1. Cheng J, Zhao Z, Chen L, Li Y, Du R, Wu Y, Zhu Q, Fan M, Duan X, Wu H. Loss of O-GlcNAcylation on MeCP2 at Threonine 203 Leads to Neurodevelopmental Disorders. Neuroscience bulletin. 2022; 38(2): 113-34.

Mutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials have revealed several putative RTT-associated mutations in MECP2, their causal relevance regarding the functional regulation of MeCP2 at the etiologic sites at the protein level requires more evidence. In this study, we demonstrated that MeCP2 was dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impaired dendrite development and spine maturation in cultured hippocampal neurons, and disrupted neuronal migration, dendritic spine morphogenesis, and caused dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreased the neuronal activity-induced induction of Bdnf transcription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via brain-derived neurotrophic factor.

Lien vers le texte intégral (Open Access ou abonnement)

2. Doenyas C. Potential Role of Epigenetics and Redox Signaling in the Gut-Brain Communication and the Case of Autism Spectrum Disorder. Cellular and molecular neurobiology. 2022; 42(2): 483-7.

The gut-brain axis refers to the bidirectional connection and communication between the gastrointestinal tract and the central nervous system. This paper explores two routes for this communication that have hitherto remained under-examined: epigenetics and redox signaling and their implications for autism spectrum disorder (ASD). The gut microbiota may induce epigenetic changes in the gut and potentially in the brain through their fermentation products. Instead of through other conceptualizations of them acting as neurotransmitters, gut microbial products may act as epigenetic agents, which are supported by the effects of gut bacterial-derived metabolites on gene regulation and expression. In addition to their epigenetic effects, gut bacterial-derived communicative agents can also influence host signaling by contributing to and even substituting host reactive oxygen species (ROS) production. These ROS can act as second messengers and exert oxidative activity on proteins to influence immune, inflammatory, and other signaling processes. ROS and epigenetic mechanisms may have interactive effects as well. ROS, in addition to their role in signaling pathways and cellular redox alterations, also influence redox-sensitive transcription factors, thereby having an effect on gene expression. Specifically, ROS are involved in the activation of transcription factors, chromatin remodeling, and histone/protein deacetylation. These two proposed mechanisms correspond with the recent findings related to ASD, where a cofactor that is shown to be lower in ASD has antioxidative properties, responds to epigenetic modulation, and increases via microbiota interventions. The current evidence reviewed here suggests the need to update models of the gut-brain communication to include these two mechanisms. Such a modeling can also contribute to understanding the unknowns of host metabolism and physiology in ASD and afford potential therapeutic avenues for this as well as other psychiatric and physiological conditions.

Lien vers le texte intégral (Open Access ou abonnement)

3. Franco C, Bonomini F, Borsani E, Castrezzati S, Franceschetti L, Rezzani R. Involvement of Intestinal Goblet Cells and Changes in Sodium Glucose Transporters Expression: Possible Therapeutic Targets in Autistic BTBR T(+)Itpr3(tf)/J Mice. International journal of environmental research and public health. 2021; 18(21).

Autism spectrum disorder is a neurodevelopmental syndrome with a complicated etiology and could be responsible for disrupted gastrointestinal tract microbiota. The aim of this work was to study intestinal samples from an autistic animal model (BTBR mouse strain) to better describe gastrointestinal alterations. We performed a morphological and biological evaluation of small intestine samples. In terms of morphology, we studied the goblet cells, cells of intestinal mucosal responsible for the production and maintenance of the protective mucous blanket. Alterations in their secretion may indicate an altered rate of mucus synthesis and this is one of the possible causes of gastrointestinal problems. In terms of biological evaluation, impaired regulation of glucose homeostasis regulated by sodium-glucose transporters has been suggested as an important component of obesity and associated comorbidities; therefore, this study analyzed the expression of sodium/glucose transporter-1 and -3 in BTBR mice to better define their role. We demonstrated that, in BTBR mice as compared to C57BL/6J (B6) strain animals: (1) The goblet cells had different protein content in their vesicles and apparently a larger number of Golgi cisternae; (2) the expression and level of sodium/glucose transporters were higher. These findings could suggest new possible targets in autism spectrum disorder to maintain mucus barrier function.

Lien vers le texte intégral (Open Access ou abonnement)

4. Gzielo K, Nikiforuk A. Astroglia in Autism Spectrum Disorder. International journal of molecular sciences. 2021; 22(21).

Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only « gluing » neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD.

Lien vers le texte intégral (Open Access ou abonnement)

5. Kaub PA, Sharp PC, Ranieri E, Fletcher JM. Isolated autism is not an indication for Smith-Lemli-Opitz syndrome biochemical testing. Journal of paediatrics and child health. 2022; 58(4): 630-5.

Several studies have demonstrated a high incidence of autistic spectrum features in individuals with Smith-Lemli-Opitz syndrome (SLOS). However, do these findings imply a converse relationship that has diagnostic utility? Is SLOS testing implicated when autism spectrum disorder (ASD) is the only clinical indication? AIM: To determine if there is any correlation with a clinical indication of ASD and a biochemical diagnosis of SLOS, based on historical test request and assay data. METHODS: Six years (2008-2013) of clinical test requests for 7-dehydrocholesterol (7-DHC) level were classified and summarised according to indication and final test result. RESULTS: From the audit period, 988 valid test results from post-natal samples were identified. In plasma/serum, mean 7-DHC level was 264.7 μmol/L (normal range < 2.0) for confirmed SLOS cases. No tests performed due to an isolated clinical indication of ASD or where no clinical information was supplied were associated with 7-DHC levels diagnostic for SLOS. CONCLUSIONS: Historical test data analysis supports the recommendation that autism/ASD as a single clinical feature is not an appropriate indication for SLOS (7-DHC) biochemical testing.

Lien vers le texte intégral (Open Access ou abonnement)

6. Lintas C, Sacco R, Azzarà A, Cassano I, Gurrieri F. Genotype-Phenotype Correlations in Relation to Newly Emerging Monogenic Forms of Autism Spectrum Disorder and Associated Neurodevelopmental Disorders: The Importance of Phenotype Reevaluation after Pangenomic Results. Journal of clinical medicine. 2021; 10(21).

ASD genetic diagnosis has dramatically improved due to NGS technologies, and many new causative genes have been discovered. Consequently, new ASD phenotypes have emerged. An extensive exome sequencing study carried out by the Autism Sequencing Consortium (ASC) was published in February 2020. The study identified 102 genes which are de novo mutated in subjects affected by autism spectrum disorder (ASD) or similar neurodevelopmental disorders (NDDs). The majority of these genes was already known to be implicated in ASD or NDDs, whereas approximately 30 genes were considered « novel » as either they were not previously associated with ASD/NDDs or very little information about them was present in the literature. The aim of this work is to review the current literature since the publication of the ASC paper to see if new data mainly concerning genotype-phenotype correlations of the novel genes have been added to the existing one. We found new important clinical and molecular data for 6 of the 30 novel genes. Though the broad and overlapping neurodevelopmental phenotypes observed in most monogenic forms of NDDs make it difficult for the clinical geneticist to address gene-specific tests, knowledge of these new data can at least help to prioritize and interpret results of pangenomic tests to some extent. Indeed, for some of the new emerging genes analyzed in the present work, specific clinical features emerged that may help the clinical geneticist to make the final diagnosis by associating the genetic test results with the phenotype. The importance of this relatively new approach known as « reverse phenotyping » will be discussed.

Lien vers le texte intégral (Open Access ou abonnement)

7. Papadopoulos N, Emonson C, Martin C, Sciberras E, Hiscock H, Lewis S, McGillivray J, Rinehart N. Autism Spectrum Disorder and Intellectual Disability: A Pilot Study Exploring Associations between Child Sleep Problems, Child Factors and Parent Factors. International journal of environmental research and public health. 2021; 18(21).

Sleep problems are common in children with autism spectrum disorder (ASD). However, few studies have undertaken group comparisons of sleep profiles and factors associated with poorer sleep between children with ASD without intellectual disability (ID; hereafter referred to as ASD) and ASD with co-occurring ID (hereafter referred to as ASD + ID). This study aimed to (1) compare child (sleep problems and emotional and behavioural problems (EBPs)) and parent factors (parenting stress and mental health) for children with ASD compared to children with ASD + ID, and (2) examine the associations between sleep problems and child and parent factors in both groups. Parents of 56 children with ASD (22 ASD, 34 ASD + ID) aged 6-13 years took part in the study. No statistically significant differences in sleep problems were found between children with ASD compared to children with ASD + ID. However, total EBPs were independently associated with child sleep problems in both groups. Further, ‘Self-Absorbed’ and ‘Communication Disturbance’ EBPs were significantly greater in the ASD + ID compared to the ASD group. Overall treatment outcomes for children with ASD may be further improved if consideration is given to the specific types of EBPs being experienced by the child and their association with sleep problems.

Lien vers le texte intégral (Open Access ou abonnement)

8. Pilunthanakul T, Goh TJ, Fung DSS, Sultana R, Allen JC, Sung M. Validity of the patient health questionnaire 9-item in autistic youths: a pilot study. BMC psychiatry. 2021; 21(1): 564.

BACKGROUND: Autistic adolescents have greater predisposition to depression and suicidality than neurotypical adolescents. Early detection is essential for timely treatment. The Patient Health Questionnaire 9-item (PHQ-9) is a brief screen for depression. The study examines the validity of the PHQ-9 for detecting major depressive disorder (MDD) in autistic youths. METHODS: English speaking youths aged 10-18 years, with DSM-IV/DSM-5/ICD-10 diagnosis of Autism Spectrum Disorder (ASD), and their parents presenting to a child psychiatric service were invited to participate between May 2018 to August 2020. Participants completed the respective self- and parent-rated PHQ-9 independently. MDD was verified using the MINI-Kid (Mini-International Neuropsychiatric Interview, Kid version). RESULTS: One hundred one youth, mean (SD) age 14.6 (2.3), were enrolled. 27 (27%) met criteria for current MDD. Mean total PHQ-9 scores, percentage ratings for severity of symptoms of depression, functional impairment, dysthymia and suicidality were compared. Areas under the ROC curve and statistically optimal cutoffs were determined. Parents rated depressive symptoms severity lower than their children. The PHQ-9 displayed low sensitivity with high false negative rates at conventional, adjusted and proposed cutoffs. CONCLUSIONS: Future studies should improve on the validity and reliability of existing depression screening tools, or develop more appropriate screening methods of depression, for autistic youths.

Lien vers le texte intégral (Open Access ou abonnement)

9. Zawadzka A, Cieślik M, Adamczyk A. The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment. International journal of molecular sciences. 2021; 22(21).

Autism spectrum disorder (ASD) is a neurodevelopmental disease that is characterized by a deficit in social interactions and communication, as well as repetitive and restrictive behaviors. Increasing lines of evidence suggest an important role for immune dysregulation and/or inflammation in the development of ASD. Recently, a relationship between inflammation, oxidative stress, and mitochondrial dysfunction has been reported in the brain tissue of individuals with ASD. Some recent studies have also reported oxidative stress and mitochondrial abnormalities in animal models of maternal immune activation (MIA). This review is focused on the hypothesis that MIA induces microglial activation, oxidative stress, and mitochondrial dysfunction, a deleterious trio in the brain that can lead to neuroinflammation and neurodevelopmental pathologies in offspring. Infection during pregnancy activates the mother’s immune system to release proinflammatory cytokines, such as IL-6, TNF-α, and others. Furthermore, these cytokines can directly cross the placenta and enter the fetal circulation, or activate resident immune cells, resulting in an increased production of proinflammatory cytokines, including IL-6. Proinflammatory cytokines that cross the blood-brain barrier (BBB) may initiate a neuroinflammation cascade, starting with the activation of the microglia. Inflammatory processes induce oxidative stress and mitochondrial dysfunction that, in turn, may exacerbate oxidative stress in a self-perpetuating vicious cycle that can lead to downstream abnormalities in brain development and behavior.

Lien vers le texte intégral (Open Access ou abonnement)