that ASD measures are not biased toward the more common male ASD phenotype. This study represents an important preliminary investigation evaluating the measurement equivalence of the Autism Impact Measure (AIM) across children and adolescents with ASD. The results indicated that the AIM demonstrated measurement invariance at the configural, metric, and scalar levels across sex in all five domains, including Repetitive Behavior, Communication, Atypical Behavior, Social Reciprocity, and Peer Interaction. These results suggest that ASD core symptoms assessed by the AIM were similar among male and female groups. In addition, the latent means for all five factors were not statistically significantly different across sex groups, revealing no systematic differences on any of the AIM subscales for males and females. Overall, this study showed that the AIM detects core ASD symptoms across all five areas equivalently in males and females and is not biased toward males with ASD.

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