1. Abbeduto L, Klusek J, Taylor JL, Abdelnur N, Sparapani N, Thurman AJ. Concurrent Associations between Expressive Language Ability and Independence in Adolescents and Adults with Fragile X Syndrome. Brain sciences. 2021; 11(9).

BACKGROUND: Few individuals with fragile X syndrome (FXS) successfully meet adult normative expectations in education, employment, peer relations, and habitation, although there is within-syndrome variability in this regard. The primary goal of this study was to determine whether expressive language skills contribute to the capacity for independent functioning in adulthood even after controlling for nonverbal cognitive ability. METHODS: Participants were 18- to 23-year-olds with FXS. Expressive language was assessed using the psychometrically validated Expressive Language Sampling (ELS) conversation and narration procedures. The language produced was transcribed and analyzed to yield measures of expressive vocabulary, syntax, and intelligibility. Parents concurrently completed questionnaires on the independent functioning of the participants with FXS. RESULTS: All three ELS measures were significantly corelated with multiple measures of independence. The magnitudes of the correlations were reduced when nonverbal IQ was controlled through partial correlation. Nonetheless, many of the partial correlations were medium to large and several were statistically significant. CONCLUSIONS: Expressive language skills appear to contribute uniquely to the capacity for independence, although longitudinal data are needed to evaluate the possibility of a bidirectional relationship between these domains. Thus, language intervention may be a prerequisite for preparing youth with FXS for an independent adult life.

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2. Adams JB, Bhargava A, Coleman DM, Frye RE, Rossignol DA. Ratings of the Effectiveness of Nutraceuticals for Autism Spectrum Disorders: Results of a National Survey. Journal of personalized medicine. 2021; 11(9).

Autism spectrum disorder (ASD) often involves a wide range of co-occurring medical conditions (« comorbidities ») and biochemical abnormalities such as oxidative stress and mitochondrial dysfunction. Nutritional supplements (« Nutraceuticals ») are often used to treat both core ASD symptoms and comorbidities, but some have not yet been formally evaluated in ASD. The potential biological mechanisms of nutraceuticals include correction of micronutrient deficiencies due to a poor diet and support for metabolic processes such as redox regulation, mitochondrial dysfunction and melatonin production. This paper reports on the results of the National Survey on Treatment Effectiveness for Autism, focusing on nutraceuticals. The Survey involved 1286 participants from across the United States. Participants rated the overall perceived benefits and adverse effects of each nutraceutical, and also indicated the specific symptoms changed and adverse effects. From these ratings the top-rated nutraceuticals for each of 24 symptoms are listed. Compared to psychiatric and seizure medications rated through the same Survey, on average nutraceuticals had significantly higher ratings of Overall Benefit (1.59 vs. 1.39, p = 0.01) and significantly lower ratings of Overall Adverse Effects (0.1 vs. 0.9, p < 0.001). Folinic acid and vitamin B12 were two of the top-rated treatments. This study suggests that nutraceuticals may have clinical benefits and favorable adverse effect profiles.

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3. Asahar SF, Malek KA, Isa MR. Quality of Life and Child’s Autism-Specific Difficulties among Malaysian Main Caregivers: A Cross-Sectional Study. International journal of environmental research and public health. 2021; 18(18).

Caring for children with autism spectrum disorder (ASD) negatively impacts quality of life (QoL). This cross-sectional study aimed to determine the factors associated with perceived QoL and how problematic a child’s autism-specific difficulties are among the main caregivers of children with ASD who attend specialized preschool programs at the National Autism Society of Malaysia and IDEAS Autism Centre located in Selangor and Kuala Lumpur. Utilizing the questions from Parts A and B of the Quality of Life in Autism Questionnaire (QoLA), the data from 116 responders were analyzed using univariate and multivariate linear regression. The mean scores of Part A and Part B were 88.55 ± 17.25 and 56.55 ± 12.35, respectively. The QoL was significantly associated with staying in an apartment/flat -11.37 (95%CI: -19.52, -1.17, p = 0.008), main caregivers attending two training sessions 10.35 (95%CI: 1.17, 19.52, p = 0.028), and more than three training sessions 13.36 (95%CI: 2.01, 24.70, p = 0.022). Main caregiver perceptions of their child’s autistic-specific difficulties were significantly associated with not receiving additional help for childcare: no maid -13.54 (95%CI: -24.17, -12.91, p = 0.013); no grandparent -8.65 (95%: -14.33, -2.96, p = 0.003); and main caregivers not having asthma 8.44 (95%CI: 0.02, 16.86, p = 0.049). These identified factors can be considered to inform main caregivers and health care providers on targeted ways to improve the QoL of main caregivers.

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4. Bruni O, Breda M, Ferri R, Melegari MG. Changes in Sleep Patterns and Disorders in Children and Adolescents with Attention Deficit Hyperactivity Disorders and Autism Spectrum Disorders during the COVID-19 Lockdown. Brain sciences. 2021; 11(9).

BACKGROUND: The COVID-19 lockdown determined important changes in the sleep of a large percentage of the world population. We assessed the modifications of reported sleep patterns and disturbances in Italian children and adolescents with autism spectrum disorders (ASD) or attention deficit hyperactivity disorders (ADHD), compared to control children, before and during the COVID-19 lockdown in Italy. METHODS: Parents of 100 ASD, 236 ADHD patients, and 340 healthy children filled out an anonymous online survey and a modified version of the Sleep Disturbance Scale for Children (SDSC), advertised via social media, to evaluate sleep patterns and disturbances of their children before and during the lockdown. RESULTS: Before the lockdown, bedtime and risetime were not different between the three groups. During the lockdown, ADHD children tended to have a later bedtime and risetime than ASD and controls, while ASD children tended to maintain similar bedtime and risetime. Overall, during the lockdown, a reduced sleep duration significantly differentiated clinical groups from controls. Anxiety at bedtime, difficulties in falling asleep, and daytime sleepiness increased in all groups during the lockdown. Hypnic jerks, rhythmic movement disorders, night awakenings, restless sleep, sleepwalking, and daytime sleepiness increased in ASD and ADHD patients, in particular. CONCLUSIONS: This is the first study comparing sleep habits and disorders in ASD and ADHD during the lockdown showing specific differences consistent with the core characteristics of two neurodevelopmental disorders.

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5. Caliendo M, Di Sessa A, D’Alterio E, Frolli A, Verde D, Iacono D, Romano P, Vetri L, Carotenuto M. Efficacy of Neuro-Psychomotor Approach in Children Affected by Autism Spectrum Disorders: A Multicenter Study in Italian Pediatric Population. Brain sciences. 2021; 11(9).

BACKGROUND: Autism Spectrum Disorder (ASD) is characterized by impairments in social interaction and reciprocal communication. ASD affects about 1% of the general population and is associated with substantial disability and economic loss. A variety of approaches to improve the core deficits and lives of people with ASD have been developed, including behavioral, developmental, educational, and medical interventions. The main objective of this study was to evaluate the efficacy of a neuro-psychomotor approach in children affected by ASD. METHODS: The sample consisted of 84 children (66 males, mean age 56.9 ± 15.8 months) affected by ASD assessed between September 2020 to March 2021. The trained therapist was asked to complete the ASD behavior inventory (ASDBI) test at baseline (T0) (September 2020) and after six months (T1) (March 2021) to assess the child’s evolution over the observational period. The study was carried out in southern Italy (Campania Region). RESULTS: ASD children showed a significant improvement for AUTISM composite after 6 months of neuro-psychomotor treatment (T1) compared to baseline (65.4 ± 12.2 vs. 75.8 ± 11.5, p < 0.0001). In particular, significant changes were observed for such domains as the problems of excitability (ECCIT), aggression (AGG), behaviors in social relations (RELSOC), expressive (all p < 0.001), sense/perceptual contact modes (SENS) (p = 0.0007), ritualisms/resistance to changes (RIT) (p = 0.0002), pragmatic/social problems (PPSOC) (p = 0.0009), specific fears (FEARS) (p = 0.01), and learning and memory (AMLR) (p = 0.0007). No differences for the domains Semantic/pragmatic problems (PPSEM) and language (LESP) were found. CONCLUSIONS: Our preliminary results suggest the usefulness of the neuro-psychomotor treatment in children with ASD. Although promising, these findings need to be tested further to better understand the long-term effects of this specific type of approach.

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6. Clipperton-Allen AE, Zhang A, Cohen OS, Page DT. Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice. Genes. 2021; 12(9).

Pten germline haploinsufficient (Pten(+/-)) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical-subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten(+/-) mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal « hard-wired » connectivity through enhancing synaptic plasticity. Thus, we reared Pten(+/-) mice and their wild-type littermates from weaning under either standard (4-5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9-10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten(+/-) mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten(+/-) mice and partially rescued increased repetitive behavior in Pten(+/-) males. We found that Pten(+/-) mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten(+/-) mice, possibly through normalizing the excitatory synaptic protein abundance.

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7. Czapski GA, Babiec L, Jęśko H, Gąssowska-Dobrowolska M, Cieślik M, Matuszewska M, Frontczak-Baniewicz M, Zajdel K, Adamczyk A. Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders. International journal of molecular sciences. 2021; 22(18).

Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease with serious neurological and mental symptoms, including autism. Mutations in the TSC1/TSC2 genes lead to the overactivation of mTOR signalling, which is also linked to nonsyndromic autism. Our aim was to analyse synaptic pathology in a transgenic model of TSC: two-month-old male B6;129S4-Tsc2(tm1Djk/J) mice with Tsc2 haploinsufficiency. Significant brain-region-dependent alterations in the expression of several synaptic proteins were identified. The most prominent changes were observed in the immunoreactivity of presynaptic VAMP1/2 (ca. 50% increase) and phospho-synapsin-1 (Ser62/67) (ca. 80% increase). Transmission electron microscopy demonstrated serious ultrastructural abnormalities in synapses such as a blurred structure of synaptic density and a significantly increased number of synaptic vesicles. The impairment of synaptic mitochondrial ultrastructure was represented by excessive elongation, swelling, and blurred crista contours. Polyribosomes in the cytoplasm and swollen Golgi apparatus suggest possible impairment of protein metabolism. Moreover, the delamination of myelin and the presence of vacuolar structures in the cell nucleus were observed. We also report that Tsc2(+/-) mice displayed increased brain weights and sizes. The behavioural analysis demonstrated the impairment of memory function, as established in the novel object recognition test. To summarise, our data indicate serious synaptic impairment in the brains of male Tsc2(+/-) mice.

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8. Frye RE, Rose S, McCullough S, Bennuri SC, Porter-Gill PA, Dweep H, Gill PS. MicroRNA Expression Profiles in Autism Spectrum Disorder: Role for miR-181 in Immunomodulation. Journal of personalized medicine. 2021; 11(9).

BACKGROUND: MicroRNAs (miRNAs) are important regulators of molecular pathways in psychiatric disease. Here, we examine differential miRNAs expression in lymphoblastoid cell lines (LCLs) derived from 10 individuals with autism spectrum disorder (ASD) and compare them to seven typically developing unrelated age- and gender-matched controls and 10 typically developing siblings. Small RNAseq analysis identified miRNAs, and selected miRNAs were validated using quantitative real-time polymerase reaction (qRT-PCR). KEGG analysis identified target pathways, and selected predicted mRNAs were validated using qRT-PCR. RESULTS: Small RNAseq analysis identified that multiple miRNAs differentiated ASD from unrelated controls and ASD from typically developing siblings, with only one, hsa-miR-451a_R-1, being in common. Verification with qRT-PCR showed that miR-320a differentiated ASD from both sibling and unrelated controls and that several members of the miR-181 family differentiated ASD from unrelated controls. Differential expression of AKT2, AKT3, TNF α and CamKinase II predicted by KEGG analysis was verified by qRT-PCR. Expression of CamKinase II βwas found to be correlated with the severity of stereotyped behavior of the ASD participants. CONCLUSIONS: This study provides insight into the mechanisms regulating molecular pathways in individuals with ASD and identifies differentiated regulated genes involved in both the central nervous system and the immune system.

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9. Fucà E, Lazzaro G, Costanzo F, Di Vara S, Menghini D, Vicari S. Implicit and Explicit Memory in Youths with High-Functioning Autism Spectrum Disorder: A Case-Control Study. Journal of clinical medicine. 2021; 10(18).

Individuals with autism spectrum disorder (ASD) usually manifest heterogeneous impairments in their higher cognitive functions, including their implicit memory (IM) and explicit memory (EM). However, the findings on IM and EM in youths with ASD remain debated. The aim of this study was to clarify such conflicting results by examining IM and EM using two comparable versions of the Serial Reaction Time Task (SRTT) in the same group of children and adolescents with ASD. Twenty-five youths with high-functioning ASD and 29 age-matched and IQ-matched typically developing youths undertook both tasks. The ability to implicitly learn the temporal sequence of events across the blocks in the SRTT was intact in the youths with ASD. When they were tested for EM, the participants with ASD did not experience a significant reduction in their reaction times during the blocks with the previously learned sequence, suggesting an impairment in EM. Moreover, the participants with ASD were less accurate and made more omissions than the controls in the EM task. The implications of these findings for the establishment of tailored educational programs for children with high-functioning ASD are discussed.

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10. Gawlińska K, Gawliński D, Borczyk M, Korostyński M, Przegaliński E, Filip M. A Maternal High-Fat Diet during Early Development Provokes Molecular Changes Related to Autism Spectrum Disorder in the Rat Offspring Brain. Nutrients. 2021; 13(9).

Autism spectrum disorder (ASD) is a disruptive neurodevelopmental disorder manifested by abnormal social interactions, communication, emotional circuits, and repetitive behaviors and is more often diagnosed in boys than in girls. It is postulated that ASD is caused by a complex interaction between genetic and environmental factors. Epigenetics provides a mechanistic link between exposure to an unbalanced maternal diet and persistent modifications in gene expression levels that can lead to phenotype changes in the offspring. To better understand the impact of the early development environment on the risk of ASD in offspring, we assessed the effect of maternal high-fat (HFD), high-carbohydrate, and mixed diets on molecular changes in adolescent and young adult offspring frontal cortex and hippocampus. Our results showed that maternal HFD significantly altered the expression of 48 ASD-related genes in the frontal cortex of male offspring. Moreover, exposure to maternal HFD led to sex- and age-dependent changes in the protein levels of ANKRD11, EIF4E, NF1, SETD1B, SHANK1 and TAOK2, as well as differences in DNA methylation levels in the frontal cortex and hippocampus of the offspring. Taken together, it was concluded that a maternal HFD during pregnancy and lactation periods can lead to abnormal brain development within the transcription and translation of ASD-related genes mainly in male offspring.

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11. Gawlińska K, Gawliński D, Kowal-Wiśniewska E, Jarmuż-Szymczak M, Filip M. Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring. International journal of molecular sciences. 2021; 22(18).

Epidemiological and preclinical studies suggest that maternal obesity increases the risk of autism spectrum disorder (ASD) in offspring. Here, we assessed the effects of exposure to modified maternal diets limited to pregnancy and lactation on brain development and behavior in rat offspring of both sexes. Among the studied diets, a maternal high-fat diet (HFD) disturbed the expression of ASD-related genes (Cacna1d, Nlgn3, and Shank1) and proteins (SHANK1 and TAOK2) in the prefrontal cortex of male offspring during adolescence. In addition, a maternal high-fat diet induced epigenetic changes by increasing cortical global DNA methylation and the expression of miR-423 and miR-494. As well as the molecular changes, behavioral studies have shown male-specific disturbances in social interaction and an increase in repetitive behavior during adolescence. Most of the observed changes disappeared in adulthood. In conclusion, we demonstrated the contribution of a maternal HFD to the predisposition to an ASD-like phenotype in male adolescent offspring, while a protective effect occurred in females.

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12. Gill PS, Clothier JL, Veerapandiyan A, Dweep H, Porter-Gill PA, Schaefer GB. Molecular Dysregulation in Autism Spectrum Disorder. Journal of personalized medicine. 2021; 11(9).

Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.

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13. Golubiani G, Lagani V, Solomonia R, Müller M. Metabolomic Fingerprint of Mecp2-Deficient Mouse Cortex: Evidence for a Pronounced Multi-Facetted Metabolic Component in Rett Syndrome. Cells. 2021; 10(9).

Using unsupervised metabolomics, we defined the complex metabolic conditions in the cortex of a mouse model of Rett syndrome (RTT). RTT, which represents a cause of mental and cognitive disabilities in females, results in profound cognitive impairment with autistic features, motor disabilities, seizures, gastrointestinal problems, and cardiorespiratory irregularities. Typical RTT originates from mutations in the X-chromosomal methyl-CpG-binding-protein-2 (Mecp2) gene, which encodes a transcriptional modulator. It then causes a deregulation of several target genes and metabolic alterations in the nervous system and peripheral organs. We identified 101 significantly deregulated metabolites in the Mecp2-deficient cortex of adult male mice; 68 were increased and 33 were decreased compared to wildtypes. Pathway analysis identified 31 mostly upregulated metabolic pathways, in particular carbohydrate and amino acid metabolism, key metabolic mitochondrial/extramitochondrial pathways, and lipid metabolism. In contrast, neurotransmitter-signaling is dampened. This metabolic fingerprint of the Mecp2-deficient cortex of severely symptomatic mice provides further mechanistic insights into the complex RTT pathogenesis. The deregulated pathways that were identified-in particular the markedly affected amino acid and carbohydrate metabolism-confirm a complex and multifaceted metabolic component in RTT, which in turn signifies putative therapeutic targets. Furthermore, the deregulated key metabolites provide a choice of potential biomarkers for a more detailed rating of disease severity and disease progression.

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14. González-Sala F, Gómez-Marí I, Tárraga-Mínguez R, Vicente-Carvajal A, Pastor-Cerezuela G. Symbolic Play among Children with Autism Spectrum Disorder: A Scoping Review. Children (Basel, Switzerland). 2021; 8(9).

Symbolic play is considered an early indicator in the diagnosis of autism spectrum disorder (ASD) and its assessment. The objective of this study was to analyze the difficulties in symbolic play experienced by children with ASD and to determine the existence of differences in symbolic play among children with ASD, children with other neurodevelopmental disorders and children with typical development. A scoping review was carried out in the Web of Science (WoS), Scopus, ERIC, and PsycInfo databases, following the extension for scoping reviews of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The number of papers included in the review was 22. The results confirm that children with ASD have greater difficulties with symbolic play than children with other neurodevelopmental disorders and children with typical development, even when controlling for their verbal age. Difficulties are greater in situations of free or spontaneous play. Results evidenced that the absence or deficiency in the symbolic play can serve as an early indicator of ASD between the first and second year of life, the developmental moment in which this type of play begins.

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15. Grosse SD, Nichols P, Nyarko K, Maenner M, Danielson ML, Shea L. Heterogeneity in Autism Spectrum Disorder Case-Finding Algorithms in United States Health Administrative Database Analyses. Journal of autism and developmental disorders. 2021.

Strengthening systems of care to meet the needs of individuals with autism spectrum disorder (ASD) is of growing importance. Administrative data provide advantages for research and planning purposes, including large sample sizes and the ability to identify enrollment in insurance coverage and service utilization of individuals with ASD. Researchers have employed varying strategies to identify individuals with ASD in administrative data. Differences in these strategies can limit the comparability of results across studies. This review describes implications of the varying strategies that have been employed to identify individuals with ASD in US claims databases, with consideration of the strengths and limitations of each approach.

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16. Haase F, Gloss BS, Tam PPL, Gold WA. WGCNA Identifies Translational and Proteasome-Ubiquitin Dysfunction in Rett Syndrome. International journal of molecular sciences. 2021; 22(18).

Rett Syndrome (RTT) is an X linked neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in severe cognitive and physical disabilities. Despite an apparent normal prenatal and postnatal development period, symptoms usually present around 6 to 18 months of age. Little is known about the consequences of MeCP2 deficiency at a molecular and cellular level before the onset of symptoms in neural cells, and subtle changes at this highly sensitive developmental stage may begin earlier than symptomatic manifestation. Recent transcriptomic studies of patient induced pluripotent stem cells (iPSC)-differentiated neurons and brain organoids harbouring pathogenic mutations in MECP2, have unravelled new insights into the cellular and molecular changes caused by these mutations. Here we interrogated transcriptomic modifications in RTT patients using publicly available RNA-sequencing datasets of patient iPSCs harbouring pathogenic mutations and healthy control iPSCs by Weighted Gene Correlation Network Analysis (WGCNA). Preservation analysis identified core gene pathways involved in translation, ribosomal function, and ubiquitination perturbed in some MECP2 mutant iPSC lines. Furthermore, differential gene expression of the parental fibroblasts and iPSC-derived neurons revealed alterations in genes in the ubiquitination pathway and neurotransmission in fibroblasts and differentiated neurons respectively. These findings might suggest that global translational dysregulation and proteasome ubiquitin function in Rett syndrome begins in progenitor cells prior to lineage commitment and differentiation into neural cells.

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17. Han JY, Park J. A Recurrent De Novo Terminal Duplication of 14q32 in Korean Siblings Associated with Developmental Delay and Intellectual Disability, Growth Retardation, Facial Dysmorphism, and Cerebral Infarction: A Case Report and Literature Review. Genes. 2021; 12(9).

The terminal 14q32 duplication has been reported often in association with other cytogenetic abnormalities, and individuals with this specific duplication showed varying degrees of developmental delay/intellectual disability (DD/ID) and growth retardation (GR), and distinct facial dysmorphisms. Herein, based on the limited cases of terminal duplication of 14q32 known to date, we present new affected siblings presenting with DD/ID, GR, and facial dysmorphism, as well as cerebral infarction caused by recurrent de novo der(14)t(14;14)(p11.2;q32.1) leading to terminal duplication of 14q32. We used coverage analysis generated via duo exome sequencing, performed chromosomal microarray (CMA) as a confirmatory test, and compared our findings with those reported previously. Coverage analysis generated via duo exome sequencing revealed a 17.2 Mb heterozygous duplication at chromosome 14q32.11-q32.33 with a Z ratio ranging between 0.5 and 1 in the proband and her elder brother. As a complementary method, CMA established a terminal duplication described as the arr[hg19]14q32.11q32.33(90,043,558_107,258,824)x3 in the proband and her elder brother; however, the parents and other siblings showed normal karyotyping and no abnormal gain or loss of CMA results. Five candidate genes, BCL11B, CCNK, YY1, DYNC1H1, and PACS2, were associated with the clinical phenotypes in our cases. Although the parents had normal chromosomes, two affected cases carrying terminal duplication of 14q32 can be explained by gonadal mosaicism. Further studies are needed to establish the association between cerebrovascular events and terminal duplication of chromosome 14q32, including investigation into the cytogenetics of patients with precise clinical descriptions.

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18. Hanley GE, Bickford C, Ip A, Lanphear N, Lanphear B, Weikum W, Zwaigenbaum L, Oberlander TF. Association of Epidural Analgesia During Labor and Delivery With Autism Spectrum Disorder in Offspring. Jama. 2021; 326(12): 1178-85.

IMPORTANCE: Evidence from studies investigating the association of epidural analgesia use during labor and delivery with risk of autism spectrum disorder (ASD) in offspring is conflicting. OBJECTIVE: To assess the association of maternal use of epidural analgesia during labor and delivery with ASD in offspring using a large population-based data set with clinical data on ASD case status. DESIGN, SETTING, AND PARTICIPANTS: This population-based retrospective cohort study included term singleton children born in British Columbia, Canada, between April 1, 2000, and December 31, 2014. Stillbirths and cesarean deliveries were excluded. Clinical ASD diagnostic data were obtained from the British Columbia Autism Assessment Network and the British Columbia Ministry of Education. All children were followed up until clinical diagnosis of ASD, death, or the study end date of December 31, 2016. EXPOSURES: Use of epidural analgesia during labor and delivery. MAIN OUTCOMES AND MEASURES: A clinical diagnosis of ASD made by pediatricians, psychiatrists, and psychologists with specialty training to assess ASD. Cox proportional hazards models were used to estimate the hazard ratio of epidural analgesia use and ASD. Models were adjusted for maternal sociodemographics; maternal conditions during pregnancy; labor, delivery, and antenatal care characteristics; infant sex; gestational age; and status of small or large for gestational age. A conditional logistic regression model matching women with 2 births or more and discordance in ASD status of the offspring also was performed. RESULTS: Of the 388 254 children included in the cohort (49.8% female; mean gestational age, 39.2 [SD, 1.2] weeks; mean follow-up, 9.05 [SD, 4.3] years), 5192 were diagnosed with ASD (1.34%) and 111 480 (28.7%) were exposed to epidural analgesia. A diagnosis of ASD was made for 1710 children (1.53%) among the 111 480 deliveries exposed to epidural analgesia (94 157 women) vs a diagnosis of ASD in 3482 children (1.26%) among the 276 774 deliveries not exposed to epidural analgesia (192 510 women) (absolute risk difference, 0.28% [95% CI, 0.19%-0.36%]). The unadjusted hazard ratio was 1.32 (95% CI, 1.24-1.40) and the fully adjusted hazard ratio was 1.09 (95% CI, 1.00-1.15). There was no statistically significant association of epidural analgesia use during labor and delivery with ASD in the within-woman matched conditional logistic regression (839/1659 [50.6%] in the exposed group vs 1905/4587 [41.5%] in the unexposed group; fully adjusted hazard ratio, 1.07 [95% CI, 0.87-1.30]). CONCLUSIONS AND RELEVANCE: In this population-based study, maternal epidural analgesia use during labor and delivery was associated with a small increase in the risk of autism spectrum disorder in offspring that met the threshold for statistical significance. However, given the likelihood of residual confounding that may account for the results, these findings do not provide strong supporting evidence for this association.

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19. Hollocks MJ, Charman T, Baird G, Lord C, Pickles A, Simonoff E. Exploring the impact of adolescent cognitive inflexibility on emotional and behavioural problems experienced by autistic adults. Autism : the international journal of research and practice. 2021: 13623613211046160.

Autistic people experience high levels of co-occurring mental health difficulties. To develop more effective treatments, a greater understanding of the thinking processes that may lead to these difficulties is needed. Cognitive inflexibility, defined as a rigid pattern of thoughts and subsequently behaviours, is one possible thinking trait which has previously been associated with both co-occurring mental health difficulties but also other features of autism such as restricted and repetitive behaviours. Restricted and repetitive behaviours include repetitive movements, ritualistic behaviours, and/or highly focused interests. This study investigates the relationship between, cognitive inflexibility, measured using neuropsychological tasks, and emotional and behavioural problems across adolescence and early adulthood. Eighty-one autistic people who were recruited to be representative of the wider autism population were assessed at 16 and 23 years on measures of emotional and behavioural problems, with cognitive inflexibility, restricted and repetitive behaviours and verbal intelligence measured at 16 years. We used statistical modelling to investigate the relationship between cognitive inflexibility and emotional and behavioural symptoms at both timepoints while accounting for the possible relationship with restricted and repetitive behaviours and verbal intelligence quotient. Our results suggest that cognitive inflexibility may be an important factor associated with emotional difficulties across adolescence and early adulthood. This suggests that developing intervention approaches targeting cognitive inflexibility may be an important step in improving the mental health of those with autism.

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20. Jensen AK, Sheldon CA, Paley GL, Szperka CL, Liu GW, Liu GT, McCormack SE. Autism Spectrum Disorder in Pediatric Idiopathic Intracranial Hypertension. Life (Basel, Switzerland). 2021; 11(9).

In recent years, the substantial burden of medical comorbidities in autism spectrum disorder (ASD) populations has been described. We report a retrospective observational case series of pediatric patients with suspected idiopathic intracranial hypertension (IIH) and concurrent ASD. Pediatric subjects with suspected IIH aged 2-18 years were identified by review of a pediatric neuro-ophthalmologist’s database spanning from July 1993 to April 2013. ASD diagnoses were identified within this cohort by an ICD-9 diagnosis code search and database review. Three subjects had concurrent ASD diagnoses; all were non-obese males. Since the retrospective observational case series was performed in April 2013, we identified three additional IIH cases in boys with ASD. Our experience suggests that IIH may be a comorbidity of ASD, particularly in non-obese boys.

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21. Kolic I, Radic Nisevic J, Vlasic Cicvaric I, Butorac Ahel I, Lah Tomulic K, Segulja S, Baraba Dekanic K, Serifi S, Ovuka A, Prpic I. GLUT1 Deficiency Syndrome-Early Treatment Maintains Cognitive Development? (Literature Review and Case Report). Genes. 2021; 12(9).

Glucose transporter type 1 (GLUT1) is the most important energy carrier of the brain across the blood-brain barrier, and a genetic defect of GLUT1 is known as GLUT1 deficiency syndrome (GLUT1DS). It is characterized by early infantile seizures, developmental delay, microcephaly, ataxia, and various paroxysmal neurological phenomena. In most cases, GLUT1DS is caused by heterozygous single-nucleotide variants (SNVs) in the SLC2A1 gene that provoke complete or severe impairment of the functionality and/or expression of GLUT1 in the brain. Despite the rarity of these diseases, GLUT1DS is of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms, especially if it is started as early as possible. We present a clinical phenotype, biochemical analysis, electroencephalographic and neuropsychological features of an 11-month-old boy with myoclonic seizures, hypogammaglobulinemia, and mildly impaired gross motor development. Using sequence analysis and deletion/duplication testing, deletion of an entire coding sequence in the SLC2A1 gene was detected. Early introduction of a modified Atkins diet maintained a seizure-free period without antiseizure medications and normal cognitive development in the follow-up period. Our report summarizes the clinical features of GLUT1 syndromes and discusses the importance of early identification and molecular confirmation of GLUT1DS as a treatable metabolic disorder.

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22. Lebon S, Quinodoz M, Peter VG, Gengler C, Blanchard G, Cina V, Campos-Xavier B, Rivolta C, Superti-Furga A. Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants. Genes. 2021; 12(9).

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.

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23. Lebrun N, Delépine C, Selloum M, Meziane H, Nectoux J, Herault Y, Bienvenu T. HDAC inhibitor ameliorates behavioral deficits in Mecp2(308/y) mouse model of Rett syndrome. Brain research. 2021; 1772: 147670.

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder. More than 95% of classic RETT syndrome cases result from pathogenic variants in the methyl-CpG binding protein 2 (MECP2) gene. Nevertheless, it has been established that a spectrum of neuropsychiatric phenotypes is associated with MECP2 variants in both females and males. We previously reported that microtubule growth velocity and vesicle transport directionality are altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared to that of their wild-type littermates suggesting deficit in microtubule dynamics. In this study, we report that administration of tubastatin A, a selective HDAC6 inhibitor, restored microtubule dynamics in Mecp2-deficient astrocytes. We furthermore report that daily doses of tubastatin A reversed early impaired exploratory behavior in male Mecp2(308/y) mice. These findings are a first step toward the validation of a novel treatment for RTT.

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24. Leung PWS, Li SX, Tsang CSO, Chow BLC, Wong WCW. Effectiveness of Using Mobile Technology to Improve Cognitive and Social Skills Among Individuals With Autism Spectrum Disorder: Systematic Literature Review. JMIR mental health. 2021; 8(9): e20892.

BACKGROUND: Mobile technology has become a necessity in the lives of people in many countries. Its characteristics and advantages also make it a potential medium of intervention for people with autism spectrum disorder (ASD). OBJECTIVE: The objective of this review was to evaluate previous evidence, obtained in randomized controlled trials (RCTs), on the effectiveness of using mobile devices as the medium of intervention targeting social and cognitive skills among individuals with ASD. METHODS: Literature search was conducted on electronic databases including Medline, PsycInfo, PsycArticles, Education Resources Information Centre, and Social Science Citation Index. Only RCTs published in English and after year 2000 were included for this review. Data extraction was carried out by 2 independent reviewers using constant comparative methods. RESULTS: Totally 10 RCTs were identified. Most of the findings indicated that mobile devices could be an effective medium of intervention for people with ASD, among which 6 indicated significant intervention effects and 2 showed mixed findings. Effective intervention was more likely to be achieved in the studies that recruited older participants (aged over 9 years), targeting practical skills that could be readily applied in real life, or using pictures or materials that were highly relevant in daily life in the apps or mobile devices. Furthermore, the use of mobile devices was also reported to promote participation in the intervention among individuals with ASD. CONCLUSIONS: The results suggested that mobile devices could be a promising means for the delivery of interventions targeting people with ASD. Although including a small number of studies was a limitation of this review, the results provided useful implications for designing effective mobile technology-assisted interventions for the ASD population in future studies.

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25. Lin R, Zhou H, Diao X, Wang J, Feng R, Wen T. A preliminary study on abnormal brain function and autistic behavior in mice caused by dcf1 deletion. Biochemical and biophysical research communications. 2021; 579: 29-34.

Autism is one of the urgent problems in neuroscience. Early research in our laboratory found that dcf1 gene-deficient mice exhibited autistic behavior. Reviewing the literature, we know that the caudate putamen (CPu) brain region is closely related to the occurrence of autism. In this study, we observed that the electrical signal in the abnormal brain region of adult mice was enhanced by using field potential detection for the corresponding brain region. We then used retrovirus markers to track neurons in the CPu brain region and found that there are neural projections in the hippocampus-CPu brain region. Therefore, we selected DREADDs (Designer receptors exclusively activated by designer drugs) to inhibit the abnormal brain region of the mouse and found, through behavioral testing, that this can inhibit the autistic behavior of mice. This research provides new evidence for the understanding of the cause of autism and has accumulated new basis for the treatment of autism. It has theoretical significance and potential application value for the understanding and treatment of autism.

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26. Lopez Garcia I, Saya UY, Luoto JE. Cost-effectiveness and economic returns of group-based parenting interventions to promote early childhood development: Results from a randomized controlled trial in rural Kenya. PLoS medicine. 2021; 18(9): e1003746.

BACKGROUND: Early childhood development (ECD) programs can help address disadvantages for the 43% of children under 5 in low- and middle-income countries (LMICs) experiencing compromised development. However, very few studies from LMIC settings include information on their program’s cost-effectiveness or potential returns to investment. We estimated the cost-effectiveness, benefit-cost ratios (BCRs), and returns on investment (ROIs) for 2 effective group-based delivery models of an ECD parenting intervention that utilized Kenya’s network of local community health volunteers (CHVs). METHODS AND FINDINGS: Between October 1 and November 12, 2018, 1,152 mothers with children aged 6 to 24 months were surveyed from 60 villages in rural western Kenya. After baseline, villages were randomly assigned to one of 3 intervention arms: a group-only delivery model with 16 fortnightly sessions, a mixed-delivery model combining 12 group sessions with 4 home visits, and a control group. At endline (August 5 to October 31, 2019), 1,070 children were retained and assessed for primary outcomes including cognitive and receptive language development (with the Bayley Scales of Infant Development, Third Edition) and socioemotional development (with the Wolke scale). Children in the 2 intervention arms showed better developmental outcomes than children in the control arm, although the group-only delivery model generally had larger effects on children. Total program costs included provider’s implementation costs collected during the intervention period using financial reports from the local nongovernmental organization (NGO) implementer, as well as societal costs such as opportunity costs to mothers and delivery agents. We combined program impacts with these total costs to estimate incremental cost-effectiveness ratios (ICERs), as well as BCRs and the program’s ROI for the government based on predictions of future lifetime wages and societal costs. Total costs per child were US$140 in the group-only arm and US$145 in the mixed-delivery arm. Because of higher intention-to-treat (ITT) impacts at marginally lower costs, the group-only model was the most cost-effective across all child outcomes. Focusing on child cognition in this arm, we estimated an ICER of a 0.37 standard deviation (SD) improvement in cognition per US$100 invested, a BCR of 15.5, and an ROI of 127%. A limitation of our study is that our estimated BCR and ROI necessarily make assumptions about the discount rate, income tax rates, and predictions of intervention impacts on future wages and schooling. We examine the sensitivity of our results to these assumptions. CONCLUSIONS: To the best of our knowledge, this study is the first economic evaluation of an effective ECD parenting intervention targeted to young children in sub-Saharan Africa (SSA) and the first to adopt a societal perspective in calculating cost-effectiveness that accounts for opportunity costs to delivery agents and program participants. Our cost-effectiveness and benefit-cost estimates are higher than most of the limited number of prior studies from LMIC settings providing information about costs. Our results represent a strong case for scaling similar interventions in impoverished rural settings, and, under reasonable assumptions about the future, demonstrate that the private and social returns of such investments are likely to largely outweigh their costs. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT03548558, June 7, 2018. American Economic Association RCT Registry trial AEARCTR-0002913.

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27. McMillion A, Tobiansky B, Wang K, Cronin AJ, Johnson A, Monteiro J, Remington A. UK-based specialist dental professionals’ experiences of working with autistic patients. Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2022; 42(2): 120-36.

Previous research has demonstrated that autistic individuals often experience difficulties accessing dental care, both as a result of autism specific difficulties and practitioners’ attitudes towards autism. However, very little research exists that explores dental professionals’ experiences of providing care to their autistic patients. The aim of this study was to investigate the strategies UK-based dental professionals’ use when working with autistic patients METHODS AND RESULTS: In this study, dental professionals (n = 16) from a variety of specialty roles (special care, paediatrics, orthodontics) were interviewed. We asked participants to talk through, in depth, specific cases they had encountered in their practice, what sorts of accommodations they had provided, and what concerns had arisen during appointments. Thematic analysis was used to analyses the data and revealed four main themes: the unique dental needs associated with being autistic, effective adaptations to practice, the crucial role of the caregiver, and the importance of specialist knowledge CONCLUSION: Recommendations for how dentists can improve the dental experiences of autistic patients can be drawn from the specialist dentists’ responses in this study. These include involving autistic patients in decisions about their treatment and being flexible and willing to work with autistic patients and their caregivers.

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28. Mikkelsen AP, Greiber IK, Scheller NM, Lidegaard Ø. Association of Labor Epidural Analgesia With Autism Spectrum Disorder in Children. Jama. 2021; 326(12): 1170-7.

IMPORTANCE: A recent cohort study found that epidural analgesia during labor was associated with an increased risk of autism in offspring. OBJECTIVE: To investigate if labor epidural increases the risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS: This nationwide retrospective cohort study identified all live-born children in Denmark between January 2006 and December 2013. Follow-up commenced at children’s first birthday and ended in December 2017. Among 485 093 live-born children, 5915 were excluded because of occurrences during the first year of life including death, emigration, misregistration of birth, diagnosis of disease inherently linked to autism, or diagnosis of autism. EXPOSURES: Administration of epidural analgesia during labor, as identified by procedure code. MAIN OUTCOMES AND MEASURES: The main outcome of interest was incident diagnosis of autism spectrum disorder based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes in the Danish Psychiatric Central Register or National Patient Register. Hazard ratios were estimated using Cox regression, adjusted for covariates describing maternal comorbidity, sociodemographic factors, lifestyle, pregnancy, psychiatric illness, psychotropic medication, medical-seeking behavior, and family history of autism. A secondary analysis used a within-mother design including only children of mothers with both exposure and nonexposure to labor epidural analgesia in different deliveries. RESULTS: The cohort included 479 178 children (233 405 girls [48.7%]; median maternal age at delivery, 30.9 [IQR, 27.6-34.2] years); of these, 92 900 (19.4%) were exposed to epidural analgesia during labor. Median follow-up was 7.0 years (IQR, 4.9-9.0 years), and by the end of follow-up, 6428 children (1.3%) had been diagnosed with autism. Exposed children had an autism diagnosis incidence rate of 23.1 per 10 000 person-years compared with 18.5 per 10 000 person-years in the unexposed group (crude hazard ratio, 1.29 [95% CI, 1.21-1.37]; adjusted hazard ratio, 1.05 [95% CI, 0.98-1.11]). A secondary within-mother analysis including 59 154 children (12.3%) estimated an autism diagnosis incidence rate of 20.8 per 10 000 person-years in the exposed group and 17.1 per 10 000 person-years in the unexposed group (adjusted hazard ratio, 1.05 [95% CI, 0.90-1.21]). CONCLUSIONS AND RELEVANCE: In this nationwide cohort study of Danish children, maternal exposure to epidural analgesia during labor was not significantly associated with autism spectrum disorder in offspring.

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29. Mitra M, Akobirshoev I, Valentine A, Brown HK, Moore Simas TA. Severe Maternal Morbidity and Maternal Mortality in Women With Intellectual and Developmental Disabilities. American journal of preventive medicine. 2021; 61(6): 872-81.

INTRODUCTION: Despite increased attention on severe maternal morbidity and maternal mortality, scant research exists on adverse maternal outcomes in women with disabilities. This study compares the rates of severe maternal morbidity and maternal mortality in women with and without intellectual and developmental disabilities. METHODS: This study used 2004-2017 Healthcare Cost and Utilization Project Nationwide Inpatient Sample data. Analyses were conducted in 2019‒2020. The risk of severe maternal morbidity with and without blood transfusion and maternal mortality during delivery among women with and without intellectual and developmental disabilities were compared using modified Poisson regression analysis. RESULTS: This study identified 32,324 deliveries to women with intellectual and developmental disabilities. Per 10,000 deliveries, 566 deliveries with severe maternal morbidity occurred in women with intellectual and developmental disabilities compared with 239 in women without intellectual and developmental disabilities. Women with intellectual and developmental disabilities had greater risk of both severe maternal morbidity (risk ratio=2.36, 95% CI=2.06, 2.69) and nontransfusion severe maternal morbidity (risk ratio=2.95, 95% CI=2.42, 3.61) in unadjusted analyses, which was mitigated in adjusted analyses for sociodemographic characteristics (risk ratio=1.74, 95% CI=1.47, 2.06; risk ratio=1.85, 95% CI=1.42, 2.41) and the expanded obstetric comorbidity index (risk ratio=1.23, 95% CI=1.04, 1.44; risk ratio=1.31, 95% CI=1.02, 1.68). The unadjusted incidence of maternal mortality in women with intellectual and developmental disabilities was 284 per 100,000 deliveries, nearly 4-fold higher than in women without intellectual and developmental disabilities (69 per 100,000 deliveries; risk ratio=4.07, 95% CI=2.04, 8.12), and the risk remained almost 3-fold higher after adjustment for sociodemographic characteristics (risk ratio=2.86, 95% CI=1.30, 6.29) and the expanded obstetric comorbidity index (risk ratio=2.30, 95% CI=1.05, 5.29). CONCLUSIONS: Women with intellectual and developmental disabilities are at increased risk of severe maternal morbidity and maternal mortality. These findings underscore the need for enhanced monitoring of the needs and maternal outcomes of women with intellectual and developmental disabilities in efforts to improve maternal health.

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30. Musetti A, Manari T, Dioni B, Raffin C, Bravo G, Mariani R, Esposito G, Dimitriou D, Plazzi G, Franceschini C, Corsano P. Parental Quality of Life and Involvement in Intervention for Children or Adolescents with Autism Spectrum Disorders: A Systematic Review. Journal of personalized medicine. 2021; 11(9).

Previous research has examined several parental, child-related, and contextual factors associated with parental quality of life (QoL) among parents with a child or an adolescent with autism spectrum disorders (ASD); however, no systematic review has examined the relationship between parental QoL and parental involvement in intervention. To fill this gap, a systematic review was conducted using four electronic databases and checked reference lists of retrieved studies. Records were included in the systematic review if they presented original data, assessed parental QoL, and involvement in intervention for children or adolescents with ASD, were published in peer-reviewed journals between 2000 and 2020, and were written in English. Among the 96 screened full-texts, 17 articles met the eligibility criteria. The selected studies included over 2000 parents of children or adolescents with ASD. Three categories of parental involvement (i.e., none, indirect, direct) were identified, which varied across studies, although most had direct parental involvement. The results from this review show that increased parental involvement in the intervention for children or adolescents with ASD may be one way to promote their QoL. However, further research specifically focused on parental involvement during the intervention for children and adolescents with ASD is warranted.

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31. Nader AM, Tullo D, Bouchard V, Degré-Pelletier J, Bertone A, Dawson M, Soulières I. Category learning in autism: Are some situations better than others?. Journal of experimental psychology General. 2022; 151(3): 578-96.

Autism is diagnosed according to atypical social-communication and repetitive behaviors. However, autistic individuals are also distinctive in the high variability of specific abilities such as learning. Having been characterized as experiencing great difficulty with learning, autistics have also been reported to learn spontaneously in exceptional ways. These contrasting accounts suggest that some situations may be better than others for learning in autism. We tested this possibility using a probabilistic category learning task with four learning situations differing either in feedback intensity or information presentation. Two learning situations compared high- versus low-intensity feedback, while two other learning situations without external feedback compared isolated sequentially presented information versus arrays of simultaneously presented information. We assessed the categorization and generalization performance of 54 autistic and 52 age-matched typical school-age children after they learned in different situations. We found that children in both groups were able to learn and generalize novel probabilistic categories in all four learning situations. However, across and within groups, autistic children were advantaged by simultaneously presented information while typical children were advantaged by high-intensity feedback when learning. These findings question some common aspects of autism interventions (e.g., frequent intense feedback, minimized simplified information), and underline the importance of improving our current understanding of how and when autistics learn optimally. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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32. Navarro L, Martinón-Torres F, Salas A. Sensogenomics and the Biological Background Underlying Musical Stimuli: Perspectives for a New Era of Musical Research. Genes. 2021; 12(9).

What is the actual impact of music on the human being and the scope for scientific research in this realm? Compared to other areas, the study of the relationship between music and human biology has received limited attention. At the same time, evidence of music’s value in clinical science, neuroscience, and social science keeps increasing. This review article synthesizes the existing knowledge of genetics related to music. While the success of genomics has been demonstrated in medical research, with thousands of genes that cause inherited diseases or a predisposition to multifactorial disorders identified, much less attention has been paid to other human traits. We argue for the development of a new discipline, sensogenomics, aimed at investigating the impact of the sensorial input on gene expression and taking advantage of new, discovery-based ‘omic’ approaches that allow for the exploration of the whole transcriptome of individuals under controlled experiments and circumstances.

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33. Neri de Souza Reis V, Tahira AC, Daguano Gastaldi V, Mari P, Portolese J, Feio Dos Santos AC, Lisboa B, Mari J, Caetano SC, Brunoni D, Bordini D, Silvestre de Paula C, Vêncio RZN, Quackenbush J, Brentani H. Environmental Influences Measured by Epigenetic Clock and Vulnerability Components at Birth Impact Clinical ASD Heterogeneity. Genes. 2021; 12(9).

Although Autism Spectrum Disorders (ASD) is recognized as being heavily influenced by genetic factors, the role of epigenetic and environmental factors is still being established. This study aimed to identify ASD vulnerability components based on familial history and intrauterine environmental stress exposure, explore possible vulnerability subgroups, access DNA methylation age acceleration (AA) as a proxy of stress exposure during life, and evaluate the association of ASD vulnerability components and AA to phenotypic severity measures. Principal Component Analysis (PCA) was used to search the vulnerability components from 67 mothers of autistic children. We found that PC1 had a higher correlation with psychosocial stress (maternal stress, maternal education, and social class), and PC2 had a higher correlation with biological factors (psychiatric family history and gestational complications). Comparing the methylome between above and below PC1 average subgroups we found 11,879 statistically significant differentially methylated probes (DMPs, p < 0.05). DMPs CpG sites were enriched in variably methylated regions (VMRs), most showing environmental and genetic influences. Hypermethylated probes presented higher rates in different regulatory regions associated with functional SNPs, indicating that the subgroups may have different affected regulatory regions and their liability to disease explained by common variations. Vulnerability components score moderated by epigenetic clock AA was associated with Vineland Total score (p = 0.0036, adjR(2) = 0.31), suggesting risk factors with stress burden can influence ASD phenotype.

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34. Ong SY, Roslan S, Ahmad NA, Ayub AFM, Chen LP, Taresh SM. Parents’ Experience in Children’s Friendship Training Programme for Their Children with Autism Spectrum Disorder: A Qualitative Inquiry. Children (Basel, Switzerland). 2021; 8(9).

BACKGROUND: Children’s Friendship Training (CFT) is a parent-assisted intervention programme that introduces children to basic sets of social rules to help them understand social contexts with specific guidance from their parents. It has been reported in several empirical studies that the friendship skills of children with autism spectrum disorder were enhanced after participating in CFT. However, previous studies only focused on the effectiveness of the training without exploring it from the parent’s perspective. As such, the objective of this study is to highlight the parents’ experience in assisting in the implementation of CFT. PURPOSE: To explore the parents’ experiences with autism spectrum disorder (ASD) in CFT and examine the experiences using the CFT as a theoretical framework. METHODOLOGY: In this study, eight parents and their school-aged children with ASD participated in 12 CFT sessions. Upon completing the CFT, the parents participated in a focus group interview. The interview session was video recorded and transcribed with the parents’ consent. Thematic analysis was employed in analysing the collected data as outlined in six different phases. RESULTS: The generated data revealed the similarities and differences in parents’ experiences in the CFT. The current study has identified four main themes: (1) fear and resistance; (2) awareness, learning, and adjustment; (3) change is hard; and (4) identifying support. CONCLUSIONS: The findings highlighted the processes that these parents experienced and encountered while attending the CFT programme, it is important to consider these processes based on how they might impact the effectiveness of the programme. The programme’s effectiveness is reliant on the ability to work closely with parents to understand their challenges and explore the type of support they need. This study has analysed the crucial factors that provide an overview of parents’ encounters in their participation in CFT.

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35. Parcerisas A, Ortega-Gascó A, Pujadas L, Soriano E. The Hidden Side of NCAM Family: NCAM2, a Key Cytoskeleton Organization Molecule Regulating Multiple Neural Functions. International journal of molecular sciences. 2021; 22(18).

Although it has been over 20 years since Neural Cell Adhesion Molecule 2 (NCAM2) was identified as the second member of the NCAM family with a high expression in the nervous system, the knowledge of NCAM2 is still eclipsed by NCAM1. The first studies with NCAM2 focused on the olfactory bulb, where this protein has a key role in axonal projection and axonal/dendritic compartmentalization. In contrast to NCAM1, NCAM2’s functions and partners in the brain during development and adulthood have remained largely unknown until not long ago. Recent studies have revealed the importance of NCAM2 in nervous system development. NCAM2 governs neuronal morphogenesis and axodendritic architecture, and controls important neuron-specific processes such as neuronal differentiation, synaptogenesis and memory formation. In the adult brain, NCAM2 is highly expressed in dendritic spines, and it regulates synaptic plasticity and learning processes. NCAM2’s functions are related to its ability to adapt to the external inputs of the cell and to modify the cytoskeleton accordingly. Different studies show that NCAM2 interacts with proteins involved in cytoskeleton stability and proteins that regulate calcium influx, which could also modify the cytoskeleton. In this review, we examine the evidence that points to NCAM2 as a crucial cytoskeleton regulation protein during brain development and adulthood. This key function of NCAM2 may offer promising new therapeutic approaches for the treatment of neurodevelopmental diseases and neurodegenerative disorders.

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36. Peralta-Marzal LN, Prince N, Bajic D, Roussin L, Naudon L, Rabot S, Garssen J, Kraneveld AD, Perez-Pardo P. The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders. International journal of molecular sciences. 2021; 22(18).

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders characterised by behavioural impairment and deficiencies in social interaction and communication. A recent study estimated that 1 in 89 children have developed some form of ASD in European countries. Moreover, there is no specific treatment and since ASD is not a single clinical entity, the identification of molecular biomarkers for diagnosis remains challenging. Besides behavioural deficiencies, individuals with ASD often develop comorbid medical conditions including intestinal problems, which may reflect aberrations in the bidirectional communication between the brain and the gut. The impact of faecal microbial composition in brain development and behavioural functions has been repeatedly linked to ASD, as well as changes in the metabolic profile of individuals affected by ASD. Since metabolism is one of the major drivers of microbiome-host interactions, this review aims to report emerging literature showing shifts in gut microbiota metabolic function in ASD. Additionally, we discuss how these changes may be involved in and/or perpetuate ASD pathology. These valuable insights can help us to better comprehend ASD pathogenesis and may provide relevant biomarkers for improving diagnosis and identifying new therapeutic targets.

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37. Perzolli S, Bentenuto A, Bertamini G, de Falco S, Venuti P. Father-Child Interactions in Preschool Children with ASD: A Systematic Review. Brain sciences. 2021; 11(9).

Studies on parental interaction in the context of ASD has mainly focused on mothers, even if fathers and their children seem to form close and supportive relationships that may have unique effects on child development. Given the impact of ASD symptoms on a child’s ability to interact with significant others, recent findings strengthen the importance of including caregivers during treatment to guarantee a better adaptation to the child’s impairments. Despite this, fathers are scarcely involved, and interventions seem to not be tailored to their interactive characteristics and needs. For this reason, a systematic review was conducted to investigate fathers and children with ASD behaviors during interaction. This review found 12 observational studies that identified social, cognitive, and affective interactive modalities in father-child dyads through three psychology-focused journal databases: PubMed, PsycINFO and Scopus. The significant variation in both sample size and in the measures used to assess dyadic outcomes limits the ability of this work to make robust recommendations for intervention. Despite this, the results revealed characteristic behaviors of this dyad that consequently allow specific targets to be worked on during intervention. In fact, from fathers’ individual strengths and weaknesses, it is possible to implement interventions that are complementary with maternal characteristics from the perspective of personalized and optimized treatment.

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38. Pines AR, Sussman B, Wyckoff SN, McCarty PJ, Bunch R, Frye RE, Boerwinkle VL. Locked-in Intact Functional Networks in Children with Autism Spectrum Disorder: A Case-Control Study. Journal of personalized medicine. 2021; 11(9).

Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to investigate abnormalities in brain network structure and connectivity on an individual level in neurodevelopmental disorders, such as autism spectrum disorder (ASD), paving the way toward using this technology for a personalized, precision medicine approach to diagnosis and treatment. Using a case-control design, we compared five patients with severe regressive-type ASD to five patients with temporal lobe epilepsy (TLE) to examine the association between brain network characteristics and diagnosis. All children with ASD and TLE demonstrated intact motor, language, and frontoparietal (FP) networks. However, aberrant networks not usually seen in the typical brain were also found. These aberrant networks were located in the motor (40%), language (80%), and FP (100%) regions in children with ASD, while children with TLE only presented with aberrant networks in the motor (40%) and language (20%) regions, in addition to identified seizure onset zones. Fisher’s exact test indicated a significant relationship between aberrant FP networks and diagnosis (p = 0.008), with ASD and atypical FP networks co-occurring more frequently than expected by chance. Despite severe cognitive delays, children with regressive-type ASD may demonstrate intact typical cortical network activation despite an inability to use these cognitive facilities. The functions of these intact cognitive networks may not be fully expressed, potentially because aberrant networks interfere with their long-range signaling, thus creating a unique « locked-in network » syndrome.

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39. Piro-Gambetti B, Rodriguez G, Papp LM, Greenlee JL, Hartley SL. Parent couple conflict and emotional and behavioral problems in youth with autism: Longitudinal investigation of bidirectional effects. Development and psychopathology. 2021: 1-11.

Families of youth with autism spectrum disorder (ASD) are vulnerable to maladaptive psychosocial experiences, including elevated youth emotional and behavioral problems (EBPs) and poor parent couple relationship outcomes. Yet, the extent to which these family psychosocial experiences are intertwined has been given little research attention. The present study longitudinally investigated the bidirectional associations between parent couple conflict (PCC) and youth EBPs in 188 families of children and adolescents with ASD (initially aged 5 to 12 years) across four time points (T1, T2, T3, T4), each spaced 12 months apart. Mother- and father-report of youth EBPs and PCC were entered into a cross-lagged panel model. After adjusting for youth age and intellectual disability status and parent education and couple relationship length, the results indicated that father-report of PCC predicted increased youth EBPs 12 months later (T1→T2 and T2→T3). In addition, father-report of youth EBPs predicted increased PCC 12 months later (T3→T4). Mother-report did not demonstrate cross-lagged effects. The findings suggest that fathers’ perceptions of PCC and youth emotional and behavioral functioning are transactionally related, highlighting the need for family-wide interventions.

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40. Popovac A, Pficer JK, Stančić I, Vuković A, Marchini L, Kossioni A. Translation and preliminary validation of the Serbian version of an ageism scale for dental students (ASDS-Serb). Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. 2022; 42(2): 160-9.

AIMS: The ageist attitudes among dental clinicians may result in inadequate treatment planning and reduce quality of life for older adults. This study aimed at performing a preliminary validation of an ageism scale for dental students (ASDS) in Serbia (ASDS-Serb). METHODS AND RESULTS: The 27-item ASDS was translated from English into Serbian and completed by 129 dental students. Principal component analysis (PCA), Confirmatory factor analysis (CFA), internal consistency reliability and discriminant validity were estimated. PCA produced a 17-item scale distributed into five factors that explain 64.24% of the total variance. All items showed high to moderate reliability (0.50-0.83). CFA indicates an acceptable model fit with significant standardized factor loadings ranging from 0.14-0.99. The first factor dealt with negative views of older adults’ life and dental treatment, the second factor related to ethical values about older people, the third factor compared younger and older adults in dental care and the fourth factor related to difficulties in medical history taking. The fifth factor related to perceptions of oral health and treatment of older adults. Discriminant validity revealed significant differences related to the semester of studies, gender and having older people in the family. CONCLUSION: The preliminary validation of the ASDS-Serb resulted in a 17-item scale distributed into the five factors with acceptable validity and reliability.

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41. Prosperi M, Santocchi E, Brunori E, Cosenza A, Tancredi R, Muratori F, Calderoni S. Prevalence and Clinical Features of Celiac Disease in a Cohort of Italian Children with Autism Spectrum Disorders. Nutrients. 2021; 13(9).

BACKGROUND: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions whose etiopathogenesis derives from a complex interaction between genetic liability and environmental factors. In this framework, mounting evidence suggests that immune system dysfunction could be a risk factor contributing to the development of ASD in at least a subpopulation of individuals. In particular, some studies suggest an association between celiac disease (CD)-a long-term autoimmune disorder that primarily affects the small intestine triggered by the ingestion of gluten-and ASD, while others hypothesized a random link. This investigation aimed to evaluate the prevalence of CD in a large sample of school-aged children with ASD and to characterize their clinical profile. METHODS: Medical records of 405 children with ASD aged 5-11 years (mean age: 7.2 years; SD: 1.8 years) consecutively referred to a tertiary-care university hospital between January 2014 and December 2018 were reviewed; among them, 362 had carried out serological testing for CD. RESULTS: Nine patients with positive CD serology were identified, eight of which satisfied the criteria for CD diagnosis. The estimated CD prevalence in ASD children was 2.18% (95% CI, 0.8-3.7), which was not statistically different (1.58%; p = 0.36) from that of an Italian population, matched for age range, considered as a control group (95% CI, 1.26-1.90). Three out of the eight ASD patients with CD did not have any symptoms suggestive of CD. CONCLUSIONS: Our findings did not show a higher prevalence of CD in ASD children than in the control population, but could suggest the utility of routine CD screening, given its frequent atypical clinical presentation in this population.

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42. Ribeiro AH, Vidal MC, Sato JR, Fujita A. Granger Causality among Graphs and Application to Functional Brain Connectivity in Autism Spectrum Disorder. Entropy (Basel, Switzerland). 2021; 23(9).

Graphs/networks have become a powerful analytical approach for data modeling. Besides, with the advances in sensor technology, dynamic time-evolving data have become more common. In this context, one point of interest is a better understanding of the information flow within and between networks. Thus, we aim to infer Granger causality (G-causality) between networks’ time series. In this case, the straightforward application of the well-established vector autoregressive model is not feasible. Consequently, we require a theoretical framework for modeling time-varying graphs. One possibility would be to consider a mathematical graph model with time-varying parameters (assumed to be random variables) that generates the network. Suppose we identify G-causality between the graph models’ parameters. In that case, we could use it to define a G-causality between graphs. Here, we show that even if the model is unknown, the spectral radius is a reasonable estimate of some random graph model parameters. We illustrate our proposal’s application to study the relationship between brain hemispheres of controls and children diagnosed with Autism Spectrum Disorder (ASD). We show that the G-causality intensity from the brain’s right to the left hemisphere is different between ASD and controls.

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43. Sanchez-Jimeno C, Blanco-Kelly F, López-Grondona F, Losada-Del Pozo R, Moreno B, Rodrigo-Moreno M, Martinez-Cayuelas E, Riveiro-Alvarez R, Fenollar-Cortés M, Ayuso C, Rodríguez de Alba M, Lorda-Sanchez I, Almoguera B. Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation. Genes. 2021; 12(9).

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3′ end of the gene, confirming the genotype-phenotype correlation initially described.

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44. Sanderson K. High-profile autism genetics project paused amid backlash. Nature. 2021; 598(7879): 17-8.

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45. Sullivan EC, Halstead EJ, Ellis JG, Dimitriou D. Anxiety, Insomnia, and Napping Predict Poorer Sleep Quality in an Autistic Adult Population. International journal of environmental research and public health. 2021; 18(18).

Autistic adults have a high prevalence of sleep problems and psychiatric conditions. In the general population sleep problems have been associated with a range of demographic and lifestyle factors. Whether the same factors contribute to different types of disturbed sleep experienced by autistic adults is unknown and served as the main aim of this study. An online survey was conducted with 493 autistic adults. Demographic information (e.g., age, gender), about lifestyle (e.g., napping), and information about comorbid conditions was collected. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and the Epworth Sleepiness Scale (ESS) was used to assess daytime somnolence. Stepwise multiple regression analyses were used to examine predictors of each subscale score on the PSQI, as well as PSQI and ESS total scores. Results indicated that individuals who reported having a diagnosis of anxiety and insomnia were more likely to have poorer sleep quality outcomes overall. Furthermore, individuals who reported habitually napping had higher daytime dysfunction, increased sleep disturbances, and increased daytime sleepiness. These results provide novel insights into the demographic and lifestyle factors that influence sleep quality and daytime somnolence in autistic adults and can be used for targeted sleep interventions.

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46. Theoharides TC. Ways to Address Perinatal Mast Cell Activation and Focal Brain Inflammation, including Response to SARS-CoV-2, in Autism Spectrum Disorder. Journal of personalized medicine. 2021; 11(9).

The prevalence of autism spectrum disorder (ASD) continues to increase, but no distinct pathogenesis or effective treatment are known yet. The presence of many comorbidities further complicates matters, making a personalized approach necessary. An increasing number of reports indicate that inflammation of the brain leads to neurodegenerative changes, especially during perinatal life, « short-circuiting the electrical system » in the amygdala that is essential for our ability to feel emotions, but also regulates fear. Inflammation of the brain can result from the stimulation of mast cells-found in all tissues including the brain-by neuropeptides, stress, toxins, and viruses such as SARS-CoV-2, leading to the activation of microglia. These resident brain defenders then release even more inflammatory molecules and stop « pruning » nerve connections, disrupting neuronal connectivity, lowering the fear threshold, and derailing the expression of emotions, as seen in ASD. Many epidemiological studies have reported a strong association between ASD and atopic dermatitis (eczema), asthma, and food allergies/intolerance, all of which involve activated mast cells. Mast cells can be triggered by allergens, neuropeptides, stress, and toxins, leading to disruption of the blood-brain barrier (BBB) and activation of microglia. Moreover, many epidemiological studies have reported a strong association between stress and atopic dermatitis (eczema) during gestation, which involves activated mast cells. Both mast cells and microglia can also be activated by SARS-CoV-2 in affected mothers during pregnancy. We showed increased expression of the proinflammatory cytokine IL-18 and its receptor, but decreased expression of the anti-inflammatory cytokine IL-38 and its receptor IL-36R, only in the amygdala of deceased children with ASD. We further showed that the natural flavonoid luteolin is a potent inhibitor of the activation of both mast cells and microglia, but also blocks SARS-CoV-2 binding to its receptor angiotensin-converting enzyme 2 (ACE2). A treatment approach should be tailored to each individual patient and should address hyperactivity/stress, allergies, or food intolerance, with the introduction of natural molecules or drugs to inhibit mast cells and microglia, such as liposomal luteolin.

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47. Tosca L, Drévillon L, Mouka A, Lecerf L, Briand A, Ortonne V, Benoit V, Brisset S, Van Maldergem L, Laudouar Q, Heide S, Goossens M, Giurgea I, Tachdjian G, Métay C. Two new cases of interstitial 7q35q36.1 deletion including CNTNAP2 and KMT2C. Molecular genetics & genomic medicine. 2021; 9(11): e1645.

BACKGROUND: Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. METHODS: We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide-based array-CGH analysis. RESULTS: The common clinical features were abnormal maternal serum screening during first-trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio-facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. CONCLUSION: Combined haploinsufficiency of GALNTL5 (alias GalNAc-T5L), CUL1, SSPO (aliases SCO-spondin, KIAA0543, and FLJ36112), AOC1 (alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient.

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48. Valicenti-McDermott M, Rivelis E, Bernstein C, Cardin MJ, Seijo R. Screening for Depression in Adolescents with Developmental Disabilities: Brief Report. Journal of child and adolescent psychopharmacology. 2021; 31(8): 572-6.

Objectives: (1) To examine adherence of universal screening for adolescent depression at initial visits by using an established screening instrument (Patient Health Questionnaire 9 [PHQ-9]) in a university-affiliated urban developmental center that serves children with developmental disabilities (DDs); (2) to study the frequency of positive screening for depression in adolescents with DD. Methods: Review of all adolescents referred for multidisciplinary evaluation in a developmental center in 2019. Data included demographics, DD diagnoses, and use of and scores on the PHQ-9 at initial visit. Statistics included chi-square and non-parametrics. Results: Of all the children evaluated in 2019 (n = 240), 52 were adolescents, 35 boys (63%)/17 girls (37%), age 14 ± 2 years old, and 27 (54%) belonging to a bilingual English-Spanish household. DD: Developmental Language Disorder (88%), Learning Disabilities (54%), attention-deficit/hyperactivity disorder (44%), Autism Spectrum Disorder (25%), Intellectual Disabilities (12%), and Phonological Disorder (8%). The PHQ-9 was administered to 30 (58%) individuals. Scores varied from minimal depression for 17 (57%), mild for 10 (33%), and moderate and severe for 3 (10%); 3 patients endorsed suicidality. Females were more likely to obtain higher scores on the PHQ-9 than males. Adolescents diagnosed with Autism Spectrum Disorder, Intellectual Disabilities, and Phonological Disorder were less likely to be screened. Conclusion: More than half of the sample of urban adolescents with DD were screened for depression at initial visit, and 10% screened positive for moderate to severe depression. Efforts to follow the U.S. Preventive Services Task Force recommendation of universal screening of adolescent depression should continue. However, given challenges with reading and verbal abilities, screening modifications (reading to them) should be considered.

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49. Veselinović A, Petrović S, Žikić V, Subotić M, Jakovljević V, Jeremić N, Vučić V. Neuroinflammation in Autism and Supplementation Based on Omega-3 Polyunsaturated Fatty Acids: A Narrative Review. Medicina (Kaunas, Lithuania). 2021; 57(9).

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction across multiple contexts and restricted, repetitive patterns of behavior, interests and activities. The maternal status of polyunsaturated fatty acids (PUFA) regulates microglial activity and neuroinflammatory pathways during a child’s brain development. In children with ASD, the metabolism of PUFA is thought to be deficient or abnormal, leading to increased production of proinflammatory cytokines, increased oxidative stress and an imbalance in the formation and action of neurotransmitters. In addition, nutritional deficits in omega-3 PUFA may affect gut microbiota and contribute to ASD by the gut-brain axis. The aim of this study was to review the possible role of neuroinflammation in ASD development and the effect of omega-3 PUFA supplementation in children with ASD. Due to a wide heterogeneity across RCTs, no definitive conclusion about omega-3 PUFA effects in ASD can be drawn. Supplementation with PUFA could be considered as one of the aspects in regulating the biological status of the organism and could provide added value to standard medical and psychological interventions for reducing behavioral deficits.

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50. Wang C. Mental health and social support of caregivers of children and adolescents with ASD and other developmental disorders during COVID-19 pandemic. Journal of affective disorders reports. 2021; 6: 100242.

BACKGROUND: Previous studies showed that caregivers of children with autism spectrum disorder (ASD) and other developmental disorders had higher levels of parenting stress, anxiety and depression. In the present study, the author examined the caregivers’ mental health and investigated the mediating role of social support between symptoms severity and parenting stress during COVID-19. METHODS: During 20 March to 8 April 2020, 1932 caregivers of children and adolescents with ASD and other developmental disorders from China were enrolled to fill in a sociodemographic questionnaire, Depression, Anxiety and Stress Scale and Social Support Rating Scale. The author also collected children’s disability severity symptoms and behavioral problems. RESULTS: The results showed that 46.01% of the caregivers reported symptoms of depression, 44.67% showed anxiety and 44.62% showed stress during COVID-19 pandemic. Fathers were found to get more subjective support than mothers (P < 0.05). Caregivers who had the highest educational attainment had the most social support (P = 0.01). People who had the more household income showed the significantly lower levels of depression and anxiety (P < 0.05). The caregivers' employment status during COVID-19 was found significantly related with their depression, anxiety, stress and social support (P < 0.05). LIMITATIONS: This study has some limitations, such as it did not conduct the longitudinal analysis of variables before COVID-19. CONCLUSIONS: The findings showed that many caregivers experienced mental health problems during COVID-19. The author suggested to promote caregivers' engagement in functional social support and the behavioral interventions for their children to reduce the impact of stress, anxiety and depression.

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51. Wang SY, Cheng YY, Guo HR, Tseng YC. Air Pollution during Pregnancy and Childhood Autism Spectrum Disorder in Taiwan. International journal of environmental research and public health. 2021; 18(18).

Air pollutants have been linked to some diseases in humans, but their effects on the nervous system were less frequently evaluated. Autism spectrum disorder (ASD) is a group of neurondevelopmental disorders of which the etiology is still unknown. We conducted a study in Taiwan to evaluate the possible associations between prenatal exposure to air pollutants and ASD. From a random sample of one million people in the National Insurance Research Database, we identified all the infants born between 1996 and 2000. We followed them till the end of 2013 and identified cases of ASD. We traced back the mothers’ residence and assessed the exposure to air pollutants using the data obtained from the air quality monitoring database maintained by the government, which included ozone (O(3)), carbon monoxide (CO), nitrogen dioxide (NO(2)), sulfur dioxide (SO(2)), and particulate matters with diameter less than 10 µm (PM(10)). Cox proportional hazard models were constructed to evaluate the associations between childhood ASD and exposures to the pollutants in the three trimesters and the whole gestation. We identified a total of 63,376 newborns and included 62,919 as the study cohort. After adjusting for other risk factors, we observed trimester-specific associations between levels of CO, NO(2), and PM(10) and the risk of childhood ASD. An increase of 1 ppm of CO in the first, second, and third trimester was associated with a hazard ratio (HR) of 1.93 (95% confidence interval [CI]: 1.55-2.39), 1.77 (95%CI: 1.41-2.22), and 1.75 (95%CI: 1.39-2.21), respectively. An increase of 10 ppb in the level of NO(2) in the first, second, and third trimester was associated with an HR of 1.39 (95%CI: 1.22-1.58), 1.25 (95%CI: 1.10-1.42), and 1.18 (95%CI: 1.03-1.34), respectively. In conclusion, we found that exposures to CO and NO(2) in all three trimesters were associated with increased risks of developing ASD.

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52. Wong CA, Stevens H. Labor Epidural Analgesia and Autism Spectrum Disorder: Is There an Association?. Jama. 2021; 326(12): 1155-7.

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53. Yoon WH. Why Fast COVID-19 Vaccination Needed for People with Disabilities and Autistics in Korea?. Journal of Korean medical science. 2021; 36(37): e267.

Coronavirus disease 2019 (COVID-19) has negatively affected the lives of people with disabilities; therefore, they need fast vaccination allocation. However, many countries, especially the Republic of Korea, have hesitated to vaccinate people with disabilities. This opinion article will explain why vaccine allocation priority is required for autistic people and people with disabilities in the COVID-19 pandemic crisis, including reporting on self-quarantine’s stresses and psychological burdens.

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54. Young N, Asif M, Jackson M, Fernández-Mayoralas DM, de la Peña MJ, Calleja-Pérez B, Álvarez S, Hunter-Featherstone E, Noegel AA, Höhne W, Nürnberg P, Obara B, Hussain MS, Karakesisoglou I, Fernández-Jaén A. Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism. Genes. 2021; 12(9).

Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

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