The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools.

The use of antidepressants during pregnancy benefits the mother's well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepressants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids - self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale transcriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids.

Association of Growth During Infancy with Neurodevelopment and Obesity in Children Born Very Preterm: The Environmental Influences on Child Health Outcomes Cohort.

OBJECTIVE: To evaluate associations between change in weight z score after neonatal intensive care unit (NICU) discharge and neurodevelopmental outcomes and obesity at 12-48 months of age among individuals born very preterm. STUDY DESIGN: This secondary analysis used data from infants born very preterm participating in the Environmental influences on Child Health Outcomes cohort (n = 1400). Growth during infancy was calculated as change in weight z score between NICU discharge and follow-up at a mean of 27 months of age. Very low weight gain was defined as a change in weight z score <-1.67; very high weight gain was a change in weight z score >1.67. Neurodevelopmental outcomes included the Bayley Scales of Infant and Toddler Development, Child Behavior Checklist 1.5-5 years, and Modified Checklist for Autism in Toddlers. Multivariable linear regression was used to estimate associations between increase in weight z score and neurodevelopmental outcomes. RESULTS: Very low weight gain between NICU discharge and follow-up (experienced by 6.4% of participants) was associated with lower scores on cognitive (adjusted mean difference: -4.26; 95% CI: -8.55, -0.04) and language (adjusted mean difference: -4.80; 95% CI: -9.70, -0.11) assessments. Very high weight gain (experienced by 13.6% of participants) was associated with an increased obesity risk (adjusted relative risk: 6.20; 95% CI: 3.99, 9.66) but not with neurodevelopmental outcomes. CONCLUSIONS: Very high weight gain in the first 12-48 months after NICU discharge was associated with a higher risk of obesity at follow-up; very low weight gain was associated with lower scores on cognitive and language assessments.

Emerging drugs for the treatment of irritability associated with autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

Folic acid and autism: updated evidences.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that impairs communication, socialization, and behavior. The association of ASD with folic acid has been investigated due to the importance of this vitamin for neurological health. This study is an update of the publication 'Folic acid and autism: What do we know?' and aims to systematically review studies examining the relationship between folic acid and ASD. The search resulted in 2,389 studies on folic acid and ASD, which were selected by two reviewers based on their titles and abstracts. Studies meeting the inclusion criteria were fully read. The 52 included studies involved 10,429 individuals diagnosed with ASD and assessed the intake of vitamin B6, folic acid, and vitamin B12; serum levels of these vitamins, homocysteine, and methionine; therapeutic interventions using folic acid; and the association between maternal exposure to this vitamin and the risk of ASD. The evidence of insufficient folic acid intake in most individuals with ASD remains consistent in this update. No association was found between maternal exposure to folic acid and the risk of ASD in their children. Despite observed improvements in communication, socialization, and behavior in individuals with ASD following folic acid interventions, it is crucial to consider the individuality and complexity of ASD. Given the relevance of the topic, there remains a need for more high-quality research and clinical trials characterized by rigorous methodological designs.

Affiliate Stigma, Resilience and Quality of Life among Parents of Children with Autism Spectrum Disorder in Two Public Hospitals in Kelantan, Malaysia.

Background: Often, the indirect impact of autism spectrum disorder (ASD) presents the family with significant challenges. One of these challenges is affiliate stigma due to parental affiliation with their child. This study aimed to explore affiliate stigma, resilience and quality of life (QoL) among parents of children with ASD. Methods: Cross-sectional study of 144 parents of children with ASD were recruited from two main tertiary hospitals in Kelantan, Malaysia, a developing country in Southeast Asia. Pearson correlation was used to examine the relationship between parental affiliate stigma, resilience and QoL. Simple and multiple linear regression analyses were used to identify the significant associated factors of affiliate stigma, resilience and QoL. Results: Correlational analyses revealed that perceived affiliate stigma demonstrated an inverse relationship with resilience and QoL. Additionally, resilience had a positive relationship with QoL. Regression analyses revealed that the father's employment status, the mother's level of education, having a disability card, the child's age at ASD diagnosis, comorbidities of the child and ASD severity perceived by parents were associated with parental affiliate stigma, resilience and QoL. Conclusion: Study findings highlight the contribution of socio-demographic characteristics of children with ASD and their families in the determination of affiliate stigma, resilience and QoL.

Biallelic variants in the SLC13A1 sulfate transporter gene cause hyposulfatemia with a mild spondylo-epi-metaphyseal dysplasia.

Sulfate is the fourth most abundant anion in human plasma but is not measured in clinical practice and little is known about the consequences of sulfate deficiency. Nevertheless, sulfation plays an essential role in the modulation of numerous compounds, including proteoglycans and steroids. We report the first patient with a homozygous loss-of-function variant in the SLC13A1 gene, encoding a renal and intestinal sulfate transporter, which is essential for maintaining plasma sulfate levels. The homozygous (Arg12Ter) variant in SLC13A1 was found by exome sequencing performed in a patient with unexplained skeletal dysplasia. The main clinical features were enlargement of joints and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. In addition, autistic features were noted. We found profound hyposulfatemia due to complete loss of renal sulfate reabsorption. Cholesterol sulfate was reduced. Intravenous N-acetylcysteine administration temporarily restored plasma sulfate levels. We conclude that loss of the SLC13A1 gene leads to profound hypersulfaturia and hyposulfatemia, which is mainly associated with abnormal skeletal development, possibly predisposing to degenerative bone and joint disease. The diagnosis might be easily missed and more frequent.

Relationship between caregiver adverse childhood events and age of autism spectrum diagnosis.

BACKGROUND: The age at which children are diagnosed with autism spectrum disorder (ASD) has not significantly decreased in the past 20 years. Adverse childhood events (ACEs) experienced by caregivers of autistic children may predict delays in caregivers attending ASD diagnostic evaluations, negatively impacting the age at which the child is diagnosed with ASD. The purpose of this study was to further explore the caregiver delay response by analyzing recurring events common in caregivers of children at risk for ASD. METHODS: We used a quantitative research design with convenience sampling to categorize caregivers of children referred for an ASD diagnostic evaluation into three groups based on their ACEs score and medical history. FINDINGS: A higher percentage of caregivers with four or more ACEs compared to the national average was noted. Parental separation or divorce, verbal aggression, emotional abuse, and parental alcohol or substance abuse occurred most frequently, and the latter predicted a prolonged time in attending the diagnostic evaluation. DISCUSSION: ACEs experienced by caregivers of children with ASD may delay the age of ASD diagnosis. Further investigation into the effect of ACEs on caregivers' mental health status and executive functioning is warranted to develop best practice for assisting caregivers in ASD recognition, diagnosis, and care management. APPLICATION TO PRACTICE: Clinicians should consider caregiver ACEs score when referring a child for a diagnostic developmental evaluation. Resources to address caregiver mental health needs should be provided at the onset of the referral process to increase the likelihood of caregiver adherence.

Excessive audio-visual stimulation leads to impaired social behaviour with an effect on amygdala: Early life excessive exposure to digital devices in male rats.

Today, the effect of extreme early-life exposure to digital devices is suggested as a risk factor for neurodevelopmental disorders. However, the multitude of factors that influence brain development with subsequent behavioural abnormalities have not been fully elucidated. Herein, we simulated extreme early-life exposure to digital devices in rats by audio and visual stimulation and investigated its effects on autism-related behaviours and brain structural alteration. Male rat pups were exposed to excessive audio-visual stimulation (EAVS) from PND (post-natal day) 12 to PND 35, with and without maternal separation (MS). Autism-related behaviours including abnormal sociability, stereotype behaviours, anxiety and locomotor dysfunction were tested at PND 42. Brain structural alternation was examined by considering the amygdala, mPFC (medial prefrontal cortex) and hippocampal regions while performing 3D quantitative stereological analysis. We found that EAVS led to social behaviour deficit and higher locomotion in rats, which were associated with increases in the number of neurons and volume of the amygdala. We also showed that MS did not exaggerate the effect of extreme sensory stimulation on behaviour and the structure of the brain. This study proposed EAVS in rats as an animal model of early exposure to digital devices for investigating possible neurobiological alternations underlying autistic-like behaviours with an emphasis on the amygdala area.

Oral health and dental caries experience among students aged 7-15 years old with autism spectrum disorders in Tehran, Iran.

BACKGROUND: Autism spectrum disorders (ASD) are a set of developmental, psychological, and neurological disorders that occur in early childhood. The most important characteristic of individuals with autism is difficulty in social interactions and communication. Researchers in the field of oral health have not paid enough attention to these individuals due to their specific behavioral characteristics. Therefore, due to the limitations of the studies in this field in Iran, increasing prevalence of autism, and importance of oral health in people with ASD, this study was conducted to evaluate the oral health status of primary school students with autism (7-15 years old) in autism schools in Tehran. METHODS: Students from seven governmental special primary schools in Tehran were selected for this study. Data about oral health behavior and the presence of each of the seven barriers of tooth brushing task was collected via questionnaires completed by parents. During the dental examination, the cooperation level according to the Frankle Index, oral hygiene status according to the Simplified Oral Hygiene Index, and caries experience (DMFT) of the students were recorded by a calibrated dentist. A psychologist assessed the level of ASD using the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM5). Data analysis including descriptive and regression analysis was done using the SPSS software version 24. RESULTS: Two hundred and seventeen students aged 7-15 years participated in this study, of whom 65.4% brushed their teeth once or more every day, 85.7% had sugary snacks twice or less per day, 73.7% used fluoridated tooth paste, and 80% brushed their teeth with parents' help. The most common barrier to tooth brushing was difficulty in brushing (51.6%). The cooperation level was definitely positive in 46.1%. The mean Simplified Oral Hygiene Index (OHI-S) and caries experience (DMFT) scores were 1.92 ± 0.55 and 2.36 ± 2.38, respectively. CONCLUSION: The clinical indices of OHI-S and caries experience (DMFT) were used to evaluate the oral health status in the students with ASD in Tehran, Iran. A better oral hygiene status was related to higher brushing frequency and lower sweet snack consumption. The findings of the present study indicate that educational interventions regarding oral hygiene and healthy diet may improve oral self-care in individuals with ASD.

Malocclusion characteristics amongst individuals with autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: To estimate the prevalence of malocclusion in individuals with autism spectrum disorders (ASD) and to assess the relationship between ASD and malocclusion. METHODS: We searched electronic databases including PubMed, Scopus, Web of Science, Cochrane, Embase, SciELO LILACS, Proquest, OpenGrey and Google Scholar. There were no language or publication dates restrictions. Two researchers independently performed selection, data extraction and quality assessment. Quality assessment and risk of bias were evaluated through the Newcastle-Ottawa scale and ROBINS-E tool. Meta-analyses using random effect models were used to estimate pooled measures of prevalence of malocclusion characteristics in individuals with ASD and pooled odds ratio (OR) on the relationship between ASD and malocclusion characteristics. Subgroup meta-analyses were conducted according to children and adolescents, history of orthodontic treatment, and occurrence of other syndromes and medical conditions. RESULTS: Searching identified 5549 papers with 238 were selected for full assessment. Eighteen cross-sectional studies were included according to inclusion criteria. Of them, eleven studies were considered of moderate quality. A judgement of critical risk of bias occurred for thirteen studies. The most prevalent malocclusion characteristics in individuals with ASD were crowding (33%; 95% CI 22 to 44%) and increased maxillary overjet (39%; 95% CI 23 to 54%). Individuals with ASD had higher odds of Angle's Class II (OR 1.92; 95% CI 1.36 to 2.72), Angle's Class III (OR 2.33; 95% CI 1.29 to 4.23), open bite (OR 1.96; 95% CI 1.21 to 3.16), and increased maxillary overjet (OR 1.53; 95% CI 1.06 to 2.21) than individuals without ASD. CONCLUSIONS: Angle's Class II, Angle's Class III, anterior open bite and increased maxillary overjet were more prevalent in individuals with ASD than those without ASD. Further high-quality studies are needed.

Outcomes of assistance dog placement in the home for individuals with autism spectrum disorder and their families: A pilot study.

INTRODUCTION: Evidence indicates that assistance dogs placed in the home are effective in supporting individuals with Autism Spectrum Disorder (ASD) by increasing social and community participation and promoting quality of life. This study aimed to examine the outcomes of assistance dog placement on quality of life, independence, and participation of families including individuals with ASD placed with an assistance dog compared to families on the waiting list for an autism assistance dog and to evaluate the feasibility of the design for future studies. METHODS: A cross-sectional comparative study was conducted. The Adaptive Behaviour Analysis System, Social Responsiveness Scale, Autism Treatment Evaluation Checklist, Canadian Occupational Performance Measure, and Autism Family Experience Questionnaire were used to evaluate adaptive skills, behaviour, social difficulties, daily functioning, and family quality of life. RESULTS: Six families who had an autism assistance dog placed with them, and 12 families who were on the waiting list were recruited using purposeful sampling. The pilot data found no significant differences between the two groups. However, trends were observed which suggested that assistance dogs can increase desired social behaviours, decrease ASD severity, and improve family wellbeing. For families with an assistance dog, more positive outcomes were observed for families who were partnered with an assistance dog for longer. Parents (and sometimes individuals with ASD) were able to complete and return the outcome measures via mail to collect the outcome data for the study. CONCLUSION: These study findings add to the developing evidence about the use of assistance dogs with this population. A larger sample size may have allowed for significant associations to be detected. The methods used were feasible to be applied in a larger study. These results may assist health professionals advocate for funding for assistance dog placement to individuals with ASD and their families.

Where are they now? An autism follow-up study.

AIM: To explore the stability of diagnosis and the relationship between behavioural, adaptive and developmental skills in early to middle childhood in children with autism spectrum disorder (ASD). METHODS: Fifty-four children recruited to the study were diagnosed with ASD before 42 months. Outcomes at follow-up after a mean interval of 64 months were measured using the Autism Diagnostic Observation Schedule, Vineland-II adaptive scale and Wechsler Intelligence Scale for Children and parental survey data. Scores before school were compared with follow-up data through descriptive, correlational and multiple regression analyses. RESULTS: ASD was confirmed in all children at follow-up (mean age 10 years). Fifty-eight percent of children were enrolled in a supported educational class or school and 42% were taking a psychotropic medication. Adaptive function improved significantly in 19% of children. Developmental and adaptive behavioural scores before school correlated with cognitive, behaviour and adaptive assessments at follow-up. CONCLUSION: At follow-up, the diagnosis was confirmed in all children. The children showed gains in their adaptive skills but and many required ongoing educational and behavioural support. Early developmental and adaptive assessments reliably predicted later educational support needs, cognitive and adaptive function and are a useful component of a diagnostic assessment.

Parents' experiences of accessing respite care for children with Autism Spectrum Disorder (ASD) at the acute and primary care interface: a systematic review.

BACKGROUND: Population prevalence estimates by the World Health Organisation suggest that 1 in 160 children worldwide has an Autism Spectrum Disorder (ASD). Accessing respite care services for children with an ASD can often be a daunting and exhaustive process, with parents sometimes forced to access acute hospital services as an initial point of contact for respite care or in a crisis situation. To gain an in-depth understanding of accessing respite care for children with an ASD, from the perspectives of parents, a systematic review of the evidence on parent's experiences and views of respite care for children with an ASD at the acute and primary interface was undertaken. METHODS: Pubmed, Embase, CINAHL and PsycINFO were systematically searched. Studies identified as relevant based on predetermined eligibility criteria were selected for inclusion. The search strategy also targeted unpublished studies and grey literature. Qualitative data and qualitative components of mixed method studies that represented the experiences of parents accessing respite care for children with an ASD were eligible for inclusion. A meta-aggregative approach was used during data synthesis. RESULTS: Database searching elicited 430 records of which 291 studies remained after removal of duplicates. These 291 studies were screened for title and abstract by two reviewers resulting in 31 studies to be screened at full text and assessed for eligibility. Six studies met the inclusion criteria and a further additional study also met the inclusion criteria during a manual search. As a result, 7 studies were selected for the review as set out in Fig. 1. CONCLUSION: In the absence of appropriate services and defined pathways to support services such as respite care, overwhelmed parents and community providers of mental health resources may not be in a position to meet the specific needs of children with an ASD and their families which may be contributing to a direct increase in hospitalizations. This systematic review identified a number of barriers to respite care, of which the findings can be used to inform future service development and further research. Knowledge of parental experiences in caring for a child with an ASD is vital in addressing the need and type of respite care required for children with an ASD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018106629.

Adapting parent engagement strategies for an evidence-based parent-mediated intervention for young children at risk for autism spectrum disorder.

AIMS: Aims included (a) characterizing provider feedback on parent engagement strategies integrated into a parent-mediated intervention for toddlers at risk for autism spectrum disorder (ASD) and (b) identifying provider characteristics that predict attitudes about parent engagement strategies. METHODS: A mixed method approach was utilized, including gathering quantitative data via survey (breadth) and collecting qualitative data via interview (depth). Acceptability, utility, appropriateness, sustainment, generalizability, and perceived effectiveness were examined. Fourteen agency leaders and 24 therapists provided input. RESULTS: Providers perceived the integration of parent engagement strategies as having a positive impact on implementation. Providers considered the strategies to be acceptable, appropriate, and effective, though barriers of time and complexity were noted. Provider characteristics did not consistently predict attitudes about the engagement strategies. CONCLUSIONS: Incorporating parent engagement strategies into parent-mediated interventions for ASD is well-received by providers and may improve quality of service delivery for families served in early intervention for ASD.

Stress and coping strategies for parenting children with hearing impairment and autism.

OBJECTIVES: To determine the level of stress experienced and coping strategies used by parents of hearing impaired and autistic children. METHODS: Using non-probability convenience sampling this cross sectional study recruited n =200 parents of hearing impaired (HI) and 100 parents of autistic children, of either gender, aged 20 to 60 years. Samples were recruited from Special Education Institutes of Islamabad and Rawalpindi, over a period of six months, from October 2018 to March 2019 and conducted at Isra Institute of Rehabilitation Sciences, Islamabad. Basic demographical sheet, Parental Stress Scale and Coping Strategies Inventory were used for data collection. Statistical analysis was done using SPSS 21. RESULTS: In parents of hearing impaired the mean parental stress score was 47.44±12.85 and commonest coping strategy was problem focused engagement (26.03) followed by problem focused dis-engagement (24.25). In the autistic group the mean parental stress score was 48.92+11.22 with problem focused engagement being the most frequently used strategy (27.4) followed by emotion focused strategy. CONCLUSION: Different level of stress experienced by parents of autistic and hearing impaired children which is statistically significant and they employed different coping strategies.

Adult Ube3a Gene Reinstatement Restores the Electrophysiological Deficits of Prefrontal Cortex Layer 5 Neurons in a Mouse Model of Angelman Syndrome.

E3 ubiquitin ligase (UBE3A) levels in the brain need to be tightly regulated, as loss of functional UBE3A protein is responsible for the severe neurodevelopmental disorder Angelman syndrome (AS), whereas increased activity of UBE3A is associated with nonsyndromic autism. Given the role of mPFC in neurodevelopmental disorders including autism, we aimed to identify the functional changes resulting from loss of UBE3A in infralimbic and prelimbic mPFC areas in a mouse model of AS. Whole-cell recordings from layer 5 mPFC pyramidal neurons obtained in brain slices from adult mice of both sexes revealed that loss of UBE3A results in a strong decrease of spontaneous inhibitory transmission and increase of spontaneous excitatory transmission potentially leading to a marked excitation/inhibition imbalance. Additionally, we found that loss of UBE3A led to decreased excitability and increased threshold for action potential of layer 5 fast spiking interneurons without significantly affecting the excitability of pyramidal neurons. Because we previously showed that AS mouse behavioral phenotypes are reversible upon Ube3a gene reactivation during a restricted period of early postnatal development, we investigated whether Ube3a gene reactivation in a fully mature brain could reverse any of the identified physiological deficits. In contrast to our previously reported behavioral findings, restoring UBE3A levels in adult animals fully rescued all the identified physiological deficits of mPFC neurons. Moreover, the kinetics of reversing these synaptic deficits closely followed the reinstatement of UBE3A protein level. Together, these findings show a striking dissociation between the rescue of behavioral and physiological deficits.SIGNIFICANCE STATEMENT Here we describe significant physiological deficits in the mPFC of an Angelman syndrome mouse model. We found a marked change in excitatory/inhibitory balance, as well as decreased excitability of fast spiking interneurons. A promising treatment strategy for Angelman syndrome is aimed at restoring UBE3A expression by activating the paternal UBE3A gene. Here we find that the physiological changes in the mPFC are fully reversible upon gene reactivation, even when the brain is fully mature. This indicates that there is no critical developmental window for reversing the identified physiological deficits in mPFC.

p21 protein-activated kinase 1 is associated with severe regressive autism, and epilepsy.

The p21-activated kinase (PAK) family of proteins function as key effectors of RHO family GTPases in mammalian cells to regulate many pathways including Ras/Raf/MEK/ERK and Wnt/ß-catenin, amongst others. Here we report an individual with a novel autosomal dominant disorder characterized by severe regressive autism, intellectual disability, and epilepsy. Exome sequencing of the proband and her parents revealed a de novo variant in the PAK1 gene ([NM_001128620] c.362C>T/p.Pro121Leu). Studies in patient cells showed a clear effect on PAK1 protein function, including altered phosphorylation of targets (JNK and ERK), decreased abundance of ß-catenin, and concomitant altered expression downstream of these key regulators. Our findings add PAK1 to the list of PAK proteins and kinases which when mutated cause rare genetic diseases.

Prevalence, characteristics, and diabetes management in children with comorbid autism spectrum disorder and type 1 diabetes.

OBJECTIVE: To determine autism spectrum disorder (ASD) prevalence within our pediatric type 1 diabetes (T1D) clinic population and determine clinical characteristics and technology used by individuals with both ASD and T1D compared to matched controls with T1D alone and compared to our overall pediatric T1D clinic. METHODS: Medical chart review showed 30 individuals with both ASD and type 1 diabetes (ASD + T1D). Controls (n = 90) were matched for age, sex, race/ethnicity, and T1D duration. ASD + T1D was compared to both matched controls and the pediatric T1D clinical population. RESULTS: ASD prevalence in the pediatric T1D population was 1.16% (CI 0.96-1.26). Compared to the T1D clinic, ASD + T1D had more males (93% vs 52%; P < 0.0001), lower hemoglobin A1c (HbA1c) (8.2% vs 8.9%; 66 vs 74 mmol/mol; P = 0.006), and lower insulin pump (CSII) use (37% vs 56%; P < 0.0001). No differences were found between ASD + T1D and matched controls in HbA1c or blood glucose checks per day. The ASD + T1D group was less likely to use CSII than matched controls (37% vs 61%; P = 0.03). HbA1c did not change after CSII initiation in ASD + T1D, but increased for matched controls. CONCLUSIONS: Prevalence of ASD in the pediatric T1D population is comparable to the general population in Colorado. Individuals with ASD may experience barriers limiting CSII use, but achieve equivalent glycemic control compared to those without ASD. CSII may be more effective in maintaining lower HbA1c over time in those with ASD than in those without ASD.

Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study.

Autism spectrum disorder (ASD) is associated with physiological abnormalities, including abnormal redox and mitochondrial metabolism. Lymphoblastoid cell lines (LCLs) from some children with ASD exhibit increased oxidative stress, decreased glutathione redox capacity, and highly active mitochondria with increased vulnerability to reactive oxygen species (ROS). Because unaffected siblings (Sibs) of individuals with ASD share some redox abnormalities, we sought to determine whether LCLs from Sibs share ASD-associated mitochondrial abnormalities. We evaluated mitochondrial bioenergetics in 10 sets of LCLs from children with ASD, Sibs, and unrelated/unaffected controls (Cons) after acute increases in ROS. Additionally, intracellular glutathione and uncoupling protein 2 (UCP2) gene expressions were quantified. Compared to Sib LCLs, ASD LCLs exhibited significantly higher ATP-linked respiration, higher maximal and reserve respiratory capacity, and greater glycolysis and glycolytic reserve. ASD LCLs exhibited a significantly greater change in these parameters, with acute increases in ROS compared to both Sib and Con LCLs. Compared to Con, both ASD and Sib LCLs exhibited significantly higher proton leak respiration. Consistent with this, intracellular glutathione redox capacity was decreased and UCP2 gene expression was increased in both ASD and Sib compared to Con LCLs. These data indicate that mitochondrial respiratory function, not abnormal redox homeostasis, distinguishes ASD from unaffected LCLs.-Rose, S., Bennuri, S. C., Wynne, R., Melnyk, S., James, S. J., Frye, R. E. Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study.