Autism-related dietary preferences mediate autism-gut microbiome associations.

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.

The effectiveness and tolerability of pharmacotherapy for psychosis in 22q11.2 Deletion Syndrome: A systematic review.

OBJECTIVE: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans with over 180 phenotypic expressions. Approximately 30-40% of affected individuals will develop psychosis and 25% meet the criteria for schizophrenia. Despite this, pharmacotherapy for managing psychosis in 22q11.2DS is poorly understood and 22q11.2DS psychosis is frequently labelled as treatment resistant. The objectives of this paper are to evaluate the effectiveness and tolerability of pharmacotherapy for 22q11.2DS psychosis and evaluate the evidence for treatment resistance. METHOD: A systematic search was performed using CINAHL, The Cochrane Library (Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials and Cochrane Clinical Answers), EMBASE, PsycINFO, PubMed, Scopus and Web of Science Core Collection from inception to December 2022. It yielded 39 case reports, 6 case series and 1 retrospective study which met the inclusion criteria. RESULTS: Based on the current literature, individuals with 22q11.2DS psychosis experience a greater rate of medical co-morbidities such as cardiac arrhythmias, seizures and movement disorders, which complicate pharmacotherapy. Poor tolerability rather than poor clinical response motivates the switching of antipsychotics, which may explain the labelling of treatment resistance in the literature. CONCLUSION: There are insufficient data to recommend a single antipsychotic for 22q11.2DS psychosis. Nonetheless, with proactive management of co-morbidities, antipsychotic medication in 22q11.2DS psychosis is an effective treatment commonly resulting in improvement in quality of life.

A novel drive-through approach to vaccination of children and young people with neurodevelopmental disability.

Disparities in preventative health care likely contribute to comorbidities associated with neurodevelopmental disability. These comorbidities are risk factors for poor outcomes of COVID-19, making COVID-19 vaccination a priority for this population. In mid-2021, the Australian Technical Advisory Group (ATAGI) recommended the COVID-19 vaccination rollout include children and young people at risk of severe COVID-19 associated disease. This cohort included children/young people severely immunocompromised, with disability, and/or complex, multiple health conditions. Children and young people with neurodevelopmental disability can be challenging to vaccinate in conventional clinic environments and may experience exacerbation of behaviours posing barriers to vaccination. Remaining unvaccinated for COVID-19 increased risk of secondary complications and affected access to carers and respite facilities. This paper describes a novel, individualised approach to safe vaccination for this cohort. In consultation with stakeholders, a drive-through clinic vaccination model was developed and implemented for children/young people with neurodevelopmental disability. The model prioritised person-centred care and minimised triggering factors experienced in community clinics. Data were collected on successfully administered vaccine doses; administration safety and adverse events following immunisation. Parents/carers and staff provided reflective feedback. Twenty-four children and young people used the model with successful vaccination rate of 96% (n = 23). Most patients received multiple doses through the clinic (n = 16). Some patients were vaccinated after unsuccessful attempts elsewhere. Feedback from carers and staff was positive and no adverse events were reported. This model is generalisable to other health services and may be applied to other vaccinations for people of all ages with neurodevelopmental disabilities.

Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.

Longitudinal change in sleep, functional, and behavioural characteristics in a cohort of children with Down syndrome.

This paper describes the longitudinal change in sleep, functional, and behavioural characteristics in a cohort of children with Down syndrome, including the effect of sleep interventions in a subset. A prospective longitudinal cohort study was undertaken in children with Down syndrome aged 3-16 years comparing (1) children referred to a tertiary sleep medicine clinic who received sleep hygiene advice and an additional sleep treatment (DSref_I) with (2) children attending the same clinic who only received sleep hygiene advice (DSref_N) and (3) children recruited from the community who, were not receiving any treatment (DScomm). Data collected included demographic and medical history information, Child Sleep Habits Questionnaire-Abbreviated (CSHQ-A), Life-Habits Questionnaire (Life-H) and Child Behaviour Checklist (CBCL) at baseline and then 6-monthly for a total of 18 months. Any sleep interventions during this time were recorded. A total of 57 children were included (DSref_I, n = 16; DSref_N, n = 25; DScomm, n = 16). At recruitment, the median CSHQ-A total score was high (>41) in all three subgroups, but highest in the DSref_I subgroup (median [interquartile range] Dsref_I score 58 [53-66] versus DSref_N score 49 [43-53], p = 0.019). Although improved, 80% of participants in the DSref_I subgroup still had a CSHQ-A total score >41 at the last assessment point. The median total Life-H and total CBCL scores were not significantly different between groups at baseline and there was no significant time, group, or interaction effect seen through the study. Over an 18-month period, sleep problems were seen to persist in children with Down syndrome. Treatment resulted in only modest improvements in sleep.

Specialist care of children with complex needs: Insights from comparison of child development and child mental health clinics.

AIM: Paediatricians and child psychiatrists review children with complex comorbidity, noting similarities between tertiary Child Development Service (CDS) and Child and Youth Mental Health Service (CYMHS) cohorts. Mental health comorbidity is common in developmental services. Developmental comorbidity in mental health cohorts is uncharacterised. The study aimed to describe CDS and CYMHS cohorts using measures of child development, mental health, physical health and psychosocial risk. METHODS: A questionnaire was completed by parents of CDS and CYMHS new clients aged 4-11. It included measures of mental health symptoms, child development, physical health, stressful life events, family functioning, parent mental health and socio-economic variables. Sample rates were compared to population norms. CDS and CYMHS cohorts were compared. RESULTS: The study population had elevated rates of psychosocial risk, family dysfunction, physical illness, developmental risk and mental health symptoms. CDS had higher levels of developmental risk and family dysfunction. Most CDS clients (81%) had mental health difficulties. CYMHS clients were older, and had more mental health symptoms, stressful life events and child safety contact; 81% of CYMHS clients demonstrated developmental risk. CDS and CYMHS had similar socio-demographic profiles and parent mental health difficulties, and similarly high rates of physical health problems. CONCLUSIONS: Consideration should be given to mental health screening and support in CDS, and to developmental screening in CYMHS. Both services support at-risk children with complex developmental, mental health and physical co-morbidity necessitating shared approaches to clinical and population health, including care integration, and collaborative cross-disciplinary models of service provision and training, and advocacy.

Cognitive parameters in children with mild obstructive sleep disordered breathing.

PURPOSE: Sleep disordered breathing (SDB) in children is commonly described as a continuum from primary snoring (PS) to obstructive sleep apnea (OSA), based on apnea indices from polysomnography (PSG). This study evaluated the difference in neurocognitive and behavioral parameters, prior to treatment, in symptomatic pre-school children with PSG-diagnosed OSA and PS. METHODS: All children had positive Pediatric Sleep Questionnaire (PSQ) results and were deemed suitable for adenotonsillectomy by an ENT surgeon. Neurocognitive and behavioral data were analyzed in pre-school children at recruitment for the POSTA study (The Pre-School OSA Tonsillectomy Adenoidectomy Study). Data were compared between PS and OSA groups, with Obstructive Apnea-Hypopnea Index, OAHI < 1/h or 1-10/h, respectively. RESULTS: Ninety-one children were enrolled, including 52 with OSA and 39 with PS. Distribution of IQ (using Brief Intellectual Ability, BIA) was slightly skewed towards higher values compared with the reference population. No significant differences were found in neurocognitive or behavioral parameters for children with OSA versus those with PS. DISCUSSION: Neurocognitive and behavioral parameters were similar in pre-school children symptomatic for OSA, regardless of whether or not PSG diagnosed PS or OSA. Despite having identical symptoms, children with PS on PSG are often treated conservatively, whereas those with OSA on PSG are considered for adenotonsillectomy. This study demonstrates that, regardless of whether or not PS or OSA is diagnosed on PSG, symptoms, neurocognition, and behavior are identical in these groups. We conclude that symptoms and behavioral disturbances should be considered in addition to OAHI when determining the need for treatment. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials registration number ACTRN12611000021976.

Correction: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Parent perceptions, beliefs, and fears around genetic treatments and cures for children with Angelman syndrome.

Genetic therapies have shown recent promise in alleviating some of the cognitive issues associated with some genetic disorders; however, these therapies may come with significant health and socio-ethical concerns, particularly when they involve child participants. Little is known about what parents of children with genetic disorders think about genetic therapies, or about their knowledge of how genetic-based therapy might treat their child's symptoms. Forty-two parents of children with Angelman syndrome (AS) and 27 parents of a mixed etiology comparison group completed an online survey reporting on their perceptions of, and priorities for, genetic therapy. Almost all parents of children with AS (95%) and the comparison group (89%) agreed that treatments aiming to reduce symptoms associated with their child's syndrome were positive. However, significantly more parents of children with AS (95%) than the comparison group (56%) felt that genetic treatment trials aiming to "cure" their child should be a research priority. AS parent priorities for the focus of clinical trials were neurology/seizures, communication skills, and motor skills/mobility. For the comparison group, the priorities were IQ, immune response, and expressive speech. Parents of both groups did not want treatments to change their child's personality or their happiness. Global assumptions cannot be made about targets for therapy between syndromes, about parental understanding of genetics, or about research evidence across syndromes. This study highlights the need for true family and patient engagement in all stages of the research design and treatment evaluation.

Neurodevelopmental and health-related quality-of-life outcomes in adolescence after surgery for congenital heart disease in infancy.

AIM: To assess outcomes in adolescence after surgery for congenital heart disease (CHD) in infancy. Domains analysed included cognition and executive function, social and emotional well-being, adaptive behaviour, academic achievement, and health-related quality of life (HRQoL). METHOD: Twenty-one participants (10 males, 11 females) ranged in age from 14 to 17 years (mean 15y 4.8mo, SD 8.4mo). Twenty had biventricular repairs. All were classified as New York Heart Association class I. Measures included: Wechsler Intelligence and Achievement scales; Wide Range Assessment of Memory and Learning, Second Edition; California Verbal Learning Test - Children's Version; Behaviour Rating Inventory of Executive Function; Conners, Third Edition; Adaptive Behavior Assessment System, Second Edition; Behavior Assessment System for Children, Second Edition; Rey-Osterrieth Complex Figure; and Pediatric Quality of Life Inventory. RESULTS: Outcomes were significantly lower (p≤0.01) than population norms for processing speed, mathematical achievement, attention, and visual-spatial ability. Participants reported more frequent learning problems but more positive family relations. HRQoL was significantly lower across most domains by self- and parent-proxy report. INTERPRETATION: Individuals with CHD may experience difficulties across a range of domains. These findings emphasize the importance of comprehensive screening, early intervention, and long-term follow-up, as deficits may extend into young adulthood. WHAT THIS PAPER ADDS: Identified cognitive, learning, and attentional impairments in adolescents after congenital heart disease surgery in infancy. Combined self-report, caregiver report, and laboratory tasks in a comprehensive neurodevelopmental assessment protocol. Health-related quality of life was lower across most domains.

Congenital Heart Disease Long-term Improvement in Functional hEalth (CHD LIFE): A partnership programme to improve the long-term functional health of children with congenital heart disease in Queensland.

Children who undergo open-heart surgery in the first year of life for congenital heart disease (CHD) are at high-risk for impaired development across multiple domains. International recommendations include systematic periodic developmental surveillance into adolescence and the establishment of long-term follow-up programmes. This article describes the establishment and evolution of the Queensland Paediatric Cardiac Service neurodevelopmental follow-up programme - CHD LIFE (Long-term Improvement in Functional hEalth). Contextualising best practice recommendations to ensure a family-centred and sustainable approach to understand and support the long-term functional health needs of high-risk children with CHD as standard care was needed. We describe the transition from a centralised pilot Programme to the implementation of an integrated statewide approach aimed at delivering consistent high-level standards of care and a platform to evaluate therapeutic interventions.

A systematic review of the effectiveness of sleep hygiene in children with ADHD.

Attention deficit/hyperactivity disorder (ADHD) is often accompanied by sleep problems in children. Sleep hygiene is defined as a set of behavioural, environmental, or cognitive modifications to improve sleep, and is routinely clinically utilised as first-line treatment for insomnia in ADHD. The objective of this systematic review of the literature is to evaluate the effectiveness of sleep hygiene interventions for sleep difficulties in children with ADHD. Sixteen relevant articles met the inclusion criteria, involving 1,469 participants, with a mean age of 9.6 years, across 6 countries. Fifteen studies found that sleep hygiene interventions were effective in improving sleep, while one did not show any significant improvement. Definite conclusions on the effectiveness of the interventions are difficult to draw due to the limited number of studies and a high risk of bias. There is growing evidence to support the use of sleep hygiene interventions to improve sleep quality in children with ADHD and sleep disturbance. However, well-conducted clinical trials are required to strengthen the evidence.

KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Expanding the phenotype of intellectual disability caused by HIVEP2 variants.

De novo pathogenic variants in the human immunodeficiency virus enhancer type I binding protein 2 (HIVEP2) gene, a large transcription factor predominantly expressed in the brain have previously been associated with intellectual disability (ID) and dysmorphic features in nine patients. We describe the phenotype and genotype of two additional patients with novel de novo pathogenic HIVEP2 variants, who have previously unreported features, including hyperphagia and Angelman-like features. Exome sequencing was utilized in the investigation of the patients who had previously incurred a rigorous genetic workup for their neurodevelopmental delay, and in whom no genetic cause had been detected. Information pertaining to phenotype and genotype for new patients was collated along with data from previous reports, showing that the phenotypic spectrum of patients with HIVEP2 variants is broader than first noted. Additional characteristics are: an increased body mass index; and features of Angelman-like syndromes including: ID, limited speech, post-natal microcephaly, and hypotonia. Dysmorphic features vary between patients. As yet, no clear association between the type of gene aberration and phenotype can be concluded. HIVEP2-related ID needs to be considered in the differential diagnosis of patients with Angelman-like phenotypes and hyperphagia, and whole-exome sequencing should be considered in the genetic diagnostic armamentarium for patients with ID of inconclusive etiology.

Impact of a behavioral intervention, delivered by pediatricians or psychologists, on sleep problems in children with ADHD: a cluster-randomized, translational trial.

BACKGROUND: We have demonstrated the efficacy of a brief behavioral intervention for sleep in children with ADHD in a previous randomized controlled trial and now aim to examine whether this intervention is effective and cost-effective when delivered by pediatricians or psychologists in community settings. METHODS: Translational, cluster-randomized trial of a behavioral intervention versus usual care from 19th January, 2015 to 30th June, 2017. Participants (n = 361) were children aged 5-13 years with ADHD and parent report of a moderate/severe sleep problem who met criteria for American Academy of Sleep Medicine criteria for chronic insomnia disorder, delayed sleep-wake phase disorder, or were experiencing sleep-related anxiety. Participants were randomized at the level of the pediatrician (n = 61) to intervention (n = 183) or usual care (n = 178). Families in the intervention group received two consultations with a pediatrician or a psychologist covering sleep hygiene and tailored behavioral strategies. RESULTS: In an intention-to-treat analysis, at 3 and 6 months respectively, the proportion of children with moderate to severe sleep problems was lower in the intervention (28.0%, 35.8%) compared with usual care group (55.4%, 60.1%; 3 month: risk ratio (RR): 0.51, 95% CI 0.37, 0.70, p < .001; 6 month: RR: 0.58; 95% CI 0.45, 0.76, p < .001). Intervention children had improvements across multiple Children's Sleep Habits Questionnaire subscales at 3 and 6 months. No benefits of the intervention were observed in other domains. Cost-effectiveness of the intervention was AUD 13 per percentage point reduction in child sleep problem at 3 months. CONCLUSIONS: A low-cost brief behavioral sleep intervention is effective in improving sleep problems when delivered by community clinicians. Greater sample comorbidity, lower intervention dose or insufficient clinician supervisions may have contributed to the lack benefits seen in our previous trial.

Defining short and long sleep duration for future paediatric research: A systematic literature review.

Short and long sleep patterns in children have been associated with a range of poor health outcomes. However, there is no consensus regarding the definitions of these abnormal sleep parameters in childhood for use in paediatric research. Given that there is a clear lack of definitions for sleep duration throughout paediatric sleep literature, this review aimed to establish recommendations for standard cut-offs of short and long sleep for children aged 1-16 years to enable homogeneity in future studies of paediatric sleep duration. Four databases were systematically searched to identify prospective studies that defined short or long sleep patterns in children. Included papers (38) were assessed for methodological quality, and their definitions were extracted to examine the current applied cut-offs in the literature for short or long sleep duration. The definitions were analysed in a regression model to summarize applied cut-offs from subjective data into cut-offs for short and long sleep duration. These models were fitted to reference values of three commonly cited paediatric population studies to establish new definitions of sleep duration for future use in research. Across the age groups there was little consensus in applied cut-offs for short and long sleep duration. This study found the best compromise for short sleep was defined as the 2.5th centile (hours = 0.25*age + 11) and long sleep as the 97.5th centile (hours = 0.017*age2  - 0.68*age + 16) of sleep duration in children. Recommendations for the hourly cut-offs of short and long sleep duration based on these percentiles were described.

Study protocol for the Australian autism biobank: an international resource to advance autism discovery research.

BACKGROUND: The phenotypic and genetic heterogeneity of autism spectrum disorder (ASD) presents considerable challenges in understanding etiological pathways, selecting effective therapies, providing genetic counselling, and predicting clinical outcomes. With advances in genetic and biological research alongside rapid-pace technological innovations, there is an increasing imperative to access large, representative, and diverse cohorts to advance knowledge of ASD. To date, there has not been any single collective effort towards a similar resource in Australia, which has its own unique ethnic and cultural diversity. The Australian Autism Biobank was initiated by the Cooperative Research Centre for Living with Autism (Autism CRC) to establish a large-scale repository of biological samples and detailed clinical information about children diagnosed with ASD to facilitate future discovery research. METHODS: The primary group of participants were children with a confirmed diagnosis of ASD, aged between 2 and 17 years, recruited through four sites in Australia. No exclusion criteria regarding language level, cognitive ability, or comorbid conditions were applied to ensure a representative cohort was recruited. Both biological parents and siblings were invited to participate, along with children without a diagnosis of ASD, and children who had been queried for an ASD diagnosis but did not meet diagnostic criteria. All children completed cognitive assessments, with probands and parents completing additional assessments measuring ASD symptomatology. Parents completed questionnaires about their child's medical history and early development. Physical measurements and biological samples (blood, stool, urine, and hair) were collected from children, and physical measurements and blood samples were collected from parents. Samples were sent to a central processing site and placed into long-term storage. DISCUSSION: The establishment of this biobank is a valuable international resource incorporating detailed clinical and biological information that will help accelerate the pace of ASD discovery research. Recruitment into this study has also supported the feasibility of large-scale biological sample collection in children diagnosed with ASD with comprehensive phenotyping across a wide range of ages, intellectual abilities, and levels of adaptive functioning. This biological and clinical resource will be open to data access requests from national and international researchers to support future discovery research that will benefit the autistic community.

Sleep in children with neurodevelopmental difficulties.

Sleep disorders in children with neurodevelopmental disorders are complex and reflect underlying genetic/biological and behavioural components. The sleep disorders are the same as in the typically developing child, although there may be some modifications to the presentation or the frequency depending on the phenotype. Consideration of the known phenotypes and environmental issues are important in defining management strategies. Despite this complexity, defined behavioural strategies with good sleep hygiene can have a significant effect on the sleep problem and on parental management of the behaviours.

Health-related quality of life in 22q11.2 deletion syndrome: The child's perspective.

AIM: The 22q11.2 deletion syndrome (22qDS) is a genetic syndrome that results in a complex physical, behavioural and psychological phenotype. Health-related quality of life (HRQOL) is an established clinical outcome that has been minimally studied in children with 22qDS. The purpose of this study was to explore HRQOL among children and adolescents with 22qDS from the perspective of the child and to determine how their HRQOL measures compare to those of a healthy peer group and a chronic disease peer group. METHODS: We recruited individuals between the ages of 8 and 18 with a positive genetic diagnosis of 22qDS (n = 28) and a parent of the child. Participants completed the paired Paediatric Quality of Life Inventory 4.0 questionnaires. Comparisons were made with a previous study of healthy and diseased children. RESULTS: Children with 22qDS had a significantly poorer HRQOL when compared to age-matched cohorts of healthy children and children with chronic disease. Within the study, there was variable proxy-self agreement, and children with 22qDS reported lower HRQOL than adolescents with 22qDS. CONCLUSION: This study is the first to explore HRQOL from the perspective of the child with 22qDS, and our findings support the existing literature that this condition is associated with a poor HRQOL.