1. Amirova A, Rakhymbayeva N, Zhanatkyzy A, Telisheva Z, Sandygulova A. Effects of Parental Involvement in Robot-Assisted Autism Therapy. Journal of autism and developmental disorders. 2022.

Parental involvement in traditional autism therapy is key to the effective treatment of children with ASD. Little is known about parental involvement in robot-assisted autism therapy (RAAT)-novel therapeutic support for children with ASD. Our study investigates the effect of parental presence on multiple-session RAAT conducted with 16 children with ASD. They interacted with the social robot in the presence or absence of their parents. We measured children’s socio-behavioral outcomes and conducted semi-structured interviews with parents. Parents did not necessarily affect the children’s outcomes during the interventions. However, children’s autism-related symptoms resulted in different socio-behavioral outcomes between sessions with and without parents. Most parents have reported positive changes in their children’s behaviors when interacting with the robot.

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2. Aydin A. Examining the Mediating Role of Mindful Parenting: A Study on the Relationship Between Parental Emotion Regulation Difficulties and Problem Behaviors of Children with ASD. Journal of autism and developmental disorders. 2022.

Parental emotion regulation plays a vital role in the parent-child relationship. This study examines the mediating role of mindful parenting in the relationship between parental emotion regulation difficulties and problem behaviors of children with autism spectrum disorder (ASD). The study was conducted with 273 parents of children with ASD in Istanbul. The study findings revealed a significant yet negative correlation between mindful parenting and emotion regulation difficulty and problem behaviors. The study model highlighted that emotion regulation difficulties significantly predicted mindful parenting and the child’s problem behavior, whereas mindful parenting significantly predicted the child’s problem behavior. Additionally, the study findings indicated that mindful parenting was a partial mediator.

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3. Gruber N, Haham LM, Raanani H, Cohen Y, Gabis L, Berkenstadt M, Ries-Levavi L, Elizur S, Pinhas-Hamiel O. Female fragile X premutation carriers are at increased risk for metabolic syndrome from early adulthood. Nutrition, metabolism, and cardiovascular diseases : NMCD. 2022; 32(4): 1010-8.

BACKGROUND AND AIMS: Women with primary ovarian insufficiency exhibit an unfavorable cardiovascular risk profile. A common cause for primary ovarian insufficiency is fragile X premutation (FXPC), and data on the cardiovascular risk factors in women with FXPC are scarce. We aimed to assess the prevalences of abnormal metabolic components among FXPC. METHODS AND RESULTS: Clinical, anthropometric and laboratory data were collected from 71 women with FXPC and compared to 78 women referred for counseling in an in-vitro fertilization clinic (control group). The mean ± SD ages of the FXPC and control groups were 33.5 ± 5.6 and 36.2 ± 5.3 years, respectively (p = 0.003). In a logistic regression analysis, the FXPC group had increased risks for hyperglycemia, hypertriglyceridemia, central obesity and low high-density lipoprotein cholesterol, of 21.8-fold (95% CI 2.7-175, p = 0.004), 6.9-fold (95% CI 2.5-18.7, p < 0.0001), 3.1-fold (95% CI 1.4-6.9, p = 0.005) and 2.4-fold (95% CI 1.1-5.2, p = 0.03), compared to the control group. The FXPC group had 2.7-fold higher prevalence of two abnormal metabolic components; 19% met the full criteria of MetS, compared to 3% of the control group. Neither CGG repeats nor ovarian reserve markers were associated with metabolic risk. CONCLUSIONS: Carriers of fragile X premutation are at increased metabolic risk from early adulthood; waist circumference, glucose and lipid levels are particularly elevated. We recommend metabolic screening for all women with FMR1 premutation, to enable early interventions for prevention of long-term cardiovascular comorbidities.

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4. Han YMY, Chan MC, Chan MMY, Yeung MK, Chan AS. Effects of working memory load on frontal connectivity in children with autism spectrum disorder: a fNIRS study. Scientific reports. 2022; 12(1): 1522.

Individuals with autism spectrum disorder (ASD) perform poorly in working memory (WM) tasks, with some literature suggesting that their impaired performance is modulated by WM load. While some neuroimaging and neurophysiological studies have reported altered functional connectivity during WM processing in individuals with autism, it remains largely unclear whether such alterations are moderated by WM load. The present study aimed to examine the effect of WM load on functional connectivity within the prefrontal cortex (PFC) in ASD using functional near-infrared spectroscopy (fNIRS). Twenty-two children with high-functioning ASD aged 8-12 years and 24 age-, intelligent quotient (IQ)-, sex- and handedness-matched typically developing (TD) children performed a number n-back task with three WM loads (0-back, 1-back, and 2-back). Hemodynamic changes in the bilateral lateral and medial PFC during task performance were monitored using a multichannel NIRS device. Children with ASD demonstrated slower reaction times, specifically during the « low load » condition, than TD children. In addition, the ASD and TD groups exhibited differential load-dependent functional connectivity changes in the lateral and medial PFC of the right but not the left hemisphere. These findings indicate that WM impairment in high-functioning ASD is paralleled by load-dependent alterations in right, but not left, intrahemispheric connectivity during WM processing in children with ASD. A disruption of functional neural connections that support different cognitive processes may underlie poor performance in WM tasks in ASD.

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5. Kong L, Chen X, Liang Y, Forsell Y, Gissler M, Lavebratt C. Association of Preeclampsia and Perinatal Complications With Offspring Neurodevelopmental and Psychiatric Disorders. JAMA network open. 2022; 5(1): e2145719.

IMPORTANCE: Maternal preeclampsia has been reported to increase the risk of autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability in offspring. However, the association between maternal preeclampsia combined with perinatal complications and neurodevelopmental and psychiatric disorders in offspring is less well documented. OBJECTIVE: To examine the association of maternal preeclampsia, separately and together with perinatal complications, with neurodevelopmental and psychiatric disorders in offspring. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used data from nationwide registries in Finland to assess all singleton live births (N = 1 012 723) between January 1, 1996, and December 31, 2014. Offspring were followed up until December 31, 2018 (when the oldest reached age 22 years). Exclusion criteria were maternal inpatient psychiatric diagnoses and pregestational diabetes. The study and data analysis were conducted from May 1, 2020, to June 1, 2021. EXPOSURES: Preeclampsia and perinatal complications (delivery earlier than 34 weeks’ gestation and/or small for gestational age). MAIN OUTCOMES AND MEASURES: The primary outcomes were neurodevelopmental and psychiatric diagnoses and dispensation of psychotropic drugs among offspring until December 31, 2018. Cox proportional hazards regression analyses were performed to assess the associations. RESULTS: Of 1 012 723 singleton live births (51.1% boys; mean [SD] maternal age at birth, 30.0 [5.4] years; specific data on race and ethnicity were not available in the data set), 21 010 children (2.1%) were exposed to preeclampsia alone, 33 625 children (3.3%) were exposed to perinatal complications alone, and 4891 children (0.5%) were exposed to both preeclampsia and perinatal complications. A total of 93 281 children (9.2%) were diagnosed with a neurodevelopmental or psychiatric disorder. Offspring exposed to both preeclampsia and perinatal complications had an increased risk of any neurodevelopmental or psychiatric disorder after adjusting for potential confounding (adjusted hazard ratio [aHR], 2.11; 95% CI, 1.96-2.26) compared with those not exposed to either preeclampsia or perinatal complications; this risk was higher than exposure to either preeclampsia alone (aHR, 1.18; 95% CI, 1.12-1.23) or perinatal complications alone (aHR, 1.77; 95% CI, 1.72-1.82). Sibling pair analyses did not detect any increase in the risk of neurodevelopmental or psychiatric disorders after exposure to preeclampsia alone, but offspring exposed to both preeclampsia and perinatal complications had increased risks of intellectual disabilities (aHR, 3.24; 95% CI, 1.05-10.06), specific developmental disorders (aHR, 3.56; 95% CI, 2.35-5.41), ADHD and conduct disorders (aHR, 2.42; 95% CI, 1.09-5.39), and other behavioral and emotional disorders (aHR, 2.45; 95% CI, 1.17-5.13). The risk estimates for specific developmental disorders (aHR, 2.82; 95% CI, 2.60-3.05) and ADHD and conduct disorders (aHR, 1.88; 95% CI, 1.65-2.14) were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications alone (aHR, 2.26 [95% CI, 2.18-2.33] and 1.60 [95% CI, 1.52-1.68], respectively). CONCLUSIONS AND RELEVANCE: In this study, exposure to both maternal preeclampsia and perinatal complications was associated with intellectual disabilities, specific developmental disorders, ADHD and conduct disorders, and other behavioral and emotional disorders in offspring. For specific developmental disorders and ADHD and conduct disorders, the risk estimates were higher among offspring exposed to both preeclampsia and perinatal complications compared with those exposed to perinatal complications only.

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6. Lybaek H, Robson M, de Leeuw N, Hehir-Kwa JY, Jeffries A, Haukanes BI, Berland S, de Bruijn D, Mundlos S, Spielmann M, Houge G. LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions. Autism research : official journal of the International Society for Autism Research. 2022; 15(3): 421-33.

LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%-26% lower than expected from Hardy-Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. LAY SUMMARY: LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females.

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7. Mlincek MM, Roemer EJ, Kraemer C, Iverson JM. Posture Matters: Object Manipulation During the Transition to Arms-Free Sitting in Infants at Elevated vs. Typical Likelihood for Autism Spectrum Disorder. Physical & occupational therapy in pediatrics. 2022: 1-15.

Aims: We investigated how infants grasped and transferred toys over a four-week period as they transitioned to arms-free sitting. We compared object manipulation in infants with typical likelihood (TL) and elevated likelihood (EL) for autism spectrum disorder (ASD) as they sat with vs. without support.Methods: Eighteen infants (7 EL; 11 TL; 5-8 months of age at the start of the study) were observed during three sessions at home across the transition to arms-free sitting. At each session, toys were presented to the infants in two different postures: sitting with support from a boppy pillow and sitting independently. Mean percentage of time spent grasping and rates of transferring objects between two hands were calculated for each infant at each session.Results: Both grasping time and transfer rate increased across the transition to arms-free sitting. EL infants, but not TL infants, spent significantly less time grasping toys when sitting independently than when sitting with support.Conclusions: Sitting plays a significant role in the development of object manipulation skills. Our results reveal a need to examine object manipulation skills in multiple posture contexts, especially in infants who exhibit motor delays.

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8. Simon AR, Ahmed KL, Limon DL, Duhon GF, Marzano G, Goin-Kochel RP. Utilization of a Best Practice Alert (BPA) at Point-of-Care for Recruitment into a US-Based Autism Research Study. Journal of autism and developmental disorders. 2022.

Provider referral is one of the most influential factors in research recruitment. To ease referral burden on providers, we adapted the Best Practice Alert (BPA) in the EPIC Electronic Health Record and assessed its utility in recruiting pediatric patients with autism spectrum disorder for the national SPARK study. During a year-long surveillance, 1203 (64.0%) patients were Interested in SPARK and 223 enrolled. Another 754 participants not recruited via the BPA also enrolled; 35.5% of these participants completed their participation compared to 58.3% of BPA-referred participants. Results suggest that (a) a BPA can successfully engage providers in the study-referral process and (b) families who learn about research through their providers may be more engaged and effectively retained.

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9. Sriram N, Madaan P, Malhi P, Sachdeva N, Negi S, Das J, Kumar R, Sahu JK, Singhi P. Evaluation of Hyperandrogenism in Children with Autism Spectrum Disorder. Indian journal of pediatrics. 2022.

This study evaluated 32 children (mean age: 8.5 y) with autism spectrum disorder (ASD) and 23 healthy controls (similar age, sex, and Tanner stage) for hyperandrogenism. These children underwent sexual maturity rating (Tanner staging), ASD severity assessment (Childhood Autism Rating Scale), and quantitative estimation for plasma testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione. There was no significant difference in androgen levels in the two groups. Elevated (> 95 centiles) testosterone, DHEAS, and androstenedione levels were seen in 12.3%, 6.2%, and 9% children with ASD, and 7/9 of these children (78%) with hyperandrogenism had severe ASD. However, there was no significant correlation between ASD severity and androgen levels.

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10. Yang HX, Zhou HY, Li Y, Cui YH, Xiang Y, Yuan RM, Lui SSY, Chan RCK. Decreased interoceptive accuracy in children with autism spectrum disorder and with comorbid attention deficit/hyperactivity disorder. Autism research : official journal of the International Society for Autism Research. 2022; 15(4): 729-39.

Interoception refers to the awareness of internal physiological state. Several previous studies reported that people with autism spectrum disorders (ASD) and adults with attention-deficit/hyperactivity disorder (ADHD) have diverse patterns of interoception, but the extent of literature is limited and inconsistent. This study aimed to investigate the interoceptive accuracy (IA) in children with ASD, children with comorbid ASD and ADHD, and typically developing (TD) children with high and low levels of autistic traits. We administered the eye-tracking interoceptive accuracy task (EIAT) to 30 children with ASD, 20 children with comorbid ASD and ADHD, and 63 TD controls with high and low levels of autistic traits. Parent-report scales concerning ASD and ADHD symptoms were collected. ASD children with and without comorbid ADHD both exhibited lower IA than TD children. Reduced IA was also found in TD children with high-autistic traits relative to those with low-autistic traits. IA was negatively correlated with autistic and ADHD symptoms. Atypical cardiac interoception could be found in children with ASD. Difficulties in sensing and comprehending internal bodily signals in childhood may be related to both ASD and ADHD symptoms. LAY SUMMARY: The present study examined interoceptive accuracy (IA) in children with autism spectrum disorders (ASD), children with comorbid ASD and attention-deficit/hyperactivity disorder (ADHD), and typically developing (TD) children with high and low levels of autistic traits. ASD children with and without comorbid ADHD both exhibited lower IA than TD children. TD children with high-autistic traits exhibited decreased IA compared to those with low-autistic traits. These results have implications for understanding sensory atypicality found in ASD and ADHD.

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11. Zug R. Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determination. Biology open. 2022; 11(1).

Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease. This article has an associated Future Leader to Watch interview with the author of the paper.

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