INTRODUCTION: Adult hypophosphatasia (HPP) patients present with diffuse heterogenous symptoms often mimicking rheumatological diseases or osteoporosis and therefore accompanied by delayed diagnosis. The aim of this study was to identify circulating miRNAs in adult HPP patients and to identify potential associations with clinical patients' characteristics. METHODS: We utilized untargeted miRNA biomarker discovery by small RNA-sequencing to investigate cell-free miRNA profiles in 24 adult HPP patients (pathogenic variant of the ALPL gene, HPP-related clinical symptoms and repeatedly low ALP) and 24 healthy controls (CTRL). RESULTS: Patients and CTRL were comparable in age (47.9±14.2 vs. 45.9±8.8y, p=0.980) and sex (55.5% vs. 47.8% females, p=1.000). In total, 91% of patients reported musculoskeletal pain, 41% diffuse neurological symptoms and 64% history of fractures. In total, 84 miRNAs were significantly differently expressed between HPP and CTRL in next generation sequencing (NGS) analysis(p<
0.05). Of these, 14 miRNAs were selected (selection criteria: p<
0.05, tissue specificity index >
0.7, log2 FC >
+0.8 or <
-0.8) for validation using RT-qPCR, which verified 6 of 14 selected miRNAs (p<
0.05
miR-122-3p, miR-140-5p, miR-143-3p, miR-155-5p, miR-451a, miR-92a-3p). Target prediction and enrichment analysis identified associations with the musculoskeletal system and the central nervous system. In total, 37 miRNAs correlated with ALP levels, but only three miRNAs with PLP (pyridoxal-5'-phosphate). CONCLUSIONS: These findings highlight a profound involvement of multiple organ systems and the potential of miRNAs as biomarkers for the effect of HPP on various systems.