Pubmed du 19/02/20

mercredi 19 février 2020

1. Albajara Saenz A, Septier M, Van Schuerbeek P, Baijot S, Deconinck N, Defresne P, Delvenne V, Passeri G, Raeymaekers H, Salvesen L, Victoor L, Villemonteix T, Willaye E, Peigneux P, Massat I. ADHD and ASD : distinct brain patterns of inhibition-related activation ?. Transl Psychiatry ;2020 (Jan 22) ;10(1):24.

Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders often co-occur. In both cases, response inhibition deficits and inhibition-related atypical brain activation have been reported, although less consistently in ASD. Research exploring the overlap/distinctiveness between ADHD and ASD has significantly increased in recent years, but direct comparison of the inhibition-related neuronal correlates between these disorders are scarce in the literature. This study aimed at disentangling the shared and specific inhibitory brain dysfunctions in ASD and ADHD. Using functional magnetic resonance imaging (fMRI), brain activity was compared between children with ADHD, ASD and typically developing (TD) children aged 8-12 years during an inhibition stop-signal task, using stringent inclusion criteria. At the behavioural level, only children with ADHD exhibited inhibition deficits when compared with the TD group. Distinct patterns of brain activity were observed during successful inhibition. In children with ADHD, motor inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared with the ADHD and the TD groups. Our results evidence different patterns of activation during inhibition in these two disorders, recruiting different regions of the fronto-parietal network associated to inhibition. Besides brain activity differences, behavioural inhibition deficits found only in children with ADHD further suggest that reactive inhibition is one of the core deficits in ADHD, but not in ASD. Our findings provide further evidence contributing to disentangle the shared and specific inhibitory dysfunctions in ASD and ADHD.

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2. Asif M, Martiniano H, Marques AR, Santos JX, Vilela J, Rasga C, Oliveira G, Couto FM, Vicente AM. Identification of biological mechanisms underlying a multidimensional ASD phenotype using machine learning. Transl Psychiatry ;2020 (Jan 28) ;10(1):43.

The complex genetic architecture of Autism Spectrum Disorder (ASD) and its heterogeneous phenotype makes molecular diagnosis and patient prognosis challenging tasks. To establish more precise genotype-phenotype correlations in ASD, we developed a novel machine-learning integrative approach, which seeks to delineate associations between patients’ clinical profiles and disrupted biological processes, inferred from their copy number variants (CNVs) that span brain genes. Clustering analysis of the relevant clinical measures from 2446 ASD cases in the Autism Genome Project identified two distinct phenotypic subgroups. Patients in these clusters differed significantly in ADOS-defined severity, adaptive behavior profiles, intellectual ability, and verbal status, the latter contributing the most for cluster stability and cohesion. Functional enrichment analysis of brain genes disrupted by CNVs in these ASD cases identified 15 statistically significant biological processes, including cell adhesion, neural development, cognition, and polyubiquitination, in line with previous ASD findings. A Naive Bayes classifier, generated to predict the ASD phenotypic clusters from disrupted biological processes, achieved predictions with a high precision (0.82) but low recall (0.39), for a subset of patients with higher biological Information Content scores. This study shows that milder and more severe clinical presentations can have distinct underlying biological mechanisms. It further highlights how machine-learning approaches can reduce clinical heterogeneity by using multidimensional clinical measures, and establishes genotype-phenotype correlations in ASD. However, predictions are strongly dependent on patient’s information content. Findings are therefore a first step toward the translation of genetic information into clinically useful applications, and emphasize the need for larger datasets with very complete clinical and biological information.

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3. De Crescenzo F, D’Alo GL, Morgano GP, Minozzi S, Mitrova Z, Saulle R, Cruciani F, Fulceri F, Davoli M, Scattoni ML, Nardocci F, Schunemann HJ, Amato L. Impact of polyunsaturated fatty acids on patient-important outcomes in children and adolescents with autism spectrum disorder : a systematic review. Health Qual Life Outcomes ;2020 (Feb 17) ;18(1):28.

BACKGROUND : Recent randomized controlled trials (RCTs) claimed PUFAs to be effective for autism spectrum disorder (ASD) but international guidelines have not considered yet this body of evidence. Our aim was to assess the effectiveness of PUFAs in children and adolescents with ASD, for the Italian national guidelines on the management of ASD in children and adolescents. METHODS : We performed a systematic review and meta-analysis of RCTs comparing PUFAs versus placebo or a healthy diet for the treatment of ASD in children and adolescents. The outcomes considered were deemed by the guideline panel to be highly relevant to children and adolescents with ASD and to their caregivers. The outcomes included hyperactivity, quality of sleep, self-harm, aggression, irritability, anxiety, attention, adaptive functioning, social interaction, restricted and repetitive interests and behavior, communication, hyperactivity and disruptive behaviors coexistent with core symptoms. The risk of bias of the included studies was assessed with the Cochrane tool, and the rating of the confidence in the effect estimates according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS : We included 9 studies with 405 participants. The strength of evidence ranged from low to very low. Six studies included preschoolers and school-age children, three studies included both children and adolescents. The majority of participants were males (83.8%), with a mean age of 6.7 years. PUFAs were superior compared to placebo in reducing anxiety in individuals with ASD (SMD -1.01, 95% CI - 1.86 to - 0.17 ; very low certainty of evidence). Moreover, PUFAs worsened quality of sleep compared to a healthy diet (SMD 1.11, 95% CI 0.21 to 2.00 ; very low certainty of evidence). PUFAs were not better than placebo in reducing aggression, hyperactivity, adaptive functioning, irritability, restricted and repetitive interests and behaviors and communication. Effects on some critical outcomes such as sleep, self-harm and disruptive behavior are currently unknown. The main limitations were the small number of participants included in the RCTs and the dosage which varied greatly (from 200 mg/day to 1540 mg/day), making it difficult to address causal inference. CONCLUSIONS : PUFAs did not show evidence of effect in children and adolescents with ASD and the certainty of evidence as measured with the GRADE was low to very low. Further research is needed on this topic because the available evidence is inconclusive.

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4. Enner S, Ahmad S, Morse AM, Kothare SV. Autism : considerations for transitions of care into adulthood. Curr Opin Pediatr ;2020 (Feb 13)

PURPOSE OF REVIEW : The steady rise in number of youth diagnosed with autism spectrum disorder (ASD) has led to the need to examine transition of care considerations specific to ASD. Improved understanding and guidance addressing these needs will allow pediatric and adult providers to work together to optimize social, medical, and occupational outcomes for these patients. RECENT FINDINGS : Health-care transition is a delicate time when children with ASD outgrow the services of pediatric programs and enter a fragmented healthcare system that is unfamiliar, insufficiently knowledgeable, and underfunded for their needs. SUMMARY : Increasing autism prevalence and an aging population with autism lend urgency to improve outcomes in children transitioning to adult-care. Research reveals poor consequences in social support, education, vocational training and employment, housing, and healthcare. Specific considerations to address these issues and ensure successful transition from pediatric to adult care are needed.

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5. Gumusoglu SB, Hing BWQ, Chilukuri ASS, Dewitt JJ, Scroggins SM, Stevens HE. Chronic maternal interleukin-17 and autism-related cortical gene expression, neurobiology, and behavior. Neuropsychopharmacology ;2020 (Feb 19)

Chronic inflammation during pregnancy (e.g., preeclampsia, diabetes) is linked to increased risk for offspring neurodevelopmental disorders such as autism spectrum disorder (ASD). However, mediators of such exposures that could be targeted with maternal intervention are unclear, as few chronic gestational inflammation models have been tested. One potential mediator is interleukin-17 (IL-17), a pro-inflammatory cytokine implicated in neurodevelopmental disorders and gestational disease. To test chronic maternal IL-17 impacts on offspring, C57BL/6J dams were administered IL-17A continuously throughout pregnancy. Offspring were assessed for body weight ; cortical volume, gene expression, and cellular composition ; and adult behavior. IL-17A-condition offspring exhibited decreased somatic and cortical size at embryonic day 18 (E18) and as adults. mRNA sequencing of E18 cortex revealed 320 differentially expressed genes in males, but none in females. These were significantly enriched for ASD (Simons Foundation Autism Research Initiative), synaptic, and cell cycle genes. By adulthood, neocortical glial cell density and gene expression were decreased, while GABAergic synaptic gene expression was increased in males. Furthermore, IL-17A-condition male but not female offspring exhibited reduced anxiety-like behavior. Social approach deficits in males were negatively correlated with neocortical GABAergic synaptic gene expression. Chronic gestational IL-17A was sufficient to cause ASD-like phenotypes early and persistently in male offspring. This echoes the male bias, altered cortical development, and behavioral findings in ASD, suggesting that chronic maternal IL-17 contributes to offspring ASD pathogenesis. Furthermore, the trajectory from embryonically dysregulated synaptic and cell cycle genes to disrupted adult glia, inhibitory synapses, and behavior suggests a mechanism for chronic maternal IL-17 effects on offspring.

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6. Haigh SM, Keller TA, Minshew NJ, Eack SM. Reduced White Matter Integrity and Deficits in Neuropsychological Functioning in Adults With Autism Spectrum Disorder. Autism Res ;2020 (Feb 19)

Autism spectrum disorder (ASD) is currently viewed as a disorder of cortical systems connectivity, with a heavy emphasis being on the structural integrity of white matter tracts. However, the majority of the literature to date has focused on children with ASD. Understanding the integrity of white matter tracts in adults may help reveal the nature of ASD pathology in adulthood and the potential contributors to cognitive impairment. This study examined white matter water diffusion using diffusion tensor imaging in relation to neuropsychological measures of cognition in a sample of 45 adults with ASD compared to 20 age, gender, and full-scale-IQ-matched healthy volunteers. Tract-based spatial statistics were used to assess differences in diffusion along white matter tracts between groups using permutation testing. The following neuropsychological measures of cognition were assessed : processing speed, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. Results indicated that fractional anisotropy (FA) was significantly reduced in adults with ASD in the anterior thalamic radiation (P = 0.022) and the right cingulum (P = 0.008). All neuropsychological measures were worse in the ASD group, but none of the measures significantly correlated with reduced FA in either tract in the adults with ASD or in the healthy volunteers. Together, this indicates that the tracts that are the most impacted in autism may not be (at least directly) responsible for the behavioral deficits in ASD. LAY SUMMARY : White matter tracts are the data cables in the brain that efficiently transfer information, and damage to these tracts could be the cause for the abnormal behaviors that are associated with autism. We found that two long-range tracts (the anterior thalamic radiation and the cingulum) were both impaired in autism but were not directly related to the impairments in behavior. This suggests that the abnormal tracts and behavior are the effects of another underlying mechanism. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc.

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7. Kumari D, Usdin K. Molecular analysis of FMR1 alleles for fragile X syndrome diagnosis and patient stratification. Expert Rev Mol Diagn ;2020 (Feb 18):1-3.

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8. Larijani B, Foroughi Heravani N, Alavi-Moghadam S, Goodarzi P, Rezaei-Tavirani M, Payab M, Gholami M, Razi F, Arjmand B. Cell Therapy Targets for Autism Spectrum Disorders : Hopes, Challenges and Future Directions. Adv Exp Med Biol ;2020 (Feb 19)

Autism spectrum disorders as a group of pediatric neurodevelopmental diseases is a crucial part of the worldwide disabilities which have influence in communication skills, social interactions, and ability to understand the concepts. The precise pathophysiology of autism spectrum disorders due to the abundance of involved mechanisms is unknown. Some of these involved mechanisms are related to genetic factors, chronic neuro inflammation, mitochondrial dysfunction, oxidative stress, immune dysregulation, hormonal imbalance, and environmental factors. Current main treatments for autisms are behavioral, nutritional and medical therapies, however there is not definitive treatment approach. Therein, more novel therapies are still required to improve the symptoms. Several preclinical and clinical evidence were shown that stem cell therapy is a potential treatment option for autism spectrum disorders individuals. Considering the significant factors which can affect the outcome of stem cell therapeutic effects including stem cell types, route and dosage of administration, and mechanism of activity along with selecting best animal models can be very important in performing clinical trials.

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9. Luo CW, Deng XY, Cheng JL, Xiao DX, Zhang CY, Feng JX, Chen SQ, Hu N. Altered anxiety and social behaviors in a mouse model of Fragile X syndrome treated with hyperbaric oxygen therapy. J Clin Neurosci ;2020 (Feb 14)

Fragile X syndrome (FXS) is a common mental retardation syndrome. Anxiety and abnormal social behaviors are prominent features of FXS in humans. To better understand the effects of hyperbaric oxygen therapy (HBOT) on these behaviors, we analyzed anxiety-related and social behaviors in Fmr1 knockout mice treated by HBOT. In the open field test, HBOT group mice preferred the periphery to central areas and tended to run or walk along the wall. The results suggested that thigmotaxis was significantly increased in the HBOT group compared with the control group. In the elevated plus maze test, the percentage of distance traveled was significantly increased in the open arm and significantly decreased in the closed arm for HBOT group mice compared with control group mice. These results suggested that HBOT group mice displayed enhanced motor activity in the open arm and exhibited fewer anxiety-related behaviors. In the three-chambered social approach test, the HBOT group mice made more approaches to the wire cup containing an acquaintance mouse than control group mice in the sociability test and made more approaches to the wire cup containing a stranger mouse than control group mice in the social novelty preference test. The results suggested that HBOT group mice showed increased levels of social interaction and decreased "social anxiety" than the control group to partner mice in this test. Our findings indicated that HBOT resulted in altered anxiety and social behavior in Fmr1 knockout mice and could possibly be used as a treatment for FXS.

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10. Oulhote Y, Lanphear B, Braun JM, Webster GM, Arbuckle TE, Etzel T, Forget-Dubois N, Seguin JR, Bouchard MF, MacFarlane A, Ouellet E, Fraser W, Muckle G. Gestational Exposures to Phthalates and Folic Acid, and Autistic Traits in Canadian Children. Environ Health Perspect ;2020 (Feb) ;128(2):27004.

BACKGROUND : The etiology of autism spectrum disorder is poorly understood. Few studies have investigated the link between endocrine-disrupting chemicals and autistic traits. We examined the relationship between gestational phthalates and autistic traits in 3- to 4-y-old Canadian children. We also investigated potential effect modification by sex and folic acid supplementation. METHODS : We enrolled 2,001 women>18 years of age during the first trimester of pregnancy between 2008 and 2011 from 10 cities in Canada. At 3-4 years of age, 610 children underwent neuropsychological assessments including the Social Responsiveness Scale-II (SRS-2) as a measure of autistic traits and social impairment. We measured 11 phthalate metabolites in maternal first trimester urine samples and assessed folic acid supplementation from reported intakes. We estimated covariate-adjusted differences in SRS-2 T-scores with a doubling in phthalate concentrations in 510 children with complete data. RESULTS : Mean total SRS T-score was 45.3 (SD=6.1). Children with higher gestational exposure to mono-n-butyl (MBP) and mono-3-carboxypropyl (MCPP) concentrations exhibited significantly higher total SRS T-scores, indicating greater overall social impairment, as well as higher scores on subdomains, indicating deficits in social cognition, social communication, social motivation, and restricted interests/repetitive behaviors. A doubling in MBP or MCPP concentrations was associated with 0.6 (95% CI : 0.1, 1.0) and 0.5 (95% CI : 0.1, 0.8) higher total SRS T-scores. Associations were consistently and significantly stronger in boys (betaMBP=1.0 ; 95% CI : 0.4, 1.6 ; n=252) compared with girls (betaMBP=0.1 ; 95% CI : -0.6, 0.7 ; n=258) and among children who had lower prenatal folic acid supplementation (<400mug/d) (betaMBP=1.3 ; 95% CI : 0.4, 2.3 ; n=59) compared with those who had adequate folic acid supplementation (>/=400mug/d) (betaMBP=0.4 ; 95% CI : -0.1, 0.8 ; n=451). CONCLUSIONS : Higher gestational concentrations of some phthalate metabolites were associated with higher scores of autistic traits as measured by the SRS-2 in boys, but not girls ; these small size effects were mitigated by first trimester-of-pregnancy folic acid supplementation.

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11. Ouss L, Palestra G, Saint-Georges C, Leitgel Gille M, Afshar M, Pellerin H, Bailly K, Chetouani M, Robel L, Golse B, Nabbout R, Desguerre I, Guergova-Kuras M, Cohen D. Behavior and interaction imaging at 9 months of age predict autism/intellectual disability in high-risk infants with West syndrome. Transl Psychiatry ;2020 (Feb 3) ;10(1):54.

Automated behavior analysis are promising tools to overcome current assessment limitations in psychiatry. At 9 months of age, we recorded 32 infants with West syndrome (WS) and 19 typically developing (TD) controls during a standardized mother-infant interaction. We computed infant hand movements (HM), speech turn taking of both partners (vocalization, pause, silences, overlap) and motherese. Then, we assessed whether multimodal social signals and interactional synchrony at 9 months could predict outcomes (autism spectrum disorder (ASD) and intellectual disability (ID)) of infants with WS at 4 years. At follow-up, 10 infants developed ASD/ID (WS+). The best machine learning reached 76.47% accuracy classifying WS vs. TD and 81.25% accuracy classifying WS+ vs. WS-. The 10 best features to distinguish WS+ and WS- included a combination of infant vocalizations and HM features combined with synchrony vocalization features. These data indicate that behavioral and interaction imaging was able to predict ASD/ID in high-risk children with WS.

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12. Reese S, Deutsch SA. Sexual Assault Victimization Among Children and Youth With Developmental Disabilities : Responding With Trauma-Informed Care. J Forensic Nurs ;2020 (Jan/Mar) ;16(1):55-60.

Sexual assault victimization is a traumatic experience for children and youth, and care of survivors requires a trauma-informed approach. Children and youth with developmental disabilities are sexually victimized at higher rates than those without disabilities. Children with autism spectrum disorder (ASD), in particular, may be at an increased risk for both traumatic events and developing traumatic sequelae after sexual assault victimization. In this report, we present the case of a youth with ASD who sought acute sexual assault care, but whose care was compromised because of multiple systems failures, including gaps in communication regarding her unique needs, and inconsistent knowledge among multidisciplinary team members regarding necessary adaptations in the implementation of trauma-informed care for youth with ASD. Lessons learned, including proposed solutions to improve communication and education, and approaches to prevent unintended retraumatization are discussed.

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13. Rodriguez CM, Wright SE, Kearse MG, Haenfler JM, Flores BN, Liu Y, Ifrim MF, Glineburg MR, Krans A, Jafar-Nejad P, Sutton MA, Bassell GJ, Parent JM, Rigo F, Barmada SJ, Todd PK. A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nat Neurosci ;2020 (Feb 17)

Repeat-associated non-AUG-initiated translation of expanded CGG repeats (CGG RAN) from the FMR1 5’-leader produces toxic proteins that contribute to neurodegeneration in fragile X-associated tremor/ataxia syndrome. Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating fragile X protein (FMRP) synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked CGG RAN. This ASO blockade enhanced endogenous FMRP expression in human neurons. In human and rodent neurons, CGG RAN-blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis, and they demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.

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14. Tan DW, Maybery MT, Gilani SZ, Alvares GA, Mian A, Suter D, Whitehouse AJO. A broad autism phenotype expressed in facial morphology. Transl Psychiatry ;2020 (Jan 16) ;10(1):7.

Autism spectrum disorder is a heritable neurodevelopmental condition diagnosed based on social and communication differences. There is strong evidence that cognitive and behavioural changes associated with clinical autism aggregate with biological relatives but in milder form, commonly referred to as the ’broad autism phenotype’. The present study builds on our previous findings of increased facial masculinity in autistic children (Sci. Rep., 7:9348, 2017) by examining whether facial masculinity represents as a broad autism phenotype in 55 non-autistic siblings (25 girls) of autistic children. Using 3D facial photogrammetry and age-matched control groups of children without a family history of ASD, we found that facial features of male siblings were more masculine than those of male controls (n = 69 ; p < 0.001, d = 0.81 [0.36, 1.26]). Facial features of female siblings were also more masculine than the features of female controls (n = 60 ; p = 0.005, d = 0.63 [0.16, 1.10]). Overall, we demonstrated for males and females that facial masculinity in non-autistic siblings is increased compared to same-sex comparison groups. These data provide the first evidence for a broad autism phenotype expressed in a physical characteristic, which has wider implications for our understanding of the interplay between physical and cognitive development in humans.

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15. Westerveld MF, Paynter J, Wicks R. Shared Book Reading Behaviors of Parents and Their Verbal Preschoolers on the Autism Spectrum. J Autism Dev Disord ;2020 (Feb 17)

Preschoolers on the autism spectrum are at risk of persistent language and literacy difficulties thus research into shared book reading (SBR) in this group is important. We observed 47 parents and their verbal preschoolers on the spectrum sharing two unfamiliar picture books and coded the interactions for parent and child behaviors. Parents were able to engage their child in SBR and demonstrated a range of print- and meaning-related SBR behaviors with no evidence of a focus on print. Multiple regressions showed direct effects of parents’ explicit teaching of story structure and use of questions on their children’s verbal participation. Further research is needed to unpack the potential transactional relationships between parent and child SBR behaviors to inform early intervention.

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16. Zhang L, Huang CC, Dai Y, Luo Q, Ji Y, Wang K, Deng S, Yu J, Xu M, Du X, Tang Y, Shen C, Feng J, Sahakian BJ, Lin CP, Li F. Correction : Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios. Transl Psychiatry ;2020 (Feb 12) ;10(1):63.

An important detail was omitted in the Method of the original Article, I.E, The CARS and other evaluations were conducted ’blind’ to condition (Bumetanide or no treatment) by experienced clinicians. This has now been updated in the HTML and PDF versions of this Article.

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17. Zhang L, Huang CC, Dai Y, Luo Q, Ji Y, Wang K, Deng S, Yu J, Xu M, Du X, Tang Y, Shen C, Feng J, Sahakian BJ, Lin CP, Li F. Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios. Transl Psychiatry ;2020 (Jan 27) ;10(1):9.

Bumetanide has been reported to alter synaptic excitation-inhibition (E-I) balance by potentiating the action of gamma-aminobutyric acid (GABA), thereby attenuating the severity of autism spectrum disorder (ASD) in animal models. However, clinical evidence of its efficacy in young patients with ASD is limited. This was investigated in the present clinical trial of 83 patients, randomised to the bumetanide group (bumetanide treatment, 0.5 mg twice daily) or the control group (no bumetanide treatment). Primary [Children Autism Rating Scale (CARS)], secondary [Clinical Global Impressions (CGI)], and exploratory [inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate, Glx) neurotransmitter concentrations measured in the insular cortex (IC) and visual cortex (VC) by magnetic resonance spectroscopy (MRS)] outcome measures were evaluated at baseline and at the 3-month follow-up. Side effects were monitored throughout the treatment course. Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score >/= 3. The improvement in clinical symptoms was confirmed by CGI. GABA/Glx ratio in both the IC and VC decreased more rapidly over the 3-month period in the bumetanide group than that in the control group. This decrease in the IC was associated with the symptom improvement in the bumetanide group. Our study confirmed the clinical efficacy of bumetanide on alleviating the core symptoms of ASD in young children and it is the first demonstration that the improvement is associated with reduction in GABA/Glx ratios. This study suggests that the GABA/Glx ratio measured by MRS may provide a neuroimaging biomarker for assessing treatment efficacy for bumetanide.

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18. Zhang Y, Li N, Li C, Zhang Z, Teng H, Wang Y, Zhao T, Shi L, Zhang K, Xia K, Li J, Sun Z. Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect. Transl Psychiatry ;2020 (Jan 15) ;10(1):4.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a male-to-female prevalence of 4:1. However, the genetic mechanisms underlying this gender difference remain unclear. Mutation burden analysis, a TADA model, and co-expression and functional network analyses were performed on de novo mutations (DNMs) and corresponding candidate genes. We found that the prevalence of putative functional DNMs (loss-of-function and predicted deleterious missense mutations) in females was significantly higher than that in males, suggesting that a higher genetic load was required in females to reach the threshold for a diagnosis. We then prioritized 174 candidate genes, including 60 shared genes, 91 male-specific genes, and 23 female-specific genes. All of the three subclasses of candidate genes were significantly more frequently co-expressed in female brains than male brains, suggesting that compensation effects of the deficiency of ASD candidate genes may be more likely in females. Nevertheless, the three subclasses of candidate genes were co-expressed with each other, suggesting a convergent functional network of male and female-specific genes. Our analysis of different aspects of genetic components provides suggestive evidence supporting the female-protective effect in ASD. Moreover, further study is needed to integrate neuronal and hormonal data to elucidate the underlying gender difference in ASD.

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