1. Almandil NB, AlSulaiman A, Aldakeel SA, Alkuroud DN, Aljofi HE, Alzahrani S, Al-Mana A, Alfuraih AA, Alabdali M, Alkhamis FA, AbdulAzeez S, Borgio JF. Integration of Transcriptome and Exome Genotyping Identifies Significant Variants with Autism Spectrum Disorder. Pharmaceuticals (Basel, Switzerland). 2022; 15(2).

Autism is a complex disease with genetic predisposition factors. Real factors for treatment and early diagnosis are yet to be defined. This study integrated transcriptome and exome genotyping for identifying functional variants associated with autism spectrum disorder and their impact on gene expression to find significant variations. More than 1800 patients were screened, and 70 (47 male/23 female) with an average age of 7.56 ± 3.68 years fulfilled the DSM-5 criteria for autism. Analysis revealed 682 SNPs of 589 genes significantly (p < 0.001) associated with autism among the putative functional exonic variants (n = 243,345) studied. Olfactory receptor genes on chromosome 6 were significant after Bonferroni correction (α = 0.05/243345 = 2.05 × 10(-7)) with a high degree of linkage disequilibrium on 6p22.1 (p = 6.71 × 10(-9)). The differentially expressed gene analysis of autistic patients compared to controls in whole RNA sequencing identified significantly upregulated (foldchange ≥0.8 and p-value ≤ 0.05; n = 125) and downregulated (foldchange ≤-0.8 and p-value ≤ 0.05; n = 117) genes. The integration of significantly up- and downregulated genes and genes of significant SNPs identified regulatory variants (rs6657480, rs3130780, and rs1940475) associated with the up- (ITGB3BP) and downregulation (DDR1 and MMP8) of genes in autism spectrum disorder in people of Arab ancestries. The significant variants could be a biomarker of interest for identifying early autism among Arabs and helping to characterize the genes involved in the susceptibility mechanisms for autistic subjects.

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2. Boemer F, Josse C, Luis G, Di Valentin E, Thiry J, Cello C, Caberg JH, Dadoumont C, Harvengt J, Lumaka A, Bours V, Debray FG. Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy. International journal of molecular sciences. 2022; 23(4).

Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999_1001delCAC; p.Thr334del) of BCKDK. Plasma and cerebrospinal fluid concentrations of BCAA were markedly reduced. Hyperactivity of BCKDH and over-consumption of BCAA were demonstrated by functional tests in cells transfected with the mutant BCKDK. Treatment with pharmacological doses of BCAA allowed the restoring of BCAA concentrations and greatly improved seizure control. Behavioral and developmental skills of the patients improved to a lesser extent. Importantly, a retrospective review of the newborn screening results allowed the identification of a strong decrease in BCAA concentrations on dried blood spots, suggesting that BCKDK is a new treatable metabolic disorder probably amenable to newborn screening programs.

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3. Burgess DJ. Organoids reveal the neurodevelopmental consequences of mutations. Nature reviews Genetics. 2022; 23(4): 195.

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4. Cortese S, Gabellone A, Marzulli L, Iturmendi-Sabater I, de La Chica-Duarte D, Piqué IM, Solmi M, Shin JI, Margari L, Arrondo G. Association between autism spectrum disorder and diabetes: systematic review and meta-analysis. Neuroscience and biobehavioral reviews. 2022; 136: 104592.

There is mixed evidence on the link between autism spectrum disorder (ASD) and diabetes. We conducted the first systematic review/meta-analysis on their association. Based on a pre-registered protocol (PROSPERO: CRD42021261114), we searched Pubmed, Ovid, and Web of Science databases up to 6 December 2021, with no language/type of document restrictions. We assessed study quality using the Newcastle-Ottawa Scale (NOS). We included 24 studies (total: 3427,773 individuals; 237,529 with ASD and 92,832 with diabetes) in the systematic review and 20 in the meta-analysis (mean stars number on the NOS: 5.89/10). There was a significant association, albeit characterized by significant heterogeneity, when pooling unadjusted OR (1.535, 95% CI = 1.109-2.126), which remained significant when restricting the analysis to children and type 2 diabetes, but became non-significant when considering adjusted ORs (OR: 1.528, 95% CI = 0.954-2.448). No significant prospective association was found (n = 2) on diabetes predicting ASD (HR: 1.232, 0.826-11.837). Therefore, the association between ASD and diabetes is likely confounded by demographic and clinical factors that should be systematically investigated in future studies.

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5. Cristiano C, Volpicelli F, Crispino M, Lacivita E, Russo R, Leopoldo M, Calignano A, Perrone-Capano C. Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism. Pharmaceuticals (Basel, Switzerland). 2022; 15(2).

Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by social deficits, repetitive stereotyped behaviors, and altered inflammatory responses. Accordingly, children with ASD show decreased plasma levels of lipoxin A4 (LXA4), a mediator involved in the resolution of inflammation, which is the endogenous ligand of the formyl peptide receptor 2 (FPR2). To investigate the role of FPR2 in ASDs, we have used a new ureidopropanamide derivative able to activate the receptor, named MR-39. The effects of MR-39 (10 mg/kg, for 8 days) on hippocampal pro-inflammatory profile, neuronal plasticity, and social behavior were evaluated in two validated animal models of ASD: BTBR mouse strain and mice prenatally exposed to valproic acid (VPA). Primary cultures of hippocampal neurons from BTBR mice were also used to evaluate the effect of MR-39 on neurite elongation. Our results show that MR-39 treatment reduced several inflammatory markers, restored the low expression of LXA4, and modulated FPR2 expression in hippocampal tissues of both ASD animal models. These findings were accompanied by a significant positive effect of MR-39 on social behavioral tests of ASD mice. Finally, MR-39 stimulates neurite elongation in isolated hippocampal neurons of BTBR mice. In conclusion, these data indicate FPR2 as a potential target for an innovative therapeutical approach for the cure of ASD.

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6. Gildin L, Rauti R, Vardi O, Kuznitsov-Yanovsky L, Maoz BM, Segal M, Ben-Yosef D. Impaired Functional Connectivity Underlies Fragile X Syndrome. International journal of molecular sciences. 2022; 23(4).

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by a developmentally regulated silencing of the FMR1 gene, but its effect on human neuronal network development and function is not fully understood. Here, we isolated isogenic human embryonic stem cell (hESC) subclones-one with a full FX mutation and one that is free of the mutation (control) but shares the same genetic background-differentiated them into induced neurons (iNs) by forced expression of NEUROG-1, and compared the functional properties of the derived neuronal networks. High-throughput image analysis demonstrates that FX-iNs have significantly smaller cell bodies and reduced arborizations than the control. Both FX- and control-neurons can discharge repetitive action potentials, and FX neuronal networks are also able to generate spontaneous excitatory synaptic currents with slight differences from the control, demonstrating that iNs generate more mature neuronal networks than the previously used protocols. MEA analysis demonstrated that FX networks are hyperexcitable with significantly higher spontaneous burst-firing activity compared to the control. Most importantly, cross-correlation analysis enabled quantification of network connectivity to demonstrate that the FX neuronal networks are significantly less synchronous than the control, which can explain the origin of the development of intellectual dysfunction associated with FXS.

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7. Hausman-Cohen S, LaValley W, Way H, Gutierrez E, Reeder J. Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder. International journal of molecular sciences. 2022; 23(4).

Molecular biology combined with genomics can be a powerful tool for developing potential intervention strategies for improving outcomes in children with autism spectrum disorders (ASD). Monogenic etiologies rarely cause autism. Instead, ASD is more frequently due to many polygenic contributing factors interacting with each other, combined with the epigenetic effects of diet, lifestyle, and environment. One limitation of genomics has been identifying ways of responding to each identified gene variant to translate the information to something clinically useful. This paper will illustrate how understanding the function of a gene and the effects of a reported variant on a molecular level can be used to develop actionable and targeted potential interventions for a gene variant or combinations of variants. For illustrative purposes, this communication highlights a specific genomic variant, SHANK3. The steps involved in developing molecularly genomically targeted actionable interventions will be demonstrated. Cases will be shared to support the efficacy of this strategy and to show how clinicians utilized these targeted interventions to improve ASD-related symptoms significantly. The presented approach demonstrates the utility of genomics as a part of clinical decision-making.

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8. Hwang YIJ, Foley KR, Elley K, Brown S, Joy-Leong D, Li X, Grove R, Trollor J, Pellicano E, Zheng L. Experiences of Performing Daily Activities in Middle-Aged and Older Autistic Adults: A Qualitative Study. Journal of autism and developmental disorders. 2022.

This is the first study to investigate instrumental activities of daily living in older autistic adults. We conducted interviews with fifteen adults (mean age = 60.1, SD = 7.4, range = 50-73) from Australia with no intellectual disability. Analysis included both deductive and inductive steps, to categorise responses using the Occupational Performance Model Australia and identify themes across participants’ experiences. Strengths and challenges were unique to the individual, as were the methods they had developed to manage tasks. Challenges occurred mostly at the interaction between aspects of the environment (sensory, cognitive, social and cultural) and personal factors such as health conditions and sensory sensitivities. Enhanced person-environment fit is needed, as is a shift in wider sociocultural attitudes to enable comfort and autonomy in later life.

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9. Kammer PV, Moro JS, Soares JP, Massignan C, Phadraig CMG, Bolan M. Prevalence of tooth grinding in children and adolescents with neurodevelopmental disorders: A systematic review and meta-analysis. Journal of oral rehabilitation. 2022; 49(6): 671-85.

AIM: To conduct a systematic review and meta-analysis on the prevalence of tooth grinding and/or clenching (TGC) in children and adolescents with a neurodevelopmental disorder or other developmental condition. METHODS: A search was performed in seven databases, two sources of grey literature and reference lists of included studies. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. We used random-effects models with Freeman-Tukey double arcsine transformation for the meta-analyses. RESULTS: After selection, 77 of the 2240 studies met inclusion criteria and were categorised by disability and type of TGC (reported, clinically observed and definitive). The pooled prevalence of reported TGC in individuals with attention-deficit hyperactivity disorder was 57.6% (95% CI [confidence interval]: 49.5-65.6), 50.4% (95% CI: 35.5-65.4) in individuals with autism spectrum disorder, 67% (95% CI: 59.2-74.8) in cerebral palsy and 68.2% (95% CI: 59.8-76.6) in Down syndrome. Pooled prevalence of clinically observed TGC was 57.5% (95% CI: 31.6-83.4) in autism spectrum disorder and 71.9% (95% CI: 52.4-91.4) in cerebral palsy. Individuals with attention-deficit hyperactivity disorder presented 39.8% (95% CI: 24-55.6) of definitive TGC. CONCLUSION: Prevalence of reported, clinically observed, and definitive TGC varies according to disabilities, although due to high heterogeneity the result should be interpreted with caution. Variations exist mainly due to sampling bias and the use of non-validated methods to assess TGC. CRD42020212640.

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10. Kara T, Alpgan Ö. Maternal perception of spousal support in raising children with developmental disability in the context of family and child variables. Journal of child and adolescent psychiatric nursing : official publication of the Association of Child and Adolescent Psychiatric Nurses, Inc. 2022.

OBJECTIVE: The purpose of this study was to examine the relationship between the variables of mental, physical, and emotional problems in children with developmental disabilities (DDs) and the spousal support perceived by the mothers of those children. METHODS: One hundred forty-three children diagnosed with autism spectrum disorder (ASD, n:43), intellectual disability (ID, n:28), cerebral palsy (CP, n:47), or Down syndrome (DS, n:25) were included in this study. The support that mothers received from their spouses was evaluated using the Spousal Support Scale (SSS). Aggressive behavior in the children was evaluated using the anger-aggression subscale of the Social Competence and Behavior Evaluation Scale (SCBE-30). The data obtained were then subjected to statistical comparisons. RESULTS: Multiple comparisons revealed no significant difference between the DD diagnosis groups (ID, CP, ASD, and DS) in terms of spousal support or spousal support sub-dimension scores (p > 0.05). Significant negative correlation was found between anger-aggression subscale scores and SSS sub-parameters (emotional support r = -0.315 p < 0.001, financial and informational support r = -0.285 p < 0.001, appreciation r = -0.299 p < 0.001, social support r = -0.381 p < 0.001, and spouse support score r = -0.389 p < 0.001). CONCLUSION: Children's anger-aggression levels were adversely affected by a lack of spousal support for their mothers.

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11. Kim T, Martinez K, Cruz BL, Huang JS, Stadnick NA. Caregiver Insights and Improvement Strategies for Youth with Autism Undergoing Gastrointestinal Endoscopy. Journal of autism and developmental disorders. 2022.

Limited guidance is available for families of youth with ASD (YASD) to prepare for invasive medical procedures. This study examined caregiver perspectives regarding YASD’s gastrointestinal endoscopy (GE) experience to improve the endoscopy experience for YASD. Thirty-four caregivers of YASD, (M = 9.85 years, SD = 4.6) who underwent GE at Rady Children’s Hospital, San Diego between May 2018 and July 2019 (identified via electronic health record) participated in a structured phone interview. Caregivers reported a positive experience due to the procedural team’s responsiveness to the needs of YASD and appropriately answering/addressing questions/concerns. Caregivers reported a need for ASD-specific information on how to prepare for GE. Specific recommendations are discussed. Study findings offer strategies to improve the care experience of YASD undergoing GE.

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12. Landowska A, Karpus A, Zawadzka T, Robins B, Erol Barkana D, Kose H, Zorcec T, Cummins N. Automatic Emotion Recognition in Children with Autism: A Systematic Literature Review. Sensors (Basel, Switzerland). 2022; 22(4).

The automatic emotion recognition domain brings new methods and technologies that might be used to enhance therapy of children with autism. The paper aims at the exploration of methods and tools used to recognize emotions in children. It presents a literature review study that was performed using a systematic approach and PRISMA methodology for reporting quantitative and qualitative results. Diverse observation channels and modalities are used in the analyzed studies, including facial expressions, prosody of speech, and physiological signals. Regarding representation models, the basic emotions are the most frequently recognized, especially happiness, fear, and sadness. Both single-channel and multichannel approaches are applied, with a preference for the first one. For multimodal recognition, early fusion was the most frequently applied. SVM and neural networks were the most popular for building classifiers. Qualitative analysis revealed important clues on participant group construction and the most common combinations of modalities and methods. All channels are reported to be prone to some disturbance, and as a result, information on a specific symptoms of emotions might be temporarily or permanently unavailable. The challenges of proper stimuli, labelling methods, and the creation of open datasets were also identified.

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13. Ma L, Liu M, Xue K, Ye C, Man W, Cheng M, Liu Z, Zhu D, Liu F, Wang J. Abnormal Regional Spontaneous Brain Activities in White Matter in Patients with Autism Spectrum Disorder. Neuroscience. 2022; 490: 1-10.

Previous studies have demonstrated patients with autism spectrum disorder (ASD) are accompanied by alterations of spontaneous brain activity in gray matter. However, whether the alterations of spontaneous brain activity exist in white matter remains largely unclear. In this study, 88 ASD patients and 87 typical controls (TCs) were included and regional homogeneity (ReHo) was calculated to characterize spontaneous brain activity in white matter. Voxel-wise two-sample t-tests were performed to investigate ReHo alterations, and cluster-level analyses were conducted to examine structural-functional coupling changes. Compared with TCs, the ASD group showed significantly decreased ReHo in the left superior corona radiata and left posterior limb of internal capsule, and decreased ReHo in the left anterior corona radiata with a trend level of significance. In addition, significantly weaker structural-functional coupling was observed in the left superior corona radiata and left posterior limb of internal capsule in ASD patients. Taken together, these findings highlighted abnormalities of white matter’s regional spontaneous brain activity in ASD, which may provide new insights into the pathophysiological mechanisms of this disorder.

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14. Mangano GD, Riva A, Fontana A, Salpietro V, Mangano GR, Nobile G, Orsini A, Iacomino M, Battini R, Astrea G, Striano P, Nardello R. De novo GRIN2A variants associated with epilepsy and autism and literature review. Epilepsy & behavior : E&B. 2022; 129: 108604.

N-methyl-D-aspartate receptors (NMDAR) are di- or tri-heterotetrameric ligand-gated ion channels composed of two obligate glycine-binding GluN1 subunits and two glutamate-binding GluN2 or GluN3 subunits, encoded by GRIN1, GRIN2A-D, and GRIN3A-B receptor genes respectively. Each NMDA receptor subtype has different temporal and spatial expression patterns in the brain and varies in the cell types and subcellular localization resulting in different functions. They play a crucial role in mediating the excitatory neurotransmission, but are also involved in neuronal development and synaptic plasticity, essential for learning, memory, and high cognitive functions. Among genes coding NMDAR subunits, GRIN2B is predominantly associated with neurodevelopmental disorders such as intellectual disability, developmental delay, autism, attention-deficit/hyperactivity disorder and, further, schizophrenia, Alzheimer’s disease. The GRIN2A seems to be predominantly associated with a more definite phenotype including an epileptic spectrum ranging from Landau-Kleffner syndrome to benign childhood epilepsy with centrotemporal spikes, speech or language impairment, intellectual disability/developmental delay often in comorbidity. On the contrary, the occurrence of autism spectrum disorders, unlike GRIN2B-associated disorders, is questionable. To contribute to elucidate the latter issue and to better define the genotype/phenotype correlation, we report the clinical and neuropsychological profile of two patients featuring autism disorder, intellectual disability, language impairment, and focal epilepsy, associated with previously unreported heterozygous de novo GRIN2A pathogenic variants. We hypothesize that the unusual phenotype may be the result of interactions of tri-heterotetrameric 2GluN1/GluN2A-D/GluN3A-B subunits with mutated GluN2A subunit and/or the dysfunction may be influenced by other unknown modifier genes and/or environmental factors.

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15. Meza N, Rojas V, Escobar Liquitay CM, Pérez I, Aguilera Johnson F, Amarales Osorio C, Irarrázaval M, Madrid E, Franco JVA. Non-pharmacological interventions for autism spectrum disorder in children: an overview of systematic reviews. BMJ evidence-based medicine. 2022.

OBJECTIVE: To assess the effectiveness of non-pharmacological interventions for the treatment of autism spectrum disorder (ASD) in children. DESIGN: Overview of systematic reviews (SRs). PARTICIPANTS: Children aged 12 years and under with ASD. SEARCH METHODS: In October 2021, we searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Epistemonikos placing no restrictions on language or date of publication. INTERVENTIONS: 17 non-pharmacological interventions compared with placebo, no-treatment (including waiting list) or other interventions (ie, usual care, as defined by the authors of each study). DATA COLLECTION AND ANALYSIS: We rated the methodological quality of the included SRs using A Measurement Tool to Assess Systematic Reviews (AMSTAR 2). We reported the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) certainty of the evidence (CoE) according to the analysis conducted by the authors of the included SRs. MAIN OUTCOME MEASURES: A multidisciplinary group of experts agreed on analysing nine critical outcomes evolving core and non-core ASD symptoms. PUBLIC AND PATIENT INVOLVEMENT STATEMENT: Organisations of parents of children with ASD participated in external revision of the final version of the report. RESULTS: We identified 52 reports that were within our scope, of which 48 were excluded for various reasons. After excluding less reliable SRs, we included four SRs. Non-pharmacological interventions (ie, Early Intensive Behavioural Intervention, Applied Behaviour Analysis, Picture Exchange Communication System and Naturalistic Developmental Behavioural Interventions) may have favourable effects on some core outcomes including language, social and functioning, play or daily living skills in children with ASD (with either no GRADE assessment, very low or low CoE). In addition, we identified a lack of report for other key outcomes in the included SRs (ie, restricted, repetitive behaviour; play and sensory processing). CONCLUSIONS: Synthesised evidence regarding the efficacy of non-pharmacological interventions for children with ASD is scarce. High-quality SRs addressing the variety of both non-pharmacological interventions and relevant outcomes are needed. PROSPERO REGISTRATION NUMBER: CRD42020206535.

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16. Muniandy M, Richdale AL, Arnold SRC, Trollor JN, Lawson LP. Associations between coping strategies and mental health outcomes in autistic adults. Autism research : official journal of the International Society for Autism Research. 2022.

Compared to the general population, mental health difficulties are commonly reported in autistic adults. However, the ways in which coping strategies are associated with mental health and well-being in this population remain unknown. Further, we do not know if, and if so, how these associations might differ to that of non-autistic adults. In this study, we hypothesized that in both our autistic (N = 255) and non-autistic (N = 165) adult samples, disengagement coping strategies (e.g., denial) would relate to poorer mental health and well-being, while engagement coping strategies (e.g., problem solving) would relate to better mental health and well-being. Regression analyses revealed that higher use of disengagement coping strategies was significantly associated with higher levels of anxiety and depression, and lower levels of well-being in both samples. In contrast, increased use of engagement coping strategies was associated with better well-being, but only in the autistic sample. Our results contribute to the characterization of negative and positive mental health outcomes in autistic adults from a coping perspective, with potential to offer novel information regarding coping strategies to consider when addressing support options for mental health difficulties in the autistic adult population.

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17. Protic DD, Aishworiya R, Salcedo-Arellano MJ, Tang SJ, Milisavljevic J, Mitrovic F, Hagerman RJ, Budimirovic DB. Fragile X Syndrome: From Molecular Aspect to Clinical Treatment. International journal of molecular sciences. 2022; 23(4).

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990-2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

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18. Thabault M, Turpin V, Maisterrena A, Jaber M, Egloff M, Galvan L. Cerebellar and Striatal Implications in Autism Spectrum Disorders: From Clinical Observations to Animal Models. International journal of molecular sciences. 2022; 23(4).

Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed.

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19. Tinker RJ, Falk MJ, Goldstein A, George-Sankoh I, Xiao R, Adang L, Ganetzky R. Early developmental delay in Leigh syndrome spectrum disorders is associated with poor clinical prognosis. Molecular genetics and metabolism. 2022; 135(4): 342-9.

BACKGROUND: Leigh spectrum syndrome (LSS) is a primary mitochondrial disorder characterized by neurodevelopmental regression and metabolic stroke typically in early life. Developmental delay (DD) is known to follow episodes of neurologic regression in LSS, although primary developmental delay (pDD) has been rarely reported. We hypothesized that pDD precedes regression in a broader subset of LSS individuals and may associate with worse long-term educational outcomes. METHODS: From a retrospective cohort, subjects with pathogenic variant(s) in a nuclear or mitochondrial gene associated with LSS and consistent clinical manifestations and neuroradiological findings. Detailed developmental histories and neurologic outcomes were extracted. RESULTS: Of 69 LSS subjects, 47 (68.1%) had a history of pDD and 53 (76.8%) had neurodevelopmental regression. We identified 3 distinct developmental phenotypes: [1] pDD followed by regression (N = 31/69, 44.9%), [2] pDD without subsequent regression (16/69, 23.2%), [3] regression without pDD (N = 22/69, 31.9%). A history of pDD was associated with earlier disease onset (p = 0.0003) and worse educational outcomes (OR 22.14). CONCLUSION: LSS is associated with multiple developmental phenotypes and pDD is associated with negative educational outcomes. pDD occurring prior to neurologic regression suggests that mitochondrial energetics impact developmental trajectories prior to acute metabolic failure and regression, providing an opportunity for earlier diagnosis and/or therapeutic intervention.

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20. Tsuji T, Furuhara K, Gerasimenko M, Shabalova A, Cherepanov SM, Minami K, Higashida H, Tsuji C. Oral Supplementation with L-Carnosine Attenuates Social Recognition Deficits in CD157KO Mice via Oxytocin Release. Nutrients. 2022; 14(4).

The outcomes of supplementation with L-carnosine have been investigated in clinical trials in children with autism spectrum disorder (ASD). However, reports on the effects of L-carnosine in humans have been inconsistent, and the efficacy of L-carnosine supplementation for improving ASD symptoms has yet to be investigated in animal studies. Here, we examined the effects of oral supplementation with L-carnosine on social deficits in CD157KO mice, a murine model of ASD. Social deficits in CD157KO mice were assessed using a three-chamber social approach test. Oral supplementation with L-carnosine attenuated social behavioral deficits. The number of c-Fos-positive oxytocin neurons in the supraoptic nucleus and paraventricular nucleus was increased with L-carnosine supplementation in CD157KO mice after the three-chamber social approach test. We observed an increase in the number of c-Fos-positive neurons in the basolateral amygdala, a brain region involved in social behavior. Although the expression of oxytocin and oxytocin receptors in the hypothalamus was not altered by L-carnosine supplementation, the concentration of oxytocin in cerebrospinal fluid was increased in CD157KO mice by L-carnosine supplementation. These results suggest that L-carnosine supplementation restores social recognition impairments by augmenting the level of released oxytocin. Thus, we could imply the possibility of a safe nutritional intervention for at least some types of ASD in the human population.

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21. Wolbert F, Fahrig IK, Gottschalk T, Luebbert C, Thommes M, Sadowski G. Factors Influencing the Crystallization-Onset Time of Metastable ASDs. Pharmaceutics. 2022; 14(2).

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus(®) were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as « larger particles always crystallize later than smaller particles » are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases.

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22. Zhang W, Zhuo S, Li X, Peng W. Autistic Traits and Empathy for Others’ Pain Among the General Population: Test of the Mediating Effects of First-Hand Pain Sensitivity. Journal of autism and developmental disorders. 2022.

Autism spectrum disorders (ASD) are characterized by reduced pain empathy-a process that is grounded in first-hand pain perception. Because autistic traits are continuously distributed in the general population, we hypothesized that first-hand pain sensitivity would mediate the link between autistic traits and pain empathy. After controlling for alexithymia, higher autistic traits were associated with lower cognitive and emotional empathy in response to others’ pain, as well as lower sensitivity to cold and heat pain (higher cold pain tolerance and lower laser heat pain-intensity ratings). Importantly, pain sensitivity fully mediated the link between autistic traits and pain empathy. These findings highlight the role of atypical first-hand pain sensitivity in the lack of pain empathy observed in people with high autistic traits or ASD.

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