{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T21:24:56Z","timestamp":1769289896666,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pathological reduction in enzymatic activity of the tissue-non-specific alkaline phosphatase (TNSALP) is the molecular hallmark of hypophosphatasia (HPP), a group of rare inborn systemic diseases, mainly characterized by pathological affections of calcified tissue mineralization and the musculoskeletal system. The disease, in all clinical forms, is biochemically characterized by variable degrees of chronically reduced activity of circulating total alkaline phosphatase (ALP). Repeated detection of low values of ALP activity is mandatory to diagnose the presence of HPP, but, alone, it is not sufficient for the diagnosis of the disease. Detection of increased circulating levels of one of the main natural substrates of TNSALP, the pyridoxal 5\u2032-phosphate (PLP), is needed to biochemically confirm the diagnosis of HPP. Urinary and\/or blood levels of phosphoethanolamine (PEA) and inorganic pyrophosphate (PPi), two other natural substrates of TNSALP, can be elevated in a percentage of HPP patients. The contemporary biochemical evaluation of ALP activity and its target substrates is of great help in the diagnosis of HPP, and also for the monitoring of a patient\u2019s response to enzymatic replacement therapy or other pharmacological treatments. Here, we describe and discuss possibilities and challenges of biochemical screenings for HPP, based also on the experience gained in our analysis laboratory.<\/jats:p>","DOI":"10.3390\/ijms27031144","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T10:41:34Z","timestamp":1769164894000},"page":"1144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Importance of Biochemical Screenings in the Diagnosis of Hypophosphatasia: Applications, Methodologies, and Challenges"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3678-4922","authenticated-orcid":false,"given":"Francesca","family":"Marini","sequence":"first","affiliation":[{"name":"FIRMOLab 2.0\u2014Italian Foundation for Research on Bone Diseases (Fondazione FIRMO Onlus), 50129 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8376-7404","authenticated-orcid":false,"given":"Gaia","family":"Palmini","sequence":"additional","affiliation":[{"name":"FIRMOLab 2.0\u2014Italian Foundation for Research on Bone Diseases (Fondazione FIRMO Onlus), 50129 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simone","family":"Donati","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-9606","authenticated-orcid":false,"given":"Francesca","family":"Giusti","sequence":"additional","affiliation":[{"name":"Donatello Bone Clinic, Villa Donatello Hospital, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8741-0592","authenticated-orcid":false,"given":"Maria Luisa","family":"Brandi","sequence":"additional","affiliation":[{"name":"FIRMOLab 2.0\u2014Italian Foundation for Research on Bone Diseases (Fondazione FIRMO Onlus), 50129 Florence, Italy"},{"name":"Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy"},{"name":"Donatello Bone Clinic, Villa Donatello Hospital, 50019 Sesto Fiorentino, Italy"},{"name":"Stabilimento Chimico Farmaceutico Militare (SCFM), 50141 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00198-023-06843-2","article-title":"Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: Results from the HPP International Working Group","volume":"35","author":"Rush","year":"2024","journal-title":"Osteoporos. 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