Potential Associations Among Alteration of Salivary miRNAs, Saliva Microbiome Structure, and Cognitive Impairments in Autistic Children.

Recent evidence has demonstrated that salivary molecules, as well as bacterial populations, can be perturbed by several pathological conditions, including neuro-psychiatric diseases. This relationship between brain functionality and saliva composition could be exploited to unveil new pathological mechanisms of elusive diseases, such as Autistic Spectrum Disorder (ASD). We performed a combined approach of miRNA expression profiling by NanoString technology, followed by validation experiments in qPCR, and 16S rRNA microbiome analysis on saliva from 53 ASD and 27 neurologically unaffected control (NUC) children. MiR-29a-3p and miR-141-3p were upregulated, while miR-16-5p, let-7b-5p, and miR-451a were downregulated in ASD compared to NUCs. Microbiome analysis on the same subjects revealed that Rothia, Filifactor, Actinobacillus, Weeksellaceae, Ralstonia, Pasteurellaceae, and Aggregatibacter increased their abundance in ASD patients, while Tannerella, Moryella and TM7-3 decreased. Variations of both miRNAs and microbes were statistically associated to different neuropsychological scores related to anomalies in social interaction and communication. Among miRNA/bacteria associations, the most relevant was the negative correlation between salivary miR-141-3p expression and Tannerella abundance. MiRNA and microbiome dysregulations found in the saliva of ASD children are potentially associated with cognitive impairments of the subjects. Furthermore, a potential cross-talking between circulating miRNAs and resident bacteria could occur in saliva of ASD.

Clinical correlates in children with autism spectrum disorder and CNVs: Systematic investigation in a clinical setting.

Autism spectrum disorder (ASD) is associated with various molecular mechanisms including copy number variants (CNVs). We investigated possible associations between CNVs and ASD clinical correlates. We evaluated pertinent physical characteristics and phenotypic measures such as cognitive level, severity of ASD symptoms and comorbid conditions in ASD patients consecutively recruited over the study period. Children with causative (C-CNVs), non-causative (NC-CNVs) and without CNVs (W-CNVs) were compared. Out of 109 patients, 31 imbalances (16 duplications and 15 deletions) were detected in 25 subjects. Seven (6.4%) had C-CNVs and 18 (16.5%) had NC-CNVs. Paired post hoc comparisons with Bonferroni adjustment showed that dysmorphisms and microcephaly were significantly more frequent in the C-CNVs group. Patients with C-CNVs had more severe autistic core symptoms, while comorbid internalizing behavioral symptoms were more represented among participants with NC-CNVs. No significant differences were observed for distribution of macrocephaly, intellectual disability, epilepsy, isolated electroencephalogram abnormalities and studied neuroimaging characteristics among groups. Recurrent and rare C-CNVs highlighting genes relevant to neurodevelopment had a statistically higher occurrence in children with more severe ASD symptoms and further developmental abnormalities. This study documents the importance of measuring the physical and neurobehavioural correlates of ASD phenotypes to unravel the underlying molecular mechanisms in patient subgroups.

Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder.

Given its prevalence and social impact, Autism Spectrum Disorder (ASD) is drawing much interest. Molecular basis of ASD is heterogeneous and only partially known. Many factors, including disorders comorbid with ASD, like TS (Tourette Syndrome), complicate ASD behavior-based diagnosis and make it vulnerable to bias. To further investigate ASD etiology and to identify potential biomarkers to support its precise diagnosis, we used TaqMan Low Density Array technology to profile serum miRNAs from ASD, TS, and TS+ASD patients, and unaffected controls (NCs). Through validation assays in 30 ASD, 24 TS, and 25 TS+ASD patients and 25 NCs, we demonstrated that miR-140-3p is upregulated in ASD vs.: NC, TS, and TS+ASD (Tukey's test, p-values = 0.03, = 0.01, < 0.0001, respectively). ΔCt values for miR-140-3p and YGTSS (Yale Global Tic Severity Scale) scores are positively correlated (Spearman r = 0.33; Benjamini-Hochberg p = 0.008) and show a linear relationship (p = 0.002). Network functional analysis showed that nodes controlled by miR-140-3p, especially CD38 and NRIP1 which are its validated targets, are involved in processes convergingly dysregulated in ASD, such as synaptic plasticity, immune response, and chromatin binding. Biomarker analysis proved that serum miR-140-3p can discriminate among: (1) ASD and NC (Area under the ROC curve, AUC: 0.70; sensitivity: 63.33%; specificity: 68%); (2) ASD and TS (AUC: 0.72; sensitivity: 66.66%; specificity: 70.83%); (3) ASD and TS+ASD (AUC: 0.78; sensitivity: 73.33%; specificity: 76%). Characterization of miR-140-3p network would contribute to further clarify ASD etiology. Serum miR-140-3p could represent a potential non-invasive biomarker for ASD, easy to test through liquid biopsy.

Importance of neuropsychiatric evaluation in children with primary monosymptomatic enuresis.

BACKGROUND: Nocturnal enuresis (NE) is an involuntary voiding during sleep. It is a very common disorder in school-age children. Comorbid psychopathologies are common in patients affected by enuresis. According to the ICCS, the rate of behavioral and emotional disorders in children with enuresis is doubled compared with healthy control (HC) children. OBJECTIVE: The aim of the present study was to investigate the prevalence of neuropsychiatric comorbidities in children affected by NE. STUDY DESIGN: Two hundred children with a diagnosis of enuresis were recruited from the Neuropsychiatric Unit of Catania University and 200 age-matched neurologically intact HC children were recruited from local schools. The inclusion criteria were a normal IQ and the absence of other pathological clinical conditions such as diabetes or kidney malformation. The exclusion criteria were failure to complete the initial evaluation or clinical/diagnostic procedures, inability (because of young age) to complete study questionnaires, and severe neurological or physical impairment. RESULTS: Age and gender proportions were not significantly different between the groups. In the NE group, 138 subjects (69%) had a familial history of NE, compared with 24 subjects (12%) in the HC group (p < 0.01). The NE group demonstrated significantly higher scores in the Child Behavior Check List, Conners' Multidimensional Anxiety Scale for Children, and the Child Depression Inventory compared than the HC group as well as the Yale Global Tic Severity Score and Child-Yale-Brown Obsessive Compulsive Scale scores (p < 0.01). Quality of life scores were significantly lower in the NE group than in the HCs group; specifically, between-group differences were significant in the relationship and self domains (p > 0.01 for both comparisons) (Figure). DISCUSSION: The present case-control study evaluates the prevalence of different neuropsychiatric comorbidities in children with NE as diagnosed according to the new ICCS criteria. An important finding was that neuropsychiatric conditions were more prevalent in NE patients than in age-matched HC subjects. To the best of our knowledge, this is the first study to report associations between enuresis and obsessive compulsive disorder as well as tic disorder, and is the first to describe the comparative psychopathological profiles of 200 children with enuresis and 200 matched HC children. CONCLUSION: The results suggest that clinicians should not underestimate the effects of enuresis on psychosocial development. Childhood NE should be managed carefully and comprehensively in order to prevent the development of more serious behavioral problems in the future.