Screening for hypophosphatasia: does biochemistry lead the way?

Corinna Melanie Held; Anic Guebelin; Andreas Krebs; Jörn Oliver Sass; Michael Wurm; Ekkehart Lausch; Natascha van der Werf-Grohmann; Karl Otfried Schwab

doi:10.1515/jpem-2021-0104

Article

Screening for hypophosphatasia: does biochemistry lead the way?

Corinna Melanie Held , Anic Guebelin , Andreas Krebs , Jörn Oliver Sass , Michael Wurm , Ekkehart Lausch , Natascha van der Werf-Grohmann and Karl Otfried Schwab

Published/Copyright: September 22, 2021

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 35 Issue 2

Abstract

Objectives

Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population.

Methods

We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5′-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP.

Results

We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease.

Conclusions

A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.

Keywords: alkaline phosphatase; heterozygous ALPL mutation; hypophosphatasia; inorganic pyrophosphate; phosphoethanolamine; pyridoxal phosphate; screening

Corresponding author: Prof. Dr. Karl Otfried Schwab, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre, Faculty of Medicine, University of Freiburg, Mathildenstr. 1, 79106 Freiburg, Germany, Phone: +49 761 270 43000, E-mail: karl.otfried.schwab@uniklinik-freiburg.de

Corinna Melanie Held and Anic Guebelin contributed equally to this work.

Funding source: Alexion Pharmaceuticals Inc. 10.13039/100006396

Award Identifier / Grant number: University of Freiburg-Schwab-API-IRS-Funding-8.21.17

Acknowledgment

EL was funded bei the INTERREG V programme RARENET. Skilled technical assistance by Hannah Rohde (Bonn-Rhein-Sieg University of Applied Sciences) is gratefully acknowledged. JOS was supported by FH Zeit für Forschung (‘KETOplus’, 005-1703-0016) of the Ministry of Culture and Science of the German State of North Rhine-Westphalia.

Research funding: CH and KOS received a research grant from Alexion Pharmaceuticals Inc. (University of Freiburg-Schwab-API-IRS-Funding-8.21.17).
Author contributions: Study conception and design were prepared by KOS and CH, all authors contributed to the study design. Material preparation, data collection, and analysis were performed by AG and CH. Laboratory analyses were supervised by JOS and AK. Genetic analyses were supervised by EL and MW. The first draft of the manuscript was written by CH and AG. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest. The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Informed consent: Informed consent was obtained from all individuals included in this study. The informed consent of the parents was obtained for all children.
Ethical approval: This study was conducted according to the current Declaration of Helsinki. The local ethics committee had neither ethical nor legal concerns about the conduct of the study (approval number 435/16).

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Received: 2021-02-12

Accepted: 2021-08-16

Published Online: 2021-09-22

Published in Print: 2022-02-23

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Articles in the same Issue

https://doi.org/10.1515/jpem-2021-0104

Keywords for this article

alkaline phosphatase; heterozygous ALPL mutation; hypophosphatasia; inorganic pyrophosphate; phosphoethanolamine; pyridoxal phosphate; screening