Longitudinal course of circulating miRNAs in a patient with hypophosphatasia: a case report

Introduction Hypophosphatasia (HPP) is a rare genetic bone disease characterized by low activity of tissue non-specific alkaline phosphatase (TSNALP), musculoskeletal pain, impaired mobility and recurrent fractures. The enzyme replacement therapy asfotase alfa has been approved for juvenile-onset forms of severe HPP. MicroRNAs (miRNAs) have recently emerged as novel disease biomarkers, potentially having a role in therapy monitoring.

Methods Circulating miRNAs were analyzed at baseline (BL), months 2 (V1), 7 (V2) and 13 (V3) in a 47-year-old woman with childhood-onset HPP and multiple non-traumatic fractures treated with asfotase alfa. Serum RNA was extracted and sequenced using miRNeasy Mini Kit (Qiagen, Germany), RealSeq Biosciences Kit (Santa Cruz, US) and miND spike-in control kit (TAmiRNA, Austria). Brief Pain Inventory Severity and Interference scores (BPI-S/BPI-I), Patient Global Impression of Improvement (PGI-I), Western Ontario and McMaster university hip disability and osteoarthritis outcome score (WOMAC) and fibromyalgia impact questionnaire (FIQ) as well as chair-rise-test (CRT) and 6-minute walk test (6MWT) were performed.

Results Out of >800 screened miRNAs, 84 significantly regulated miRNAs were identified. Of the latter, six were up- or down-regulated by ≥50% at V3 (hsa-let-7i-5p, hsa-miR-1-3p, hsa-miR-1294, hsa-miR-206, hsa-miR-375-3p and hsa-miR-624-5p). hsa-miR-1-3p and hsa-miR-206 were identified as musculoskeletal miRNAs and displayed a down-regulation by 67% and 86%, respectively. Hsa-let-7i-5p, which is expressed in numerous tissue types, hence being non-specific with regards to bone and muscle tissue increased by 50%. BPI-S, BPI-I, PGI-I, WOMAC and FIQ showed a reduction of 59%, 68%, 75%, 63% and 43% at months 16, respectively. CRT improved from 15.3 seconds at baseline to 8.5 seconds (44%) and 6MWT from 357.6 meters at BL to 478.8 meters (34%) at months 10, respectively.

Discussion miRNA profiles change over the course of therapy with asfotase alpha, accompanying improvements in functionality and quality of life scores. Especially musculoskeletal miRNAs are regulated differently under enzyme replacement therapy, reflecting the nature of disease. Thus, miRNAs could potentially be used as a novel biomarker for monitoring of treatment in HPP patients.

Keywords Hypophosphatasia, HPP, microRNAs, miRNAs, ALP, Asfotase alfa

Korrespondenzadresse Benjamin Hadzimuratovic, Hanusch-Krankenhaus der ÖGK, Ludwig Boltzmann Institut für Osteologie, 1. Medizinische Abteilung, Heinrich-Collin-Straße 30, 1140 Wien, Österreich, E-Mail: [e-mail]

Publication History

Article published online:
16 June 2023