1. Abe K, Kibe R, David K, Reddy V, Allard B, Fakaosita M. Reversible right-sided heart failure and pulmonary hypertension caused by scurvy in a 7-year-old boy with autism spectrum disorder and a review of the literature. Paediatrics and international child health. 2021: 1-5.

Scurvy, a condition caused by vitamin C deficiency, is rare, especially in high-income countries. Symptoms of scurvy are typically characterised by dermatological disorders such as poor wound healing and tooth loss, but there is not usually cardiac involvement. A case of reversible pulmonary hypertension and right-sided heart failure owing to scurvy in a 7-year-old boy with autism spectrum disorder is reported. He had a very restricted diet and presented with polyarthralgia, gingival hyperplasia with ecchymosis, and fatigue. His condition, including pulmonary hypertension and right-sided heart failure, completely resolved with vitamin C supplementation. Paediatricians should have a high index of suspicion for scurvy in children with nutritional selectivity and be aware that it can manifest with cardiac symptoms. Scurvy may be life-threatening if not treated, but the symptoms can improve rapidly with vitamin C supplementation.

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2. Alho J, Bharadwaj H, Khan S, Mamashli F, Perrachione TK, Losh A, McGuiggan NM, Joseph RM, Hämäläinen MS, Kenet T. Altered maturation and atypical cortical processing of spoken sentences in autism spectrum disorder. Progress in neurobiology. 2021; 203: 102077.

Autism spectrum disorder (ASD) is associated with widespread receptive language impairments, yet the neural mechanisms underlying these deficits are poorly understood. Neuroimaging has shown that processing of socially-relevant sounds, including speech and non-speech, is atypical in ASD. However, it is unclear how the presence of lexical-semantic meaning affects speech processing in ASD. Here, we recorded magnetoencephalography data from individuals with ASD (N = 22, ages 7-17, 4 females) and typically developing (TD) peers (N = 30, ages 7-17, 5 females) during unattended listening to meaningful auditory speech sentences and meaningless jabberwocky sentences. After adjusting for age, ASD individuals showed stronger responses to meaningless jabberwocky sentences than to meaningful speech sentences in the same left temporal and parietal language regions where TD individuals exhibited stronger responses to meaningful speech. Maturational trajectories of meaningful speech responses were atypical in temporal, but not parietal, regions in ASD. Temporal responses were associated with ASD severity, while parietal responses were associated with aberrant involuntary attentional shifting in ASD. Our findings suggest a receptive speech processing dysfunction in ASD, wherein unattended meaningful speech elicits abnormal engagement of the language system, while unattended meaningless speech, filtered out in TD individuals, engages the language system through involuntary attention capture.

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3. Benevides TW, Carretta HJ, Rust G, Shea L. Racial and ethnic disparities in benefits eligibility and spending among adults on the autism spectrum: A cohort study using the Medicare Medicaid Linked Enrollees Analytic Data Source. PloS one. 2021; 16(5): e0251353.

BACKGROUND: Research on children and youth on the autism spectrum reveal racial and ethnic disparities in access to healthcare and utilization, but there is less research to understand how disparities persist as autistic adults age. We need to understand racial-ethnic inequities in obtaining eligibility for Medicare and/or Medicaid coverage, as well as inequities in spending for autistic enrollees under these public programs. METHODS: We conducted a cross-sectional cohort study of U.S. publicly-insured adults on the autism spectrum using 2012 Medicare-Medicaid Linked Enrollee Analytic Data Source (n = 172,071). We evaluated differences in race-ethnicity by eligibility (Medicare-only, Medicaid-only, Dual-Eligible) and spending. FINDINGS: The majority of white adults (49.87%) were full-dual eligible for both Medicare and Medicaid. In contrast, only 37.53% of Black, 34.65% Asian/Pacific Islander, and 35.94% of Hispanic beneficiaries were full-dual eligible for Medicare and Medicare, with most only eligible for state-funded Medicaid. Adjusted logistic models controlling for gender, intellectual disability status, costly chronic condition, rural status, county median income, and geographic region of residence revealed that Black beneficiaries were significantly less likely than white beneficiaries to be dual-eligible across all ages. Across these three beneficiary types, total spending exceeded $10 billion. Annual total expenditures median expenditures for full-dual and Medicaid-only eligible beneficiaries were higher among white beneficiaries as compared with Black beneficiaries. CONCLUSIONS: Public health insurance in the U.S. including Medicare and Medicaid aim to reduce inequities in access to healthcare that might exist due to disability, income, or old age. In contrast to these ideals, our study reveals that racial-ethnic minority autistic adults who were eligible for public insurance across all U.S. states in 2012 experience disparities in eligibility for specific programs and spending. We call for further evaluation of system supports that promote clear pathways to disability and public health insurance among those with lifelong developmental disabilities.

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4. Gilbertson M, Richardson C, Eastwood P, Wilson A, Jacoby P, Leonard H, Downs J. Determinants of sleep problems in children with intellectual disability. Journal of sleep research. 2021; 30(5): e13361.

Children with intellectual disabilities are more likely to experience sleep disorders of insomnia, excessive daytime sleepiness and sleep breathing disorders than typically developing children. The present study examined risk factors for these sleep disorders in 447 children (aged 5-18 years), diagnosed with an intellectual disability and comorbid autism spectrum disorder, cerebral palsy, Down syndrome or Rett syndrome. Primary caregivers reported on their child’s sleep using the Sleep Disturbance Scale for Children (SDSC), as well as medical comorbidities and functional abilities. Multivariate linear and logistic regressions were used to examine the effects of these factors on SDSC t scores and a binary indicator, respectively for the relevant subscales. Receiving operating characteristic curves were generated for each logistic regression model to determine their ability to discriminate between poor and good sleep. Comorbidities rather than functional abilities were associated with poorer sleep. In particular, recurrent pain, frequent seizures, frequent coughing, constipation and prescription of sleep medications were associated with abnormal sleep across the entire sample, but predictors differed between diagnostic groups. The present study suggests that comorbidities are more strongly associated with quality of sleep than functional impairments. The present study provides new information on potential associations between frequent coughing, prescription sleep medications and sleep quality that should be further investigated.

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5. Haan N, Westacott LJ, Carter J, Owen MJ, Gray WP, Hall J, Wilkinson LS. Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms. Translational psychiatry. 2021; 11(1): 313.

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

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6. Hartley M, Due C, Dorstyn D. Barriers and facilitators to engaging individuals and families with autism spectrum disorder in mindfulness and acceptance-based therapies: a meta-synthesis. Disability and rehabilitation. 2021: 1-12.

PURPOSE: Third-wave psychological therapies can benefit individuals and families living with autism spectrum disorder (ASD). To date, little is known about individuals’ perceptions and experiences of therapy. This meta-synthesis aimed to capture participants’ own reflections of mindfulness and acceptance-based therapies, including potential barriers and facilitators to therapy engagement. MATERIALS AND METHODS: Database searches identified 10 independent studies targeting caregivers (N(studies) = 3), dyadic parent-child interventions (N(studies) = 6), or adults with ASD (N(studies) = 1). Studies were subject to quality assessment and thematically analysed. RESULTS: Caregivers highlighted a need to adapt the length and frequency of daily mindfulness practice around busy lifestyles. Adults with ASD also identified therapy barriers, although these data were less robust. Children with ASD focused on therapy benefits. CONCLUSIONS: All three participant groups commented on the importance of mindfulness as a method to enhance self-awareness, self-regulation and self-care. Peer support provided in group-based therapy was also seen as beneficial. Future research should examine the application of mindfulness therapies to adults with ASD, with little currently known about this cohort’s therapy experiences. Whether traditional mindfulness approaches can be effectively modified to accommodate ongoing, cumulative daily demands these families experience also requires investigation.Implications for rehabilitationIndividuals with autism spectrum disorders (ASD) and their caregivers often experience high levels of anxiety and stress.Mindfulness and acceptance-based therapies can enhance an individual’s self-awareness and self-regulation, thereby reducing distress – with benefits extending to familiesGroup-based therapy is an important adjunct to the support of caregivers developing mindfulness-awareness.

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7. Lai YYL, Downs JA, Wong K, Zafar S, Walsh LJ, Leonard HM. Oral parafunction and bruxism in Rett syndrome and associated factors: An observational study. Oral diseases. 2021.

OBJECTIVES: To explore patterns of parafunction, and bruxism, and its relationships with genotype and snoring in individuals with Rett syndrome (RTT). METHODS: Retrospective observational data of those with confirmed MECP2 mutations in the InterRett database (n = 216) were used to investigate experience of parafunctional habits, and bruxism and their relationships with genotype and snoring using multivariable linear regression. RESULTS: The prevalence of parafunction was 98.2%. Bruxism was reported (66.2%) with the patterns mostly both diurnal and nocturnal (44.1%) and exclusively diurnal (42.7%). Compared to individuals with C-terminal deletion, individuals with p.Arg106Trp mutations were less likely to have bruxism reported (aOR = 0.15; 95% CI 0.02-0.98, p = 0.05) and those with p.Arg168* mutation were more likely to have frequent bruxism than none or occasional bruxism reported (aROR 3.4; 95% CI 1.1-10.7 p = 0.04). The relative odds of having nocturnal bruxism constantly, compared to none/occasionally, were higher among those ‘always’ snoring (aROR 6.24; 95% CI 2.1-18.2, p = 0.001) than those with no snoring. CONCLUSIONS: There appeared to be genotypic association with bruxism in p.Arg168* and p.Arg106Trp mutations and association between nocturnal bruxism and frequent snoring in an international sample of individuals with RTT. Clinical significance of the high prevalence of bruxism should be highlighted in relation to difficulty communicating pain and increased dental treatment need in RTT.

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8. Le J, Zhao W, Kou J, Fu M, Zhang Y, Becker B, Kendrick KM. Oxytocin facilitates socially directed attention. Psychophysiology. 2021; 58(9): e13852.

Socially directed gaze following is an important component of social interaction and communication, allowing us to attend mutually with others to objects or people so that we can share their experience and also learn from them. This type of joint social attention is impaired in disorders such as autism. Previous research has demonstrated that the neuropeptide oxytocin can facilitate attention toward social cues, although to date no study in humans has investigated its influence on socially directed gaze or on associations of the latter with autistic and empathic traits. In a within-subject, randomized, placebo-controlled trial we used eye-tracking to investigate the effects of intranasal oxytocin (24 IU) on socially directed gaze toward one of two objects in 40 adult male subjects. Subjects viewed videos of an actor and actress directing their gaze toward one of two objects by either moving only their eyes, moving both their eyes and head, or moving their eyes and head and pointing with a finger. Results showed that OXT increased the proportion of time subjects viewed the object the actor or actress were looking/pointing at across all three conditions, although unexpectedly we found no associations with trait autism or empathy under either placebo or OXT treatments. These findings demonstrate that OXT can facilitate socially directed gaze following to promote mutual attention toward objects which may be potentially beneficial therapeutically in disorders with impaired social communication and interaction.

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9. MacLennan K, Rossow T, Tavassoli T. The relationship between sensory reactivity, intolerance of uncertainty and anxiety subtypes in preschool-age autistic children. Autism : the international journal of research and practice. 2021; 25(8): 2305-16.

This study found links between greater sensory hyperreactivity (e.g., over-sensitive to sensory input), intolerance of uncertainty and anxiety, including separation anxiety, in autistic pre-schoolers. Sensory hyperreactivity may predict both anxiety and intolerance of uncertainty, and anxiety and intolerance of uncertainty may both be mutually important, mediating factors. These findings have implications for early anxiety interventions. But there is a pressing need for objective assessments that can be used with preschool-age autistic children.

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10. Menezes M, Robinson MF, Harkins C, Sadikova E, Mazurek MO. Unmet health care needs and health care quality in youth with autism spectrum disorder with and without intellectual disability. Autism : the international journal of research and practice. 2021; 25(8): 2199-208.

The increase in the prevalence of autism spectrum disorder has placed greater demands on the health care system. Children and adolescents with autism spectrum disorder often experience challenges accessing high-quality physical and mental health care due to characteristic social-communication deficits and behavioral difficulties, as well as high rates of complex medical and psychiatric comorbidities. Intellectual disability commonly co-occurs with autism spectrum disorder and individuals affected by this co-occurrence may have additional impairments that compound challenges accessing health care. This study investigated the relations among co-occurring intellectual disability, unmet physical and mental health care needs, and health care quality in a large, nationally distributed sample of youth with autism spectrum disorder using structural equation modeling techniques. Co-occurring intellectual disability was significantly associated with unmet mental health care needs in children with autism. In addition, unmet mental health care needs mediated the relationship between co-occurring intellectual disability and health care quality; youth with autism spectrum disorder and co-occurring intellectual disability who had a past-year unmet mental health need had significantly poorer caregiver-reported health care quality. These findings suggest that youth with autism spectrum disorder and co-occurring intellectual disability may be more likely to experience unmet mental health care needs and receive poorer quality of care than the broader autism spectrum disorder population.

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11. Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev G, Nicolas A, Sommer C, Kreuzinger C, Dotter CP, Knaus LS, Dobler Z, Cacci E, Schur FKM, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature communications. 2021; 12(1): 3058.

De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). In mouse, constitutive Cul3 haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.

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12. Poole RL, Curry PDK, Marcinkute R, Brewer C, Coman D, Hobson E, Johnson D, Lynch SA, Saggar A, Searle C, Scurr I, Turnpenny PD, Vasudevan P, Tatton-Brown K. Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant. American journal of medical genetics Part A. 2021; 185(8): 2445-54.

Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence-based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.

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13. Sone BJ, Kaat AJ, Roberts MY. Measuring parent strategy use in early intervention: Reliability and validity of the Naturalistic Developmental Behavioral Intervention Fidelity Rating Scale across strategy types. Autism : the international journal of research and practice. 2021; 25(7): 2101-11.

Children with autism spectrum disorder benefit from early intervention to improve social communication, and parent-implemented interventions are a feasible and family-centered way to increase the amount of treatment they receive. For these treatments to be effective, it is important for the parent to implement the strategies as intended. However, measurement of parent strategy use is inconsistent across studies of parent-implemented interventions. This study evaluates the quality of the NDBI-Fi, an efficient measure, compared to a more time-consuming measure that is known to be precise. Videos of parents playing with their children were used to compare these two measurement methods. Results demonstrated that the NDBI-Fi was of good quality: scorers had high levels of agreement, the NDBI-Fi was similar to the more precise measure in rating parents after intervention, it detected changes from before to after intervention, and it detected differences when parents learned different types of intervention strategies. The NDBI-Fi was not as precise as the other measure across all strategies before parents learned intervention. Taken together, the findings of this study support the use of the NDBI-Fi as a high-quality outcome measure.

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