1. Dickstein DP, Barthelemy CM, Jenkins GA, DeYoung LLA, Gilbert AC, Radoeva P, Kim KL, MacPherson HA. This Is Your Brain on Irritability: A Clinician’s Guide to Understanding How We Know What We Know Now, and What We Need to Know in the Future, About Irritability in Children and Adolescents. Child and adolescent psychiatric clinics of North America. 2021; 30(3): 649-66.

Irritability is a common reason why children and adolescents are brought for psychiatric care. Although research is advancing what is known about the underlying brain and behavior mechanisms of irritability, clinicians often are shut out of that research. This article explains some of these research methods, providing brief summaries of what is known about brain/behavior mechanisms in disorders involving irritability, including bipolar disorder, disruptive mood dysregulation disorder, attention-deficit/hyperactivity disorder, and autism spectrum disorder. Greater access to these methods may help clinicians now and in the future, with such mechanisms translated into improved care, as occurs in the treatment of childhood leukemia.

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2. Hansen N, Luedecke D, Malchow B, Lipp M, Vogelgsang J, Timäus C, Zindler T, Gingele S, Kühn S, Gallinat J, Wiedemann K, Denk J, Moschny N, Fiehler J, Skripuletz T, Riedel C, Wattjes MP, Zerr I, Esselmann H, Poustka L, Karow A, Hartmann H, Frieling H, Bleich S, Wiltfang J, Neyazi A. Autoantibody-associated psychiatric syndromes in children: link to adult psychiatry. Journal of neural transmission (Vienna, Austria : 1996). 2021; 128(6): 735-47.

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

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3. Holm KN, Herren AW, Taylor SL, Randol JL, Kim K, Espinal G, Martínez-Cerdeño V, Pessah IN, Hagerman RJ, Hagerman PJ. Corrigendum: Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome. Frontiers in molecular biosciences. 2021; 8: 695407.

[This corrects the article DOI: 10.3389/fmolb.2020.600840.].

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4. Jeckel P, Kriebel M, Volkmer H. Autism Spectrum Disorder Risk Factor Met Regulates the Organization of Inhibitory Synapses. Frontiers in molecular neuroscience. 2021; 14: 659856.

A common hypothesis explains autism spectrum disorder (ASD) as a neurodevelopmental disorder linked to excitatory/inhibitory (E/I) imbalance in neuronal network connectivity. Mutation of genes including Met and downstream signaling components, e.g., PTEN, Tsc2 and, Rheb are involved in the control of synapse formation and stabilization and were all considered as risk genes for ASD. While the impact of Met on glutamatergic synapses was widely appreciated, its contribution to the stability of inhibitory, GABAergic synapses is poorly understood. The stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin. Here, we show in vivo and in vitro that Met is necessary and sufficient for the stabilization of GABAergic synapses via induction of gephyrin clustering. Likewise, we provide evidence for Met-dependent gephyrin clustering via activation of mTOR. Our results support the notion that deficient GABAergic signaling represents a pathomechanism for ASD.

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5. Li Q, Yang T, Chen L, Dai Y, Wu LJ, Jia FY, Hao Y, Li L, Zhang J, Ke XY, Yi MJ, Hong Q, Chen JJ, Fang SF, Wang YC, Wang Q, Jin CH, Dong ZF, Chen J, Li TY. Serum Folate Status Is Primarily Associated With Neurodevelopment in Children With Autism Spectrum Disorders Aged Three and Under-A Multi-Center Study in China. Frontiers in nutrition. 2021; 8: 661223.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Folate has been demonstrated to be associated with ASD. However, current studies on the correlation between folate and symptoms of children with ASD have inconsistent conclusions, use mainly small samples, and lack age-stratified analysis. This study aimed to explore the association between serum folate and symptoms of autistic children at different age groups from a multi-center perspective. Methods: We enrolled 1,300 children with ASD and 1,246 typically developing (TD) children under 7 years old from 13 cities in China. The Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Childhood autism rating scale (CARS) were used to evaluate the symptoms of children with ASD. China neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016) scale was used to evaluate the neurodevelopment of children with ASD. Serum folate was measured by chemiluminescence assay in the two groups. Results: The serum folate levels of children with ASD were lower than that of TD children. In terms of core symptoms of ASD, we found that the serum folate levels were not associated with ABC, SRS, and CARS scores in ASD children of all ages but negatively associated with communication warning behavior scores of CNBS-R2016 in ASD children aged three and under. Concerning development quotients, it was at the age of three and under that serum folate levels were positively associated with gross motor, fine motor, language, and general quotient of ASD children. These ASD children aged three and under were further divided into two groups according to the median of serum folate (14.33 ng/mL); we found that compared to ASD children with folate ≤ 14.33 ng/mL, those with folate >14.33 ng/mL had lower communication warning behavior score and higher gross motor, fine motor, adaptive behavior, language, person-social, and general development quotients. Conclusion: We found that serum folate status was primarily associated with the neurodevelopment of children with ASD aged three and under. Furthermore, relatively higher serum folate levels may be more beneficial for children with ASD. Our results suggest that folate level should be paid more attention in ASD children, especially in early life, to better promote the intervention of ASD children.

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6. Lin PI, Moni MA, Gau SS, Eapen V. Identifying Subgroups of Patients With Autism by Gene Expression Profiles Using Machine Learning Algorithms. Frontiers in psychiatry. 2021; 12: 637022.

Objectives: The identification of subgroups of autism spectrum disorder (ASD) may partially remedy the problems of clinical heterogeneity to facilitate the improvement of clinical management. The current study aims to use machine learning algorithms to analyze microarray data to identify clusters with relatively homogeneous clinical features. Methods: The whole-genome gene expression microarray data were used to predict communication quotient (SCQ) scores against all probes to select differential expression regions (DERs). Gene set enrichment analysis was performed for DERs with a fold-change >2 to identify hub pathways that play a role in the severity of social communication deficits inherent to ASD. We then used two machine learning methods, random forest classification (RF) and support vector machine (SVM), to identify two clusters using DERs. Finally, we evaluated how accurately the clusters predicted language impairment. Results: A total of 191 DERs were initially identified, and 54 of them with a fold-change >2 were selected for the pathway analysis. Cholesterol biosynthesis and metabolisms pathways appear to act as hubs that connect other trait-associated pathways to influence the severity of social communication deficits inherent to ASD. Both RF and SVM algorithms can yield a classification accuracy level >90% when all 191 DERs were analyzed. The ASD subtypes defined by the presence of language impairment, a strong indicator for prognosis, can be predicted by transcriptomic profiles associated with social communication deficits and cholesterol biosynthesis and metabolism. Conclusion: The results suggest that both RF and SVM are acceptable options for machine learning algorithms to identify AD subgroups characterized by clinical homogeneity related to prognosis.

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7. Manolova H, Hristova M, Staykova S. The Importance of Early Psychological Assessment for Differential Diagnosis and Detection of Comorbidity in Children With Autism Spectrum Disorder. Frontiers in psychiatry. 2021; 12: 671744.

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8. Rea V, Van Raay TJ. Corrigendum: Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts. Frontiers in molecular neuroscience. 2021; 14: 695317.

[This corrects the article DOI: 10.3389/fnmol.2020.575575.].

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9. Tsuboyama M, Iqbal MA. CHL1 deletion is associated with cognitive and language disabilities – Case report and review of literature. Molecular genetics & genomic medicine. 2021; 9(7): e1725.

BACKGROUND: There is a small, but growing number of reports of pediatric patients with terminal deletions at 3p26.3 involving only the cell adhesion molecule L1-like (CHL1) gene that has been found to have language delays and intellectual disability. Here we report a one month of age patient who developed seizures and tone abnormalities, with persistent and prominent gross and fine motor delays. The patient has microcephaly and deficits in language and cognitive delays, similar to what has been seen in previous case reports. METHODS: Chromosome and microarray comparative genomic hybridization (aCGH) analysis was performed to identify clinically significant copy number variants (CNVs). In addition, Fluorescent in-situ hybridization (FISH) was performed to confirm the aCGH findings. RESULTS: Chromosome analysis revealed an apparently normal (46,XX) female karyotype. Microarray CGH analysis revealed a 639 kb loss at 3p26.3 from 62199 to 701052 base pairs encompassing the whole CHL1 gene that was confirmed by FISH. Parental follow-up revealed the deletion as maternal in origin. CONCLUSION: This case report adds to the limited body of literature that exists on this terminal deletion at 3p26.3 that involves CHL1 gene, and supports prior proposals of an emerging CHL1 microdeletion syndrome that results in language and cognitive delays. Further studies are needed to understand the degree of phenotypic heterogeneity associated with CHL1 gene deletion and whether the size of the deletion or presence of additional copy number variants (CNVs) which were seen in other case reports help predict the expected phenotype for a patient.

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10. Williams ZJ, Gotham KO. Retraction Note to: Improving the measurement of alexithymia in autistic adults: a psychometric investigation and refinement of the twenty-item Toronto Alexithymia Scale. Molecular autism. 2021; 12(1): 40.

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11. Xi H, Xie W, Chen J, Tang W, Deng X, Li H, Peng Y, Wang D, Yang S, Zhang Y, Duan R, Fang J, Wang H. Implementation of fragile X syndrome carrier screening during prenatal diagnosis: A pilot study at a single center. Molecular genetics & genomic medicine. 2021; 9(7): e1711.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Prenatal screening of FXS allows for early identification and intervention. The present study explored the feasibility of FXS carrier screening during prenatal diagnosis for those who were not offered screening early in pregnancy or prior to conception. METHODS: Pregnant women to be offered amniotic fluid testing were recruited for the free voluntary carrier screening at a single center between August, 2017 and September, 2019. The number of CGG repeats in the 5′ un-translated region of the fragile X mental retardation gene 1 (FMR1) was determined. RESULTS: 4286 of 7000 (61.2%) pregnant women volunteered for the screening. Forty (0.93%), five (0.11%), and three (0.07%) carriers for intermediate mutation (45-54 repeats), premutation (55-200 repeats) and full mutation (>200 repeats) of the FMR1 gene were identified respectively. None of the detected premutation alleles were inherited by the fetuses. Of the three full mutation carrier mothers, all had a family history and one transmitted a full mutation allele to her male fetus. CONCLUSION: Implementation of FXS carrier screening during prenatal diagnosis may be considered for the need to increase screening for FXS.

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12. Zivan M, Morag I, Yarmolovsky J, Geva R. Hyper-Reactivity to Salience Limits Social Interaction Among Infants Born Pre-term and Infant Siblings of Children With ASD. Frontiers in psychiatry. 2021; 12: 646838.

The ability to engage attention with selected stimuli is essential for infants to explore the world and process information relating to their surroundings. There are two main populations with a higher risk to develop attentional and social deficits whose deficits may arise from difficulties in regulating attention to salient cues: (1) siblings of children diagnosed with Autism; and (2) infants who were born pre-term. This study investigated infants’ (N = 97) attention-engagement and pupil-dilation (PD) at 9 months of age, using a gaze-contingent paradigm and a structured social interaction. Specifically, we explored attention to stimuli with simple salient features (e.g., clear defined shapes, colors, and motions) vs. more complex non-social cues (amorphous shapes, colors, and motions) and social interaction in typically developing infants (TD, N = 25) and among two groups of infants at-risk to develop social difficulties (pre-terms, N = 56; siblings of children with Autism, N = 16). Findings show that the two risk groups preferred stimuli with simple features (F = 11.306, p < 0.001), accompanied by increased PD (F = 6.6, p < 0.001). Specifically, pre-term infants showed increased PD toward simple vs. complex stimuli (p < 0.001), while siblings showed a pervasive hyper-arousal to both simple and complex stimuli. Infants in the TD group preferred complex stimuli with no change in PD. Finally, the preference for the simple stimulus mediated the relationship between increased risk for social difficulties and decreased engagement duration in face-to-face interaction with the experimenter. Results suggest that activation of the attention-salience network shapes social abilities at infancy. Further, hyper-reactivity to salient stimuli limits social interaction among infants born pre-term and siblings of children with ASD.

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