Inorganic Pyrophosphate Plasma Levels Are Decreased in Pseudoxanthoma Elasticum Patients and Heterozygous Carriers but Do Not Correlate with the Genotype or Phenotype

Matthias Van Gils; Justin Depauw; Paul J Coucke; Shari Aerts; Shana Verschuere; Lukas Nollet; Olivier M Vanakker

doi:10.3390/jcm12051893

Inorganic Pyrophosphate Plasma Levels Are Decreased in Pseudoxanthoma Elasticum Patients and Heterozygous Carriers but Do Not Correlate with the Genotype or Phenotype

J Clin Med. 2023 Feb 27;12(5):1893. doi: 10.3390/jcm12051893.

Authors

Matthias Van Gils^{1

2

3}, Justin Depauw³, Paul J Coucke^{1

2

3}, Shari Aerts^{1

2

3}, Shana Verschuere^{1

2

3}, Lukas Nollet^{1

2

3}, Olivier M Vanakker^{1

2

3}

Affiliations

¹ Center for Medical Genetics, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
² Department of Biomolecular Medicine, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium.
³ Ghent Ectopic Mineralization Research Group, 9000 Ghent, Belgium.

Abstract

Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification disorder affecting soft connective tissues that is caused by biallelic ABCC6 mutations. While the underlying pathomechanisms are incompletely understood, reduced circulatory levels of inorganic pyrophosphate (PPi)-a potent mineralization inhibitor-have been reported in PXE patients and were suggested to be useful as a disease biomarker. In this study, we explored the relation between PPi, the ABCC6 genotype and the PXE phenotype. For this, we optimized and validated a PPi measurement protocol with internal calibration that can be used in a clinical setting. An analysis of 78 PXE patients, 69 heterozygous carriers and 14 control samples revealed significant differences in the measured PPi levels between all three cohorts, although there was overlap between all groups. PXE patients had a ±50% reduction in PPi levels compared to controls. Similarly, we found a ±28% reduction in carriers. PPi levels were found to correlate with age in PXE patients and carriers, independent of the ABCC6 genotype. No correlations were found between PPi levels and the Phenodex scores. Our results suggest that other factors besides PPi are at play in ectopic mineralization, which limits the use of PPi as a predictive biomarker for severity and disease progression.

Keywords: ABCC6; biomarker; genotype–phenotype correlation; heterozygous carriers; inorganic pyrophosphate; pseudoxanthoma elasticum.

Grants and funding

M.V.G. is supported by a BOF research fellowship from Ghent University (BOF 01N04315). O.M.V. is a senior clinical investigator of Research Foundation Flanders (FWO), Belgium. This research was also supported by a Methusalem grant (BOF08/01M01108) and a GOA grant (GOA019-21) from the Ghent University.