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Musculoskeletal pain and muscular weakness as the main symptoms of adult hypophosphatasia in a Spanish cohort: clinical characterization and identification of a new ALPL gene variant

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Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

Hypophosphatasia (HPP) is a rare inherited disorder, caused by mutations in the alkaline phosphatase (ALPL) gene, which encodes for the tissue non-specific alkaline phosphatase (TNSALP) isoform of alkaline phosphatase (ALP). Adult HPP is one of the mild forms that presents with unspecific signs such as osteopenia, osteomalacia and muscle involvement. Our purpose was to identify and characterize possibly misdiagnosed adult HPP patients at a clinical and biochemical level.

Material and Methods

At the laboratory of Miguel Servet University Hospital we retrospectively reviewed serum ALP levels in adults over a 48-month period. The clinical records of individuals with consistently low ALP levels were reviewed to exclude secondary causes. Those with persistent hypophosphatasemia were screened for symptoms of HPP. The study participants were evaluated at biochemical and genetic levels.

Results

We identified 705 ALP determinations (out of 384,000 processed) in 589 patients below the reference range (30 U/l). Only 21 patients with clinical signs and symptoms of HPP were selected for genetic testing. Finally, only 12 patients participated in the study, 83.3% of whom (10/12) harbored a pathogenic or likely pathogenic variant in a heterozygous state. The major symptoms of our cohort were the presence of musculoskeletal pain (100% of patients) and muscular weakness (83.3% patients).

Conclusion

Mild HPP patients presenting with diffuse symptoms such as musculoskeletal pain may be undiagnosed or misdiagnosed as osteoporosis patients by routine diagnosis. It is important to identify these individuals, to avoid inappropriate treatment with antiresorptive drugs.

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Availability of data and materials

The study provides full data transparency and availability of data and material. Web resources: ALPL gene variant database: https://alplmutationdatabase.jku.at/. Last accessed April 7th gnomAD variant database: https://gnomad.broadinstitute.org/. Last accessed April 7th EVS database: https://evs.gs.washington.edu /EVS/. Last accessed April 7th.

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Authors and Affiliations

  1. Clinical Biochemistry Department, IIS Aragón, Miguel Servet University Hospital, Network Research Center in Cardiovascular Diseases (CIBERCV), University of Zaragoza, 50009, Zaragoza, Spain

    Pilar Calmarza

  2. Preventive Medicine Department, Miguel Servet University Hospital, 50009, Zaragoza, Spain

    Carlos Lapresta

  3. Endocrinology Department, Barbastro Hospital, 22300, Barbastro, Huesca, Spain

    María Martínez García

  4. Occupational Risk Prevention Service, MAS Prevention, Zaragoza, Spain

    José Ochoa

  5. Clinical Biochemistry Department, Miguel Servet University Hospital, 50009, Zaragoza, Spain

    Paula Sienes Bailo

  6. Endocrinology Department, Miguel Servet University Hospital, 50009, Zaragoza, Spain

    Javier Acha Pérez

  7. Rheumatology department, Miguel Servet University Hospital, 50009, Zaragoza, Spain

    Jesús Beltrán Audera

  8. Molecular Biology Core Lab/Immunology Department, CDB. Hospital Clínic, Barcelona, Spain

    Eva González-Roca

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  1. Pilar Calmarza
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Contributions

PC carried out the conception and design and data interpretation, drafting and reviewing the manuscript and approved the final version of the manuscript. CL contributed to data analysis and interpretation, revising the manuscript and approved the final version of the manuscript. MMG contributed to the acquisition and interpretation of data, revising the manuscript and approved the final version of the manuscript. JO contributed to the acquisition and interpretation of data, revising the manuscript and approved the final version of the manuscript. JAP contributed to the acquisition and analysis of data, revising the manuscript and approved the final version of the manuscript. JBA contributed to the acquisition and interpretation of data, revising the manuscript and approved the final version of the manuscript. EG-R contributed to data analysis and interpretation, the drafting and reviewing of the manuscript and approved the final version of the manuscript.

Corresponding author

Correspondence to Pilar Calmarza.

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Conflict of interest

"Author 1, Author 2, Author 3, Author 4, Author 5, Author 6 and Author 7 declare that they have no conflict of interest." Eva González-Roca (Author 8): has been on the advisory board and received honoraria for lectures from Alexion.

Ethical approval

The study was approved by the Research Ethics Committee of the Autonomous Community of Aragon (CEICA) and all participants provided informed written consent.

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Calmarza, P., Lapresta, C., Martínez García, M. et al. Musculoskeletal pain and muscular weakness as the main symptoms of adult hypophosphatasia in a Spanish cohort: clinical characterization and identification of a new ALPL gene variant. J Bone Miner Metab 41, 654–665 (2023). https://doi.org/10.1007/s00774-023-01440-z

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