1. Bacrot S, Monnot S, Haddad G, Barcia G, Rachid M, Boisson M, Pasquier N, Rondeau S, Munnich A, Steffann J, Bonnefont JP, Raynaud M. {{Prenatal diagnosis of Fragile X syndrome: small meiotic recombination events at the FMR1 locus}}. {Prenatal diagnosis}. 2019.
OBJECTIVE: Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, is caused by an expansion over 200 CGG repeats (full mutation) in the FMR1 gene. Intergenerational instability of an expanded FMR1 allele is linked to the carrier’s gender (female), the CGG repeat size and the number of AGG interspersions within the CGG repeat, making genetic counseling a complex task. The objective of our work was to emphasize the importance of combining haplotype analysis with FMR1 linked markers and CGG repeat sizing for prenatal diagnosis (PND) of FXS. METHODS: Two PND of FXS were performed using haplotype analyzes and sizing of the FMR1 allele. RESULTS: We detected two cases of meiotic recombination at the FMR1 locus, i.e., reciprocal double crossover or non-crossover, resulting in coexistence of the mutant maternal haplotype and the normal-size maternal CGG repeat. CONCLUSION: These rare and unexpected cases (1/120 frequency in our experience) have to be kept in mind in PND of FXS since they prohibit using polymorphic marker haplotyping as the only tool to predict the fetus status.
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2. Ford T, Kenchington R, Norman S, Hancock J, Smalley A, Henley W, Russell G, Hayes J, Logan S. {{The agreement between the referrer, practitioner and research diagnosis of autistic spectrum conditions among children attending child and adolescent mental health services}}. {Eur Child Adolesc Psychiatry}. 2019.
We aimed to explore the levels of agreement about the diagnoses of Autistic Spectrum Conditions between the referrer, CAMHS practitioner and a research diagnosis, as well as the stability of the practitioner’s diagnosis over time in a secondary analysis of data from 302 children attending two Child and Adolescent Mental Health Services over two years. Kappa coefficient was used to assess the agreement between the referrer and research diagnosis. Kendall’s tau b coefficient was used to assess the agreement between the practitioner and the research diagnosis assigned using the Development and Well-Being Assessment, as well as the agreement between the referrer’s indication of presenting problems and the practitioner diagnosis. Diagnostic stability was explored in children with and without a research diagnosis of Autistic Spectrum Condition. There was a moderate level of agreement between the referrer and research diagnosis (Kappa = 0.51) and between practitioner’s and research diagnosis (Kendall’s tau = 0.60) at baseline, which reduced over the subsequent two years. Agreement between the referrer and practitioner’s diagnosis at baseline was fair (Kendall’s tau = 0.36).The greatest diagnostic instability occurred among children who practitioners considered to have possible Autistic Spectrum Conditions but who did not meet research diagnostic criteria. Further studies could explore the approaches used by practitioners to reach diagnoses and the impact these may have on diagnostic stability in Autistic Spectrum Conditions. Standardised assessment using a clinically rated diagnostic framework has a potential role as an adjunct to standard clinical care and might be particularly useful where practitioners are uncertain.
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3. Montazeri F, de Bildt A, Dekker V, Anderson GM. {{Network Analysis of Behaviors in the Depression and Autism Realms: Inter-Relationships and Clinical Implications}}. {J Autism Dev Disord}. 2019.
Depression-, anxiety-, OCD- and autism-related behaviors were assessed in 118 high-functioning individuals with autism spectrum disorders (ASD) and in 2016 controls. The ASD group had a higher rate of clinical depression and markedly higher « insomnia » and « restlessness » scores. Network analysis and hierarchical cluster analysis in the ASD group revealed that depression and anxiety items clustered together, but separately from autism-related items. Compared to controls, « insomnia » and « restlessness » items in the ASD network of depression items were much more central (higher closeness, and betweenness centrality). Combined networks of depression-, anxiety-, and OCD-related items revealed that the control group depression item module was not preserved in ASD. The results indicate that depression is atypical in autism and suggest specific intervention targets.
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4. Nadeem A, Ahmad SF, Al-Harbi NO, Attia SM, Bakheet SA, Ibrahim KE, Alqahtani F, Alqinyah M. {{Nrf2 activator, sulforaphane ameliorates autism-like symptoms through suppression of Th17 related signaling and rectification of oxidant-antioxidant imbalance in periphery and brain of BTBR T+tf/J mice}}. {Behav Brain Res}. 2019.
Autism is a neurodevelopmental disease which is characterized by its core behavioral symptoms such as impairment in social interaction and stereotyped repetitive behavior. Th17 immune responses and oxidative stress are reported to be elevated in both human autistic subjects and BTBR T + Itpr3tf/J (BTBR) mice. On the other hand, activation of nuclear factor erythroid 2 related factor (Nrf2), a master transcription factor is essential for the management of anti-inflammatory and antioxidant genes. Sulforaphane activates Nrf2 and thus is considered a potential approach to treat several neurological disorders including autism. In the current work, we used sulforaphane in asocial BTBR mice and its social counterpart C57/BL6 (C57) mice to assess its therapeutic potential and molecular mechanisms (Th17 immune responses, and oxidant-antioxidant balance) through which it acts. Our results demonstrate that BTBR treated with sulforaphane had reduced self-grooming/marble burying behavior, and increased social interaction in three chambered sociability test as compared to untreated BTBR mice. Further, sulforaphane-treated BTBR mice had reduced Th17 immune responses (STAT3, RORC, IL-17 A and IL-23R expression in CD4 + T cells), oxidative stress parameters in neutrophils/cerebellum (NFkB, iNOS, and lipid peroxides). Furthermore, sulforaphane-treated BTBR and C57 mice had upregulated enzymatic antioxidant defenses in neutrophils/cerebellum (SOD, GPx and GR expression and activity). We reason that activation of Nrf2 by sulforaphane corrected Th17 immune dysfunction and oxidant-antioxidant imbalance in periphery and brain in BTBR mice. These mechanisms lead to improvement in autism-like symptoms in BTBR mice.
