Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues

Movement disorders in patients with Rett syndrome:A systematic review of evidence and associated clinical considerations

AIM: This systematic review identified and thematically appraised clinical evidence of movement disorders in patients with Rett syndrome (RTT). METHOD: Using PRISMA criteria, six electronic databases were searched from inception to April 2021. A thematic analysis was then undertaken on the extracted data to identify potential themes. RESULTS: Following the thematic analysis, six themes emerged: (i) clinical features of abnormal movement behaviors; (ii) mutational profile and its impact on movement disorders; (iii) symptoms and stressors that impact on movement disorders; (iv) possible underlying neurobiological mechanisms; (v) quality of life and movement disorders; and (vi) treatment of movement disorders. Current guidelines for managing movement disorders in general were then reviewed to provide possible treatment recommendations for RTT. CONCLUSION: Our study offers an enriched data set for clinical investigations and treatment of fine and gross motor issues in RTT. A detailed understanding of genotype–phenotype relationships of movement disorders allows for more robust genetic counseling for families but can also assist healthcare professionals in terms of monitoring disease progression in RTT. The synthesis also showed that environmental enrichment would be beneficial for improving some aspects of movement disorders. The cerebellum, basal ganglia, alongside dysregulation of the cortico‐basal ganglia‐thalamo‐cortical loop, are likely anatomical targets. A review of treatments for movement disorders also helped to provide recommendations for treating and managing movement disorders in patients with RTT

Phonic and Motor Stereotypies in Autism Spectrum Disorder: Video Analysis and Neurological Characterization

Stereotypies are among the core symptoms of Autism spectrum disorder (ASD) and can cause significant clinical impairment. At present, phonic stereotypies in ASD have been scarcely explored. This study investigates the frequency, variability, and typologies of phonic and motor stereotypies in children with ASD and their association with clinical neurological variables. We examined 35 patients by recording standardized video sessions and administering the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). Phonic stereotypies were present in 83.0% of the patients. The most prevalent subtypes were noncommunicative vocalizations (60.0%), single syllables (37.1%), and echolalic stereotypies (22.9%). Noncommunicative vocalizations were more frequent in nonverbal patients (OR = 4.629, p = 0.008), while echolalic stereotypies were more represented in verbal patients (OR = 0.279, p = 0.028). Patients with intellectual disability (ID) showed a higher number (F(1,26) = 9.406, p = 0.005) and variability (F(1,25) = 7.174, p = 0.013) of motor stereotypies, with a higher number (F(1,26) = 13.268, p = 0.005) and variability (F(1,26) = 9.490, p = 0.005) of stereotypies involving the head/trunk/shoulders category. Patients with guttural stereotypies showed a higher variability of total motor stereotypies (OR = 1.487, p = 0.032) and self-directed motor stereotypies (OR = 4.389, p = 0.042). These results, combined with a standardized video-analysis, document the frequency and variability of phonic stereotypies among children with ASD. Correlations between specific phonic stereotypies and verbal abilities should be investigated further