Enrichment and Correlation Analysis of Serum miRNAs in Comorbidity Between Arnold-Chiari and Tourette Syndrome Contribute to Clarify Their Molecular Bases

Abstract

Due to its rarity, coupled to a multifactorial and very heterogeneous nature, the molecular etiology of Arnold-Chiari (AC) syndrome remains almost totally unknown. Its relationship with other neuropsychiatric disorders such as Tourette syndrome (TS) is also undetermined. The rare comorbid status between both disorders (ACTS) complicates the framework of diagnosis and negatively affects the patients' quality of life. In this exploratory study, we aimed to identify serum microRNA expression profiles as molecular fingerprints for AC, TS, and ACTS, by using a high-throughput approach. For this aim, 10 AC patients, 11 ACTS patients, 6 TS patients, and 8 unaffected controls (NC) were recruited. Nine miRNAs resulted significantly differentially expressed (DE): let-7b-5p (upregulated in ACTS vs. TS); miR-21-5p (upregulated in ACTS vs. AC; downregulated in AC vs. TS); miR-23a-3p (upregulated in TS vs. NCs; downregulated in AC vs. TS); miR-25-3p (upregulated in AC vs. TS and NCs; downregulated in ACTS vs. AC); miR-93-5p (upregulated in AC vs. TS); miR-130a-3p (downregulated in ACTS and TS vs. NCs); miR-144-3p (downregulated in ACTS vs. AC; upregulated in AC vs. TS); miR-222-3p (upregulated in ACTS vs. NCs); miR-451a (upregulated in AC vs. TS and NCs; in ACTS vs. NCs). Altered expression of miRNAs was statistically correlated to neuroimaging and neuropsychological anomalies. Furthermore, computational analyses indicated that DE miRNAs are involved in AC and TS pathomechanisms. Finally, we propose the dysregulation of the miRNA set as a potential molecular tool for supporting the current diagnosis of AC, TS, and ACTS by using liquid biopsies, in an unbiased and non-invasive way.

The Aetiology of Tourette Syndrome and Chronic Tic Disorder in Children and Adolescents: A Comprehensive Systematic Review of Case-Control Studies

“…However, among the four studies, only the Guo et al study was of high quality. Differential expressions of several miRNAs in TS were reported in the studies by Rizzo et al [ 23 ] and Mirabella et al [ 22 ], and both studies were identified as high quality.…”

“…Rizzo et al [ 23 ] identified downregulated expression of miR-429 by analyzing 52 TS patients and 15 NC patients (Wilcoxon test p = 0.01; t -test p = 0.004). The study by Mirabella et al [ 22 ] compared TS ( n = 6), TS with Arnold-Chiari syndrome (ACTS) ( n = 11) and NC ( n = 8). The results showed that miR-23a-3p was upregulated in TS compared to NC (1.67-fold), miR-130a-3p was downregulated in ACTS or TS compared to NC (−1.56-fold; −1.61-fold), miR-222-3p and miR-451a were upregulated in ACTS compared to NC (1.95-fold; 1.58-fold), and the FDR was <0.05 for each pairwise comparison.…”

“…Seven studies [ 14 , 15 , 16 , 19 , 20 , 22 , 23 ] were judged to be of high quality, and six studies [ 13 , 17 , 18 , 21 , 24 , 25 ] were judged as fair quality according to the NOS. The studies by Lei et al [ 18 ] and Ferrari et al [ 13 ] highlighted the defects in the selection and description of controls, and potential selection biases of cases.…”

Recent progress on Tourette syndrome

“…MicroRNAs (miRNAs) have attracted attention as biomarkers for diseases, intercellular communication, and neural development 49 . A clinical study using serum miRNA expression profiles as molecular fingerprints for children with either TS or Arnold–Chiari malformation showed nine differentially expressed miRNAs as potential molecular tools for the diagnosis of TS 50 . These pathophysiological studies have converged to suggest the importance of CSTC circuits and their associated neurotransmitters and other brain regions but have not yet supported a clear, inclusive theory of tic pathophysiology.…”