1. Begum-Ali J, Kolesnik-Taylor A, Quiroz I, Mason L, Garg S, Green J, Johnson MH, Jones EJH. Early differences in auditory processing relate to Autism Spectrum Disorder traits in infants with Neurofibromatosis Type I. Journal of neurodevelopmental disorders. 2021; 13(1): 22.

BACKGROUND: Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies. METHODS: In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD. RESULTS: In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits. CONCLUSIONS: These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD.

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2. Burns W, Bird LM, Heron D, Keren B, Ramachandra D, Thiffault I, Del Viso F, Amudhavalli S, Engleman K, Parenti I, Kaiser FJ, Wierzba J, Riedhammer KM, Liptay S, Zadeh N, Porrmann J, Fischer A, Gößwein S, McLaughlin HM, Telegrafi A, Langley KG, Steet R, Louie RJ, Lyons MJ. Syndromic neurodevelopmental disorder associated with de novo variants in DDX23. American journal of medical genetics Part A. 2021; 185(10): 2863-72.

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23). The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA. Our cohort of patients, gathered through GeneMatcher, exhibited features including tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The individuals presented in this article provide evidence of a syndrome related to alterations in DDX23 characterized predominantly by atypical neurodevelopment.

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3. Cheng C, Hou Y, Zhang Z, Wang Y, Lu L, Zhang L, Jiang P, Gao S, Fang Q, Zhu C, Gao J, Liu X, Xie W, Jia Z, Xu Z, Gao X, Chai R. Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice. Journal of genetics and genomics = Yi chuan xue bao. 2021; 48(4): 324-32.

Several clinical studies have reported that hearing loss is correlated with autism in children. However, little is known about the underlying mechanism between hearing loss and autism. p21-activated kinases (PAKs) are a family of serine/threonine kinases that can be activated by multiple signaling molecules, particularly the Rho family of small GTPases. Previous studies have shown that Pak1 mutations are associated with autism. In the present study, we take advantage of Pak1 knockout (Pak1(-/-)) mice to investigate the role of PAK1 in hearing function. We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell (HC) apoptosis and severe hearing loss. Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of βII-spectrin, which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1(-/-) mice. Overall, our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function. As the first candidate gene linking autism and hearing loss, Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.

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4. Curtiss SL, Ebata AT. A dialectic of control and acceptance: Mealtimes with children on the autism spectrum. Appetite. 2021; 165: 105327.

Shared family meals have important implications for child health and wellbeing, however, mealtimes with children on the autism spectrum are often characterized by stress and problematic behavior. A better understanding of the underlying processes can elucidate the mealtimes challenges that families with children on the spectrum face as well as how families overcome those challenges in order to promote family health and wellbeing. Through a grounded theory analysis of mealtime observations, parent interviews, and child interviews with 16 families in the United States, we identified a theory of A Dialectic of Control and Acceptance. Integral to the role of mealtimes is for parents to express love through control and acceptance, however, these parallel processes are in tension with one another. How parents negotiate this tension dictates the degree to which their expectations are well aligned with their children’s strengths and challenges and are able to provide effective support.

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5. Halloun R, Habib C, Ekhilevitch N, Weiss R, Tiosano D, Cohen M. Expanding the spectrum of endocrinopathies identified in Schaaf-Yang syndrome – A case report and review of the literature. European journal of medical genetics. 2021; 64(8): 104252.

Schaaf-Yang syndrome is a genetic disorder caused by mutations in the paternal allele of the MAGEL2 gene. Developmental delay, feeding difficulties, joint contractures and a high prevalence of autism spectrum disorders are characteristic of the syndrome. Endocrine abnormalities include mostly various pituitary hormonal deficiencies, presenting as hypoglycemia in 48% of reported cases. Persistent hyperinsulinism was only described in two siblings and responded to diazoxide treatment. We describe a unique case of an infant with Schaaf-Yang syndrome that presented with persistent hyperinsulinism unresponsive to diazoxide. Furthermore, we conducted a literature review of the endocrine abnormalities described in MAGEL2 related disorders. The case presented expands the clinical phenotype of Schaaf-Yang syndrome and emphasizes the importance of endocrine follow-up in these patients. Further investigation into the role of MAGEL2 in the regulation of pancreatic beta-cell insulin secretion, will improve our understanding of the abnormalities in glucose regulation in this syndrome.

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6. Han E, Tan MMJ, Crane L, Legido-Quigley H. A qualitative study of autism services and supports in Singapore: Perspectives of service providers, autistic adults and caregivers. Autism : the international journal of research and practice. 2021; 25(8): 2279-90.

Because autism is a lifelong and complex condition, autistic people may need a range of supports cutting across different sectors (e.g. health, education and social care) at different stages of their lives. Studies in some countries have shown that autistic people and their families face difficulties accessing the services they need, but no research has been done on this topic in Singapore. To start addressing this gap, we interviewed 21 service providers, autistic adults and caregivers/parents of autistic children to find out their perceptions and experiences of autism services and supports in Singapore. Our participants told us that beyond improving access to autism-specific services, they also hoped to see more flexible supports in an inclusive environment and a broader change in societal attitudes. This study highlights that autism service provision should be informed by autistic voices and not only focus on impairment but also recognise the strengths of autistic people alongside their very real needs. The whole of society – including policymakers, professionals, employers, educators, families and autistic people themselves – needs to work together to fight autism stigma and discrimination.

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7. Joung KE, Rifas-Shiman SL, Oken E, Mantzoros CS. Maternal Midpregnancy Leptin and Adiponectin Levels as Predictors of Autism Spectrum Disorders: A Prenatal Cohort Study. The Journal of clinical endocrinology and metabolism. 2021; 106(10): e4118-e27.

CONTEXT: Autism spectrum disorders (ASDs) are a group of conditions characterized by impaired social function and repetitive behaviors. Their etiology is largely unknown. OBJECTIVE: This work aims to examine the associations of maternal second-trimester and cord blood leptin and adiponectin levels with ASDs in offspring. METHODS: We used data from 1164 mother-child pairs enrolled in Project Viva, a prospective prebirth cohort. We used logistic regression analysis to examine the associations of leptin and adiponectin levels in maternal second-trimester blood and cord blood obtained at birth with ASDs. Additionally, we examined the association of maternal prepregnancy body mass index (BMI) as an exposure. Main outcome measures included doctor-diagnosed ASDs reported by mothers using questionnaires in midchildhood and early adolescence. RESULTS: The cumulative incidence of ASDs was 3.4%. Maternal prepregnancy BMI (per 5 points) was positively associated with ASDs in a logistic regression model adjusted for maternal race/ethnicity, education, smoking status and child sex (adjusted odds ratio [OR] 1.38; 95% CI, 1.06-1.79). Higher second-trimester adiponectin was associated with lower odds of ASD in offspring (unadjusted OR 0.49; 95% CI, 0.30-0.78; and OR 0.54; 95% CI, 0.32-0.91 after adjusting for maternal race/ethnicity, education, child sex, OR 0.55; 95% CI, 0.33-0.93 after adjusting for BMI, gestational weight gain, gestational diabetes, and smoking status). Maternal leptin and cord blood leptin and adiponectin levels were not associated with ASDs. CONCLUSION: Prepregnancy BMI and adiponectin during pregnancy may be useful as a tool to monitor the risk of autism. Increasing adiponectin levels prenatally may play a role in the prevention of ASDs.

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8. Krishnan L, Iyer K, Kumar PDM. Effectiveness of two sensory-based health education methods on oral hygiene of adolescent with autism spectrum disorders: An interventional study. Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2021; 41(5): 626-33.

AIM: This study was undertaken with an aim to evaluate the effectiveness of two sensory-based interventions namely – Visual pedagogy and Mobile based application (Brush Up) on oral health education in promoting oral health status among 13-17 year old school going adolescents with Autism Spectrum Disorder (ASD) in Chennai city. METHODOLOGY: An interventional parallel arm study consisting of 13- to 17-year-old school going adolescent with ASD in Chennai city. Plaque Index (Sillness and Loe, 1964) and gingival index (Loe and Sillness, 1963) were assessed at baseline, 6th week and after 12th week. RESULTS: A significant difference in plaque (p = < 0.001) and gingival scores (p = < 0.001) were seen among the groups after 6 and 12 weeks post-intervention. There was no statistically significant difference in dental plaque (p = 0.912, 1.023, 0.812) and gingival scores (p = 0.932, 0.264, 0.283) between the groups at all the timelines. CONCLUSION: In this present study we found that both the visual cards and mobile based application (Brush Up) had significantly reduced the dental plaque and gingival scores; hence both the modalities can be used as an effective tool in educating these children and thus improve their oral hygiene.

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9. Lawrence KE, Hernandez LM, Fuster E, Padgaonkar NT, Patterson G, Jung J, Okada NJ, Lowe JK, Hoekstra JN, Jack A, Aylward E, Gaab N, Van Horn JD, Bernier RA, McPartland JC, Webb SJ, Pelphrey KA, Green SA, Bookheimer SY, Geschwind DH, Dapretto M. Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect. Brain : a journal of neurology. 2022; 145(1): 378-87.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

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10. Levin MD, Bianconi S, Smith A, Cawley NX, Do AD, Hammond D, Grafstein JF, Thurm A, Miller J, Perreault J, Noguchi A, Springer D, Kozel BA, Spurney CF, Wassif CA, Yu ZX, Schulze A, Porter FD, Hannah-Shmouni F. X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model. Genetics in medicine : official journal of the American College of Medical Genetics. 2021; 23(10): 1864-72.

PURPOSE: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures, and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. METHODS: We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8(-/y)) using ECG, echocardiography, exercise testing, and indirect calorimetry. RESULTS: Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P < 0.0001. The QTc ≥ 470 milliseconds cohort had increased left ventricular internal dimension (diastole) ([LVIDd] Z-score: 0.22 ± 0.74, n = 7 vs. -0.93 ± 1.0, n = 11, P = 0.0059), and diminished left ventricular posterior wall dimension (diastole) ([LVPWDd, in mm]: 5.0 ± 0.6, n = 7 vs. 5.7 ± 0.8, n = 11, P = 0.0183), when compared to subjects with normal or borderline QTc prolongation. Similar ECG and echocardiographic abnormalities were seen in Slc6a8(-/y) mice. Additionally, Slc6a8(-/y) mice had diminished survival (65%). CONCLUSION: Prolonged QTc and abnormal echocardiographic parameters consistent with developing cardiomyopathy are seen in some male subjects with CTD. Slc6a8(-/y) mice recapitulated these cardiac abnormalities. Male CTD subjects may be at increased risk for cardiac dysfunction and sudden death.

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11. McQuillan VA, Swanwick RA, Chambers ME, Schlüter DK, Sugden DA. A comparison of characteristics, developmental disorders and motor progression between children with and without developmental coordination disorder. Human movement science. 2021; 78: 102823.

BACKGROUND AND AIM: Children with Developmental Coordination Disorder (DCD) have difficulty in the development of motor coordination and with learning new motor skills. Studies demonstrate that children with DCD differ in terms of the nature and severity of their motor difficulties, the incidence of co occurring conditions and family background. However, little is known whether these profiles may relate to motor progression over time. The aim of this study was to describe the profiles of children with and without DCD and track motor progression over time. METHOD: The characteristics of thirty-four 7-14 year old children (M = 10.07, 85.3% boys) with and without DCD were compared and their motor progression monitored over a two academic years. DCD was identified using DSM5 criteria. The Movement Assessment Battery for Children-2 (MABC-2) was used to classify children as TD (≥25th percentile), having moderate motor coordination difficulties (6-16th percentile) or severe motor coordination difficulties (≤ 5th percentile). The Kaufman Brief Intelligence Test – 2 (KBIT-2) was used to measure full scale IQ. Parent questionnaires were used to gather information on socio economic status and co occurrence of other developmental disorders. We used ANOVA to assess whether there were differences in characteristics between the TD children, children with severe motor coordination difficulties and children with moderate motor coordination difficulties. Linear mixed effect modelling was used to estimate any change in motor performance over time and whether this differed between the three groups of children. RESULTS: Children with severe motor coordination difficulties had distinct profiles in motor and non-motor domains, lower IQ and a greater likelihood of having associated characteristics of 2 or more developmental disorders. We found significant differences between the poor motor performance of the severe group compared to the other two groups. Longitudinal analyses revealed stable, persistent and lower motor competence for the severe group. The rate of change in motor proficiency for the typical and severe groups was similar. However, the group with moderate motor difficulties gained on average more points per week compared to the typical group and achieved motor scores in the typically developing range over time. CONCLUSIONS: This is one of the first studies to compare the characteristics and rate of motor progression of children with and without DCD using different motor proficiency cut off scores. The children with severe motor coordination difficulties progressed at the same rate as typically developing peers but remained in the severe group over time, whereas the children with moderate motor coordination difficulties caught up to TDC. The results indicate that different intervention may be required according to the nature and severity of the characteristics in both the motor and non-motor domains of children with DCD.

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12. Mullegama SV, Klein SD, Williams SR, Innis JW, Probst FJ, Haldeman-Englert C, Martinez-Agosto JA, Yang Y, Tian Y, Elsea SH, Ezashi T. Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes. Scientific reports. 2021; 11(1): 11295.

MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q < 0.05), including 20 ASD-associated genes. Comparison of DEGs in MAND with SFARI syndromic autism genes revealed a striking significant overlap in biological processes commonly altered in neurodevelopmental phenotypes, with TGFβ, Hippo signaling, DNA replication, and cell cycle among the top enriched pathways. Overall, these transcriptome deviations provide potential connections to the overlapping neurocognitive and neuropsychiatric phenotypes associated with key high-risk ASD genes, including chromatin modifiers and epigenetic modulators, that play significant roles in these disease states.

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13. Nishi E, Uehara T, Yanagi K, Hasegawa Y, Ueda K, Kaname T, Yamamoto T, Kosaki K, Okamoto N. Clinical spectrum of individuals with de novo EBF3 variants or deletions. American journal of medical genetics Part A. 2021; 185(10): 2913-21.

Hypotonia, ataxia and delayed development syndrome (HADDS) (MIM#617330) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in EBF3 (MIM; 607,407), which is located on chromosome 10q26, and was first reported in 2017. To date, missense, nonsense and frameshift variants have been reported as causes of HADDS, and EBF3 pathogenic variants have been predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. It was also reported that total deletion of EBF3 associated with a 10q26.3 microdeletion also causes HADDS symptoms, supporting the concept that HADDS results from haploinsufficiency of EBF3. Here, we report eight unrelated individuals with heterozygous pathogenic variants of EBF3 or haploinsufficiency of EBF3 due to 10q26 deletion, who exhibit clinical findings including craniofacial features of HADDS. In a detailed examination of clinical manifestations in this study, revealed that neurogenic bladder was diagnosed in infancy (the median 6.5 months), was more frequent than previously reported, and required cystostomy in all but one case. For psychomotor delay, it was also found that their motor/skills values were significantly lower than their cognition/adaptation values (p = 0.0016; paired t-test). Therefore, that HADDS is a recognizable syndrome that shares its characteristic facial features, and that neurogenic bladder diagnosed in infancy and psychomotor delay with marked delay in motor/skills are noteworthy findings in the diagnosis and management of individuals with HADDS.

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14. Wang H, Wang Q, Hu X, Han ZR. Mindfulness and Stress Among Parents of Children with Autism Spectrum Disorder in China. Journal of autism and developmental disorders. 2022; 52(5): 2035-45.

Parenting a child with autism spectrum disorder (ASD) can be tremendously challenging. It is important to identify factors associated with parenting stress. This study examined the indirect effect of parental dispositional mindfulness on their anxiety and depressive symptoms and family quality of life (FQOL) through mindful parenting and then parenting stress. Seventy-nine Chinese parents (24.1% fathers) of children with ASD aged 3-13 years completed self-report questionnaires. Results indicated that higher dispositional mindfulness was associated with higher mindful parenting, which was related to lower parenting stress, and further related to lower anxiety and depressive symptoms and higher FQOL. The findings provide valuable insight into the potential pathways through which general mindfulness and mindful parenting may positively impact parental outcomes.

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15. Webb EL, Moffat A, Morris D, Satti F. Untangling the relationship between early adversity, placement breakdowns, and obesity in a secure adolescent developmental disorder service: A cross-sectional study. Disability and health journal. 2021; 14(4): 101121.

BACKGROUND: Obesity is a growing global health concern, and those with a developmental disorder are at particular risk. Elevated levels of childhood trauma, placement breakdowns and obesity have been documented in the developmental disorder population, yet their relative associations remain unclear. OBJECTIVE: A previous study (Morris et al., 2020) highlighted a high prevalence of adverse childhood experiences (ACEs) and obesity in adolescents with developmental disorders residing in a secure inpatient setting. The current cross-sectional study sought to further explore the prevalence of placement breakdowns and its relationship with Body Mass Index (BMI) in this sample. METHODS: Secondary analysis was conducted on existing data for 34 adolescents, aged 10-17 years at admission, held in a secure mental health hospital developmental disorder service in the United Kingdom (UK) under the Mental Health Act. RESULTS: Almost half of participants had experienced a placement breakdown (47.1%), the majority of whom typically experienced multiple breakdowns (M = 3.94, SD = 2.14). Placement breakdowns significantly predicted BMI and had a predictive effect that was independent to and above that of ACEs. CONCLUSIONS: Placement breakdowns significantly contribute to risk for obesity, above that explained by early adversity. Those who have experienced placement breakdowns have a greater risk for obesity, irrespective of their level of exposure to ACEs. A history of previous placement breakdowns may act as a red flag for obesity.

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