1. Albers J, Kraja G, Eller D, Eck K, McBrian D, Bain JM. Assessing the Feasibility of Using the Ketogenic Diet in Autism Spectrum Disorder. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2022.

Evidence demonstrating efficacy of dietary interventions for autism spectrum disorder (ASD) remains inconsistent. Recent research on the ketogenic diet (KD) for the treatment of ASD has suggested benefit. Children with ASD often demonstrate ritualized food specific behaviors, taste and texture aversions, and an increased prevalence of food restrictions and allergies. There is a need to investigate how these features contribute to initiation and adherence of the KD. Two surveys were administered to assess the feasibility of utilizing the KD for ASD. First, paper surveys were given to caregivers of children presenting to outpatient neurology clinics. Next, experienced clinicians were recruited and surveyed online using Redcap. χ(2) analysis was used to compare ASD and non ASD caregiver responses. Descriptive metrics were used to present clinician responses. Responses to each question were evaluated individually. This article is protected by copyright. All rights reserved.

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2. Alusi G, Berry-Kravis E, Nelson D, Orefice LL, Booker SA. Emerging Therapeutic Strategies for Fragile X Syndrome: Q&A. ACS chemical neuroscience. 2022; 13(24): 3544-6.

Understanding how best to treat aspects of Fragile X syndrome has the potential to improve the quality of life of affected individuals. Such an effective therapy has, as yet, remained elusive. In this article, we ask those researching or affected by Fragile X syndrome their views on the current state of research and from where they feel the most likely therapy may emerge.

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3. Amiri S, Shekari Khaniani M, Mohammadi A, Asadian M, Mehdizadeh Fanid L, Shafiee-Kandjani AR. Molecular Evaluation of Ex3 VNTR Polymorphism of the DRD4 Gene in Patients With Autism Spectrum Disorder. Iranian journal of child neurology. 2022; 16(4): 23-31.

OBJECTIVE: Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders that affect social and communication skills. These diseases are characterized by severe communication and social skills disabilities and limited and repetitive activities. The prevalence of these disorders appears to be steadily increasing. It is proposed that the genes involved in the dopamine pathway may play an essential role in the development of autism. In this study, we investigated the possible association between Ex3 VNTR polymorphism of the DRD4 gene and autism spectrum disorders in the Iranian population. MATERIALS & METHODS: In this case-control study, 97 children with autism and 103 healthy individuals from a northwestern area of Iran as the case and control groups, respectively. After genomic xtraction from peripheral blood samples by the proteinase K method, the polymerase chain reaction (PCR) technique was used to determine the polymorphism genotypes. The data were then coded and analyzed using SPSS version 22 software. RESULTS: The study results showed that the allele frequencies differed in the two groups, some of them being statistically significant. The most common allele in both the ASD and the control group was the 700 bp allele, and its frequency was significantly different in the two groups and was more common in the ASD group (p-value=0.0018). The other allele with a statistically different frequency was the 800 bp allele which was less frequent in the ASD group (p-value=0.0017). CONCLUSION: These results suggest a potential association between Ex3 VNTR polymorphism of the DRD4 gene and autism spectrum disorder in the Iranian population. This necessitates further studies for the evaluation of the DRD4 gene.

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4. Barone R, Cirnigliaro L, Saccuzzo L, Valdese S, Pettinato F, Prato A, Bernardini L, Fichera M, Rizzo R. PARK2 microdeletion in a multiplex family with autism spectrum disorder. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2022.

BACKGROUND: PARK2 (PRKN; MIM*602544) encodes Parkin protein, an ubiquitin-protein ligase required for proteasomal degradation and operating in the synaptic compartments. Copy number variations (CNVs) involving PARK2 have been associated with autism spectrum disorder (ASD). We report on a family with ASD (multiplex family) harbouring a microdeletion at chr. 6q26 causing PARK2 disruption. METHODS: CNV analyses were performed using CGH/SNP-array platforms, and the detected microdeletion was confirmed by real-time quantitative PCR. Standardized psychometric evaluation was used for neurobehavioral characterization. RESULTS: We found an intragenic ~157 kb microdeletion of the chromosomal region 6q26 causing PARK2 disruption in two male sibs with ASD and syndromic phenotype. They both had dysmorphic facial features with coarse faces, deeply set eyes with long horizontal palpebral fissures, long eyelashes and thick eyebrows, fleshy lips and mild skeletal problems. We found an intrafamilial clinical heterogeneity owing to different severity of the autism symptoms between the affected sibs: the younger one had minimally verbal autism and severe intellectual disability, whereas his older brother presented high-functioning autism and preserved speech. Parental analysis and real-time PCR using a PRKN fragment mapping within the deletion demonstrated that the deletion was inherited from their father having subthreshold features of ASD consisting with broad autism phenotype. CONCLUSIONS: The study corroborates the hypothesis that PARK2 aberrations may be associated with ASD and highlights correlations between CNV affecting PARK2 and ASD in a multiplex family. We show remarkable intrafamilial variability in the severity of inherited ASD associated with PARK2 microdeletion.

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5. Berkins S, Koshy B, Livingstone RS, Jasper A, Grace H, Ravibabu P, Rai E. Morphometric analysis of Corpus Callosum in autistic and typically developing Indian children. Psychiatry research Neuroimaging. 2022; 328: 111580.

Corpus callosum (CC) is the largest commissural white matter bundle in the brain, responsible for the integration of information between hemispheres. Reduction in the size of the CC structure has been predominantly reported in children with autism spectrum disorder (ASD) compared to typically developing children (TD). However, most of these studies are based on high-functioning individuals with ASD but not on an inclusive sample of individuals with ASD with varying abilities. Our current study aimed to examine the CC morphometry between children with ASD and TD in the Indian population. We also compared CC morphometry in autistic children with autism severity, verbal IQ (VIQ) and full-scale IQ (FSIQ). T1-weighted structural images were acquired using a 3T MRI scanner to examine the CC measures in 62 ASD and 17 TD children. The length and height of the CC and the width of genu were decreased in children with ASD compared to TD. There was no significant difference in CC measures based on autism severity, VIQ or FSIQ among children with ASD. To our knowledge, this is the first neuroimaging study to include a significant number (n = 56) of low-functioning ASD children. Our findings suggest the atypical interhemispheric connectivity of CC in ASD.

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6. Bishop L, Charlton RA, McLean KJ, McQuaid GA, Lee NR, Wallace GL. Cardiovascular disease risk factors in autistic adults: The impact of sleep quality and antipsychotic medication use. Autism research : official journal of the International Society for Autism Research. 2022.

Approximately 40% of American adults are affected by cardiovascular disease (CVD) risk factors (e.g., high blood pressure, high cholesterol, diabetes, and overweight or obesity), and risk among autistic adults may be even higher. Mechanisms underlying the high prevalence of CVD risk factors in autistic people may include known correlates of CVD risk factors in other groups, including high levels of perceived stress, poor sleep quality, and antipsychotic medication use. A sample of 545 autistic adults without intellectual disability aged 18+ were recruited through the Simons Foundation Powering Autism Research, Research Match. Multiple linear regression models examined the association between key independent variables (self-reported perceived stress, sleep quality, and antipsychotic medication use) and CVD risk factors, controlling for demographic variables (age, sex assigned at birth, race, low-income status, autistic traits). Overall, 73.2% of autistic adults in our sample had an overweight/obesity classification, 45.3% had high cholesterol, 39.4% had high blood pressure, and 10.3% had diabetes. Older age, male sex assigned at birth, and poorer sleep quality were associated with a higher number of CVD risk factors. Using antipsychotic medications was associated with an increased likelihood of having diabetes. Poorer sleep quality was associated with an increased likelihood of having an overweight/obesity classification. Self-reported CVD risk factors are highly prevalent among autistic adults. Both improving sleep quality and closely monitoring CVD risk factors among autistic adults who use antipsychotic medications have the potential to reduce risk for CVD.

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7. Brandsma T, Visser K, Volk JJG, Rijn ABV, Dekker LP. A Pilot Study on the Effect of Peer Support on Quality of Life of Adolescents with Autism Spectrum Disorder and Gender Dysphoria. Journal of autism and developmental disorders. 2022.

Gender dysphoria (GD) and Autism Spectrum Disorder (ASD) co-occur relatively often, but there is no evidence-based treatment for this specific group. Therefore, we examined the effects of a group intervention for adolescents with ASD and GD in a pilot study with a pre-post-test design. The adolescents completed questionnaires on quality of life, self-esteem, gender dysphoric feelings, and social responsiveness. Results show that participating in this peer support group seems to increase aspects of quality of life, i.e., increased parent-reported psychological well-being and decreased psychological complaints. Even though more research is needed, these results indicate that peer support is an invaluable part of treatment for adolescents with ASD and GD.

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8. Cao W, Li JH, Lin S, Xia QQ, Du YL, Yang Q, Ye YZ, Zeng LH, Li XY, Xu J, Luo JH. NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice. Cell reports. 2022; 41(10): 111771.

Neuroligins (NLs), a family of postsynaptic cell-adhesion molecules, have been associated with autism spectrum disorder. We have reported that dysfunction of the medial prefrontal cortex (mPFC) leads to social deficits in an NL3 R451C knockin (KI) mouse model of autism. However, the underlying molecular mechanism remains unclear. Here, we find that N-methyl-D-aspartate receptor (NMDAR) function and parvalbumin-positive (PV+) interneuron number and expression are reduced in the mPFC of the KI mice. Selective knockdown of NMDAR subunit GluN1 in the mPFC PV+ interneuron decreases its intrinsic excitability. Restoring NMDAR function by its partial agonist D-cycloserine rescues the PV+ interneuron dysfunction and social deficits in the KI mice. Interestingly, early D-cycloserine administration at adolescence prevents adult KI mice from social deficits. Together, our results suggest that NMDAR hypofunction and the resultant PV+ interneuron dysfunction in the mPFC may constitute a central node in the pathogenesis of social deficits in the KI mice.

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9. Duński E, Pękowska A. Keeping the balance: Trade-offs between human brain evolution, autism, and schizophrenia. Frontiers in genetics. 2022; 13: 1009390.

The unique qualities of the human brain are a product of a complex evolutionary process. Evolution, famously described by François Jacob as a « tinkerer, » builds upon existing genetic elements by modifying and repurposing them for new functions. Genetic changes in DNA may lead to the emergence of new genes or cause altered gene expression patterns. Both gene and regulatory element mutations may lead to new functions. Yet, this process may lead to side-effects. An evolutionary trade-off occurs when an otherwise beneficial change, which is important for evolutionary success and is under strong positive selection, concurrently results in a detrimental change in another trait. Pleiotropy occurs when a gene affects multiple traits. Antagonistic pleiotropy is a phenomenon whereby a genetic variant leads to an increase in fitness at one life-stage or in a specific environment, but simultaneously decreases fitness in another respect. Therefore, it is conceivable that the molecular underpinnings of evolution of highly complex traits, including brain size or cognitive ability, under certain conditions could result in deleterious effects, which would increase the susceptibility to psychiatric or neurodevelopmental diseases. Here, we discuss possible trade-offs and antagonistic pleiotropies between evolutionary change in a gene sequence, dosage or activity and the susceptibility of individuals to autism spectrum disorders and schizophrenia. We present current knowledge about genes and alterations in gene regulatory landscapes, which have likely played a role in establishing human-specific traits and have been implicated in those diseases.

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10. Eidelman AI. Challenges to the Autistic Mother Who Wishes to Breastfeed. Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine. 2022; 17(12): 979-80.

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11. Friedman C. The Impact of Emergency Pandemic HCBS Funding on the Continuity and Security of People with Intellectual and Developmental Disabilities. Journal of autism and developmental disorders. 2022: 1-10.

This study’s aim was to examine the impact of pandemic emergency Home- and Community-Based Services (HCBS) payments on the continuity and security of people with intellectual and developmental disabilities (IDD). Using a multilevel logistic regression, we analyzed secondary Personal Outcome Measures interviews from 738 people with IDD (March 2020 through April 2022), and state pandemic emergency HCBS payment data from 16 states. The odds of people with IDD experiencing continuity and security during the pandemic increased by 3% for every 1% states increased their payment rates, and by 398% when states offered retainer payments. Increased reimbursement rates and retainer payments can help providers maintain operations and promote the continuity and security of people with IDD.

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12. Gao L, Liu XN. Status Quo and Advanced Progress in Oral Health Care and Treatment of Children with Autism Spectrum Disorder: A Literatiure Review. The Chinese journal of dental research : the official journal of the Scientific Section of the Chinese Stomatological Association (CSA). 2022; 25(4): 251-9.

Autism spectrum disorder (ASD) has become one of the fastest growing diseases in the world, causing a great burden to ASD children’s families and society. Children with ASD face more disadvantages relating to their oral health than those without ASD. There is a positive correlation between prevalence of caries lesions and severity of ASD. Poorer oral hygiene, higher detection rates of dental calculus and far more frequent cases of gingivitis occur in children with ASD. Traumatic injuries and various types of malocclusions are more frequent in children with ASD. Poorer oral health care and treatment status are caused by multiple adverse factors. Ways of promoting effective oral health care and treatment include pretreatment counselling; improvement of the individualised treatment environment; routine behaviour guidance techniques (BGTs) including tell-show-do, distraction, role model presentation, voice control, visual education and social stories, encouragement and reinforcement; targeted BGTs including visual education, behaviour modelling, applied behaviour analysis (ABA) and systematic desensitisation; passive BGTs including protective restraint, pharmaceutically administrated sedation and general anaesthesia; oral health education for guardians; and interdisciplinary collaboration and professional dental care/treatment. Dentists, families with children with ASD and schools should cooperate to improve family-centred oral health care and treatment for ASD children not only in China, but also the whole world.

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13. Genc-Tosun D, Kurt O, Cevher Z, Gregori EV. Teaching Children with Autism Spectrum Disorder to Answer Questions Using an iPad-Based Speech-Generating Device. Journal of autism and developmental disorders. 2022.

This study investigated whether a systematic instruction package was effective in child acquisition of question answering using an iPad-based speech generating device (SGD). The study was conducted with two children with autism using a multiple probe across behaviors design. Results demonstrated that the systematic instruction package consisting of graduated guidance, discrete trial teaching, time delay, and reinforcement resulted in acquisition of answering all questions. Follow-up data were collected one, three, and five weeks after instruction ended. For all participants, skills maintained during follow-up and generalized to novel settings and skills. Social validity data were also collected and indicated that teachers without experience using SGDs found them to be effective and feasible for teaching communication skills.

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14. Guo Q, Pan Q, Liu Q, Wang T, Cao S, Lin Y, Hu B. Relationship between different types of complement syntax and false belief in Mandarin-speaking children with autism spectrum disorder and typically developing children. Frontiers in psychology. 2022; 13: 1045227.

Previous studies have shown that complement syntax is closely associated with false belief (FB) in children with autism spectrum disorder (ASD). However, the relationship between different types of complement syntax and FB remains unclear. This study examined the relationship between different types of complement syntax and FB in both ASD and typically developing (TD) children. Thirty Mandarin-speaking ASD and TD children, each matched for language ability, were included. Children completed different types of complement syntax tasks, verbal and nonverbal FB. For the ASD children, results demonstrated that sentential complement syntax independently predicted verbal and nonverbal FB, while phrasal complement syntax only predicted nonverbal FB. For the TD children group, sentential complement syntax only predicted verbal FB. This indicates that as the language demands of the FB task decrease, ASD children can use both types of complement syntax for its prediction. Moreover, the characteristics of ASD children differ from TD children in terms of the relationship between different types of complement syntax and FB. The results of this study support de Villiers’ point of view from the Mandarin perspective and provide evidence for the social-cognitive component of the theory of mind.

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15. Hirai M, Asada K, Kato T, Ikeda T, Hakuno Y, Ikeda A, Matsushima K, Awaya T, Okazaki S, Kato T, Funabiki Y, Murai T, Heike T, Hagiwara M, Yamagata T, Tomiwa K, Kimura R. Correction to: Comparison of the social responsiveness scale-2 among individuals with Autism Spectrum Disorder and Williams Syndrome in Japan. Journal of autism and developmental disorders. 2022.

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16. Huang Y, Arnold SRC, Foley KR, Trollor JN. A Qualitative Study of Adults’ and Support Persons’ Experiences of Support After Autism Diagnosis. Journal of autism and developmental disorders. 2022: 1-14.

Adulthood autism diagnosis has become increasingly common, but little is known about post-diagnosis support experiences and needs. We interviewed 19 autistic adults and 4 support persons on experiences of formal and informal post-diagnosis support. Reflexive thematic analysis was used to identify themes. Participants reported difficulties accessing suitable formal support, especially regarding education and employment. Informal support was helpful but created challenges in the relationships between autistic adults and support persons. For autistic adults, support from autistic peers fostered belonging and self-acceptance. We also identified complex interactions between adults’ post-diagnosis identity development and support experiences as they resolved the dilemma between self-acceptance and a desire to change. Findings have important implications for services working with autistic adults and their families.

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17. Jalnapurkar I, Frazier JA, Roth M, Cochran DM, Foley A, Merk T, Venuti L, Ronco L, Raines S, Cadavid D. The feasibility and utility of hair follicle sampling to measure FMRP and FMR1 mRNA in children with or without fragile X syndrome: a pilot study. Journal of neurodevelopmental disorders. 2022; 14(1): 57.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (> 200 base pairs) on the promotor region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, fragile X messenger ribonucleoprotein 1 (FMRP). FMRP has a central role in the translation of mRNAs involved in synaptic connections and plasticity. Recent studies have demonstrated the benefit of therapeutics focused on reactivation of the FMR1 locus towards improving key clinical phenotypes via restoration of FMRP and ultimately disease modification. A key step in future studies directed towards this effort is the establishment of proof of concept (POC) for FMRP reactivation in individuals with FXS. For this, it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 mRNA and FMRP. METHODS: Individuals, ages 3 to 22 years of age, with FXS and those who were typically developing participated in this single-site pilot clinical biomarker study. The repeated collection of hair follicles was compared with the collection of blood and buccal swabs for detection of FMR1 mRNA and FMRP and related molecules. RESULTS: There were n = 15 participants, of whom 10 had a diagnosis of FXS (7.0 ± 3.56 years) and 5 were typically developing (8.2 ± 2.77 years). Absolute levels of FMRP and FMR1 mRNA were substantially higher in healthy participants compared to full mutation and mosaic FXS participants and lowest in the FXS boys. Measurement of FMR1 mRNA and FMRP levels by any method did not show any notable variation by collection location at home versus office across the various sample collection methodologies of hair follicle, blood sample, and buccal swab. CONCLUSION: Findings demonstrated that repeated sampling of hair follicles in individuals with FXS, in both, home, and office settings, is feasible, repeatable, and can be used for measurement of FMR1 mRNA and FMRP in longitudinal studies.

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18. Kaiser FMP, Gruenbacher S, Oyaga MR, Nio E, Jaritz M, Sun Q, van der Zwaag W, Kreidl E, Zopf LM, Dalm V, Pel J, Gaiser C, van der Vliet R, Wahl L, Rietman A, Hill L, Leca I, Driessen G, Laffeber C, Brooks A, Katsikis PD, Lebbink JHG, Tachibana K, van der Burg M, De Zeeuw CI, Badura A, Busslinger M. Correction: Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder. The Journal of experimental medicine. 2023; 220(1).

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19. Laidi C, Neu N, Watilliaux A, Martinez-Teruel A, Razafinimanana M, Boisgontier J, Hotier S, d’Albis MA, Delorme R, Amestoy A, Holiga Š, Moal ML, Coupé P, Leboyer M, Houenou J, Rondi-Reig L, Paradis AL. Preserved navigation abilities and spatio-temporal memory in individuals with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2022.

Cerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric learning and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD.

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20. Li Y, Fan T, Li X, Liu L, Mao F, Li Y, Miao Z, Zeng C, Song W, Pan J, Zhou S, Sunday ME, Wang H, Wang Y, Sun ZS. Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors. Cell reports. 2022; 41(10): 111767.

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21. Milner V, Colvert E, Mandy W, Happé F. A comparison of self-report and discrepancy measures of camouflaging: Exploring sex differences in diagnosed autistic versus high autistic trait young adults. Autism research : official journal of the International Society for Autism Research. 2022.

Camouflaging describes masking or compensating for autistic traits and/or related difficulties. Some evidence suggests autistic females camouflage more than autistic males, potentially contributing to delayed or missed diagnosis. Studies predominantly adopt self-report measures of camouflaging, potentially reflecting a person’s intent to camouflage without accurately measuring effectiveness (i.e., success in fulfilling the intended effect of minimizing the appearance of autistic traits) of camouflaging. Discrepancy scores between underlying cognitive difficulties (e.g., theory of mind) and observed autistic traits (henceforth camo(ToM) ), or between self-reported autistic traits and observed autistic traits (henceforth camo(SRS) ), may provide a more accurate measure of camouflaging effectiveness. Three measures of camouflaging administered to autistic males (n = 46) and females (n = 40), and adults with equally high levels of autistic traits but no diagnosis (n = 45 males, n = 43 females) recruited from a large population-based sample were compared. Self-report measures of camouflaging were significantly correlated with camo(SRS) scores only. Both discrepancy scores were correlated with each other. Adults with high autistic traits, but no diagnosis, had higher discrepancy camouflaging scores than diagnosed adults, but self-reported scores were similar. Diagnosed females scored higher than diagnosed males across all camouflaging measures, but no sex difference occurred in the high trait group. This might indicate that autistic females have higher intentions and greater effectiveness when camouflaging, compared with autistic males. For camo(SRS) only, high trait males scored significantly higher than diagnosed males; no group difference occurred for females. These results suggest that, despite all participants intending to camouflage to some extent, effective camouflaging as measured by discrepancy scores is higher in undiagnosed high autistic trait individuals. One interpretation is that effective camouflaging reduces the likelihood of autism diagnosis in males and females with high autistic traits.

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22. Ng KM, Ding Q, Tse YL, Chou OH, Lai WH, Au KW, Lau YM, Ji Y, Siu CW, Tang CS, Colman A, Tsang SY, Tse HF. Isogenic Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes Reveal Activation of Wnt Signaling Pathways Underlying Intrinsic Cardiac Abnormalities in Rett Syndrome. International journal of molecular sciences. 2022; 23(24).

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by MeCP2 mutations. Nonetheless, the pathophysiological roles of MeCP2 mutations in the etiology of intrinsic cardiac abnormality and sudden death remain unclear. In this study, we performed a detailed functional studies (calcium and electrophysiological analysis) and RNA-sequencing-based transcriptome analysis of a pair of isogenic RTT female patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) that expressed either MeCP2(wildtype) or MeCP2(mutant) allele and iPSC-CMs from a non-affected female control. The observations were further confirmed by additional experiments, including Wnt signaling inhibitor treatment, siRNA-based gene silencing, and ion channel blockade. Compared with MeCP2(wildtype) and control iPSC-CMs, MeCP2(mutant) iPSC-CMs exhibited prolonged action potential and increased frequency of spontaneous early after polarization. RNA sequencing analysis revealed up-regulation of various Wnt family genes in MeCP2(mutant) iPSC-CMs. Treatment of MeCP2(mutant) iPSC-CMs with a Wnt inhibitor XAV939 significantly decreased the β-catenin protein level and CACN1AC expression and ameliorated their abnormal electrophysiological properties. In summary, our data provide novel insight into the contribution of activation of the Wnt/β-catenin signaling cascade to the cardiac abnormalities associated with MeCP2 mutations in RTT.

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23. Rivard M, Mestari Z, Coulombe P, Morin D, Mello C, Morin M. Developmental and behavioral groupings can predict changes in adaptive behavior over time in young children with neurodevelopmental disorders. Research in developmental disabilities. 2023; 132: 104390.

The heterogeneity within, and the overlap between, diagnostic categories for neurodevelopmental disorders (NDDs) remain poorly understood. Developmental trajectories may diverge among children with the same diagnosis, who may also respond very differently to treatment. In a previous study, we used statistical clustering methods in a sample of 194 preschoolers who were referred for NDD assessment. We identified three distinct subgroups based on multiple developmental and behavioral variables. The present study aimed to identify: (1) early developmental markers at the surveillance and screening period that are predictive of subgroup membership at the diagnostic period (i.e., around age 5), (2) associations between subgroups and the evolution of adaptive behavior over the course of two years, and (3) predictors of adaptive behavior change. Subgroup membership was the only significant predictor of adaptive behavior change over time, which suggests that a clustering method based on developmental and behavioral profiles may be useful in treatment planning.

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24. Schmitt LM, Li J, Liu R, Horn PS, Sweeney JA, Erickson CA, Pedapati EV. Altered frontal connectivity as a mechanism for executive function deficits in fragile X syndrome. Molecular autism. 2022; 13(1): 47.

BACKGROUND: Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and autism spectrum disorder. Executive function (EF), necessary for adaptive goal-oriented behavior and dependent on frontal lobe function, is impaired in individuals with FXS. Yet, little is known how alterations in frontal lobe neural activity is related to EF deficits in FXS. METHODS: Sixty-one participants with FXS (54% males) and 71 age- and sex-matched typically-developing controls (TDC; 58% males) completed a five-minute resting state electroencephalography (EEG) protocol and a computerized battery of tests of EF, the Test of Attentional Performance for Children (KiTAP). Following source localization (minimum-norm estimate), we computed debiased weighted phase lag index (dWPLI), a phase connectivity value, for pairings between 18 nodes in frontal regions for gamma (30-55 Hz) and alpha (10.5-12.5 Hz) bands. Linear models were generated with fixed factors of group, sex, frequency, and connection. Relationships between frontal connectivity and EF variables also were examined. RESULTS: Individuals with FXS demonstrated increased gamma band and reduced alpha band connectivity across all frontal regions and across hemispheres compared to TDC. After controlling for nonverbal IQ, increased error rates on EF tasks were associated with increased gamma band and reduced alpha band connectivity. LIMITATIONS: Frontal connectivity findings are limited to intrinsic brain activity during rest and may not generalize to frontal connectivity during EF tasks or everyday function. CONCLUSIONS: We report gamma hyper-connectivity and alpha hypo-connectivity within source-localized frontal brain regions in FXS compared to TDC during resting-state EEG. For the first time in FXS, we report significant associations between EF and altered frontal connectivity, with increased error rate relating to increased gamma band connectivity and reduced alpha band connectivity. These findings suggest increased phase connectivity within gamma band may impair EF performance, whereas greater alpha band connectivity may provide compensatory support for EF. Together, these findings provide important insight into neurophysiological mechanisms of EF deficits in FXS and provide novel targets for treatment development.

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25. Shaheen G, Fleischman D. A case of JOAG in a patient with Rett syndrome. American journal of ophthalmology case reports. 2023; 29: 101762.

PURPOSE: In this report, we describe a case of juvenile open angle glaucoma in a patient with Rett syndrome. OBSERVATIONS: A 39- year-old white woman with a notable history of Rett syndrome was referred to our center with a ten-year diagnosis of juvenile open angle glaucoma. Initial exam was notable for complete cupping of the optic nerve. Upon follow up visits, intraocular pressures were elevated and remained refractory to multiple therapies, including SLT and pressure-lowering drops. Medical management was continued due to the risk of surgery and limited visual potential. Because it was declared that patient did not have substantial feedback to visual stimuli and did not exhibit any signs of pain, conservative management with drops was continued. CONCLUSION AND IMPORTANCE: This is the first report of a patient with concurrent Rett syndrome and juvenile open angle glaucoma, thus expanding on the literature of an ocular manifestation occurring presumably coincidentally with this disorder.

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26. Shevkoplyas D, Vuu YM, Davie JR, Rastegar M. The Chromatin Structure at the MECP2 Gene and In Silico Prediction of Potential Coding and Non-Coding MECP2 Splice Variants. International journal of molecular sciences. 2022; 23(24).

Methyl CpG binding protein 2 (MeCP2) is an epigenetic reader that binds to methylated CpG dinucleotides and regulates gene transcription. Mecp2/MECP2 gene has 4 exons, encoding for protein isoforms MeCP2E1 and MeCP2E2. MeCP2 plays key roles in neurodevelopment, therefore, its gain- and loss-of-function mutations lead to neurodevelopmental disorders including Rett Syndrome. Here, we describe the structure, functional domains, and evidence support for potential additional alternatively spliced MECP2 transcripts and protein isoforms. We conclude that NCBI MeCP2 isoforms 3 and 4 contain certain MeCP2 functional domains. Our in silico analysis led to identification of histone modification and accessibility profiles at the MECP2 gene and its cis-regulatory elements. We conclude that the human MECP2 gene associated histone post-translational modifications exhibit high similarity between males and females. Between brain regions, histone modifications were found to be less conserved and enriched within larger genomic segments named as « S1-S11 ». We also identified highly conserved DNA accessibility regions in different tissues and brain regions, named as « A1-A9 » and « B1-B9 ». DNA methylation profile was similar between mid-frontal gyrus of donors 35 days-25 years of age. Based on ATAC-seq data, the identified hypomethylated regions « H1-H8 » intersected with most regions of the accessible chromatin (A regions).

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27. Soyer-Gobillard MO, Gaspari L, Courtet P, Sultan C. Diethylstilbestrol and autism. Frontiers in endocrinology. 2022; 13: 1034959.

It is acknowledged that diethylstilbestrol (DES), a synthetic diphenol with powerful estrogenic properties, causes structural anomalies of the reproductive tract and increases the risk of cancer and genital malformations in children and grandchildren of mothers treated during pregnancy. Conversely, data on DES effects on neurodevelopment and psychiatric disorders in in-utero exposed children and their descendants are rare, especially concerning Autism Spectrum Disorders (ASD). Recent studies presented in this review strengthen the hypothesis that in-utero exposure to DES and also other synthetic estrogens and progestogens, which all are endocrine disruptors, contributes to the pathogenesis of psychiatric disorders, especially ASD. A large epidemiological study in the USA in 2010 reported severe depression in in-utero exposed children (n=1,612), and a French cohort study (n=1,002 in-utero DES exposed children) in 2016 found mainly bipolar disorders, schizophrenia, major depression, suicide attempts, and suicide. Few publications described ASD in in-utero exposed children, mainly a Danish cohort study and a large Chinese epidemiological study. Molecular studies on endocrine disruptors demonstrated the transgenerational induction of diseases and DES epigenetic impact (DNA methylation changes) at two genes implicated in neurodevelopment (ZFP57 and ADAM TS9). We recently described in an informative family, somatic and psychiatric disorders in four generations, particularly ASD in boys of the third and fourth generation. These data show that the principle of precaution must be retained for the protection of future generations: women (pregnant or not) should be extremely vigilant about synthetic hormones.

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28. Tao J, Hao R, Guo YT, Zhang W. [Characteristics of visual function in children with autism complicated with mental retardation]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology. 2022; 58(12): 1051-7.

Objective: To explore the characteristics of visual function and eye diseases in children with autism spectrum disorder (ASD) and mental retardation. Methods: It was a cross-sectional study. Two hundred and ninety-two cases (584 eyes) of children with ASD combined with mental retardation from 7 special education schools in Chaoyang District of Beijing, including 235 males (80.48%) and 57 females (19.52%); The age ranged from 2 to 18 years old. Subjective far and near vision, near stereoacuity, objective vision, diopter, anterior segment and fundus were examined. In addition, 300 students with normal intelligence level, aged 2 to 18 years, were included as controls. LogMAR was used to record vision examination. Subjective, objective vision and diopter were examined. Mann Whitney U test or Kruskal Wallis H test was used for the data of children with different genders, different age. Results: Among 584 eyes of children with ASD and mental retardation, 272 eyes (47.22%) were ametropia, 260 eyes (45.14%) were astigmatism, 29 eyes (5.03%) were hyperopia, 10 eyes (1.74%) were myopia, and 47 eyes (8.16%) were amblyopia risk factors. Among 292 children, there were 20 cases of strabismus (6.85%), 3 cases of color weakness (1.03%), and 4 cases of external eye abnormalities (1.37%). Two hundred and eleven children completed near stereopsis examination, of which 54 (25.59%) were within 100″ and 157 (74.41%) were within 200″ to 900″. Two hundred and seventy-two eyes with ametropia, 157 eyes (57.72%) needed correction but did not. The median and quartile of subjective and objective logMAR visual acuity were 0.22(0.10, 0.35), 0.10(0.00, 0.22), respectively; There were no significant differences in far visual acuity, near visual acuity, objective visual acuity, diopter, and near stereoacuity between different genders of ASD children with mild or moderate mental retardation (all P>0.05); There was a statistically significant difference in ASD children with mild mental retardation at different age rangs (H=21.453, P<0.001). There was a statistically significant difference in subjective tests such as far visual acuity and near visual acuity, for children with moderate mental retardation (Z=-3.508, -4.503; P<0.001). There was no statistically significant difference in objective visual acuity, diopter and near stereo acuity(all P>0.05). There are 300 healthy children as the control group, with LogMar’s subjective far vision is 0.10(0.00, 0.22), and the objective vision is 0.00(0.00, 0.10), diopter 0.25 (-0.25, 0.50) D. Compared with healthy children, ASD children with mental retardation had a significant difference in subjective far vision and objective vision (Z=-8.527, -10.393; P<0.001). There was no significant difference in diopter (Z=-1.274, P=0.203). Conclusions: The subjective and objective visual acuity of children with ASD combined with mental retardation was lower than that of healthy children. The prevalence and uncorrected rate of refractive errors, strabismus, amblyopia and other eye diseases were significantly higher than those of healthy children. Their refractive errors were mainly astigmatism, and the rates of correction and treatment were low.

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29. Taylor SC, Gehringer BN, Dow HC, Langer A, Rawot E, Smernoff Z, Steeman S, Almasy L, Rader DJ, Bučan M, Brodkin ES. Contrasting Views of Autism Spectrum Traits in Adults, Especially in Self-Reports vs. Informant-Reports for Women High in Autism Spectrum Traits. Journal of autism and developmental disorders. 2022: 1-13.

There is uncertainty among researchers and clinicians about how to best measure autism spectrum dimensional traits in adults. In a sample of adults with high levels of autism spectrum traits and without intellectual disability (probands, n = 103) and their family members (n = 96), we sought to compare self vs. informant reports of autism spectrum-related traits and possible effects of sex on discrepancies. Using correlational analysis, we found poor agreement between self- and informant-report measures for probands, yet moderate agreement for family members. We found reporting discrepancy was greatest for female probands, often self-reporting more autism-related behaviors. Our findings suggest that autism spectrum traits are often underrecognized by informants, making self-report data important to collect in clinical and research settings.

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30. Vithayathil J, Freeman C, Jacobwitz M, Schwartz ES, Agarwal S. Prolonged neurologic deficits with brain MRI changes following ECT in an adolescent with a CACNA1a-related disorder; a case report. BMC neurology. 2022; 22(1): 466.

BACKGROUND: Electroconvulsive therapy is used to treat depression and schizophrenia with infrequent use in pediatric patients. We report a case of an adolescent with autism spectrum disorder and acute catatonia that presented with status epilepticus (SE) and prolonged neurologic deficits with unilateral left cerebral edema on imaging following unilateral electroconvulsive therapy (ECT) on the right side, subsequently found to have a CACNA1a pathogenic variant. This case highlights a potential adverse effect of ECT in patients with CACNA1a related disorders. CASE: The patient received unilateral ECT to the right side and subsequently had an episode of SE with right-sided hemiplegia for 72 h prior to regaining some function with persistent mild right-hand weakness that persisted for at least 1-2 weeks. A brain MRI 2 days after ECT was unremarkable, but a repeat MRI on day four of admission showed left hemisphere cortical diffusion restriction, increased perfusion and T2 prolongation suggestive of cortical edema. They had whole exome genetic testing sent after discharge that showed a known pathogenic CACNA1a variant (p.I1709T). CACNA1a encodes the P/Q type calcium channels and deleterious variants in this gene result in a channelopathy associated with a spectrum of neurodevelopmental disorders that include autism spectrum disorder, hemiplegic migraine with unilateral cerebral edema, epileptic encephalopathies, or episodic ataxia syndromes. CONCLUSION: A literature review of ECT and neurologic deficits showed that most neurologic deficits resolve within 30 min of ECT. Case reports of prolonged deficits are rare and there are no prior reports of acute MRI changes related to ECT. Thus, the acute deterioration and MRI findings in this patient are likely related to the underlying CACNA1a channelopathy disorder with ECT as a precipitating event. This case report suggests care should be taken when using ECT in patients with pathogenic variants in CACNA1a. Furthermore, it reinforces the utility and importance of expanded genetic testing in patients with neurodevelopmental disorders as findings can provide valuable information that can guide treatment decisions.

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31. Wei Q, Cao H, Shi Y, Xu X, Li T. Machine learning based on eye-tracking data to identify Autism Spectrum Disorder: A systematic review and meta-analysis. Journal of biomedical informatics. 2022; 137: 104254.

BACKGROUND: Machine learning has been widely used to identify Autism Spectrum Disorder (ASD) based on eye-tracking, but its accuracy is uncertain. We aimed to summarize the available evidence on the performances of machine learning algorithms in classifying ASD and typically developing (TD) individuals based on eye-tracking data. METHODS: We searched Medline, Embase, Web of Science, Scopus, Cochrane Library, IEEE Xplore Digital Library, Wan Fang Database, China National Knowledge Infrastructure, Chinese BioMedical Literature Database, VIP Database for Chinese Technical Periodicals, from database inception to December 24, 2021. Studies using machine learning methods to classify ASD and TD individuals based on eye-tracking technologies were included. We extracted the data on study population, model performances, algorithms of machine learning, and paradigms of eye-tracking. This study is registered with PROSPERO, CRD42022296037. RESULTS: 261 articles were identified, of which 24 studies with sample sizes ranging from 28 to 141 were included (n = 1396 individuals). Machine learning based on eye-tracking yielded the pooled classified accuracy of 81 % (I(2) = 73 %), specificity of 79 % (I(2) = 61 %), and sensitivity of 84 % (I(2) = 61 %) in classifying ASD and TD individuals. In subgroup analysis, the accuracy was 88 % (95 % CI: 85-91 %), 79 % (95 % CI: 72-84 %), 71 % (95 % CI: 59-91 %) for preschool-aged, school-aged, and adolescent-adult group. Eye-tracking stimuli and machine learning algorithms varied widely across studies, with social, static, and active stimuli and Support Vector Machine and Random Forest most commonly reported. Regarding the model performance evaluation, 15 studies reported their final results on validation datasets, four based on testing datasets, and five did not report whether they used validation datasets. Most studies failed to report the information on eye-tracking hardware and the implementation process. CONCLUSION: Using eye-tracking data, machine learning has shown potential in identifying ASD individuals with high accuracy, especially in preschool-aged children. However, the heterogeneity between studies, the absence of test set-based performance evaluations, the small sample size, and the non-standardized implementation of eye-tracking might deteriorate the reliability of results. Further well-designed and well-executed studies with comprehensive and transparent reporting are needed to determine the optimal eye-tracking paradigms and machine learning algorithms.

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32. Wilson JE. Transcranial direct current stimulation for children with autism spectrum disorder: Implications for school-based settings. Developmental medicine and child neurology. 2022.

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33. Zhang Z, Hou M, Ou H, Wang D, Li Z, Zhang H, Lu J. Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders. Frontiers in endocrinology. 2022; 13: 1067529.

The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2-MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD.

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