Presentation and outcome in carriers of pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter NPT 2a and 2c

Pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter 2a and 2c are rare causes of phosphate wasting. Since data on presentation and outcomes are scarce, we collected clinical, biochemical and genetic data via an online questionnaire and the support of European professional organizations. One hundred thirteen patients (86% children) from 90 families and 17 countries with pathogenic or likely pathogenic variants in SLC34A1 or SLC34A3 and a median follow-up of three years were analyzed. Biallelic SLC34A1 variant carriers showed polyuria, failure to thrive, vomiting, constipation, hypercalcemia and nephrocalcinosis in infancy, while biallelic SLC34A3 carriers presented in childhood or even adulthood with rickets/osteomalacia and/or osteopenia/osteoporosis, hypophosphatemia and, less frequently, nephrocalcinosis, while the prevalences of kidney stones were comparable. Adult biallelic SLC34A3 carriers had a six-fold increase chronic kidney disease (CKD) prevalence compared to the general population. All biallelic variant carriers shared a common biochemical pattern including elevated 1,25(OH)<sub>2</sub>D and alkaline phosphatase levels, suppressed parathyroid hormone (PTH), and hypercalciuria. Heterozygous carriers showed similar but less pronounced phenotypes. In biallelic SLC34A1 carriers, an attenuation of clinical features was observed after infancy, independent of treatment. Phosphate treatment was given in 55% of patients, median duration two years, and resulted in significant reduction, although not normalization, of alkaline phosphatase and of hypercalciuria but an increase in PTH levels, while 1,25(OH)<sub>2</sub>D levels remained elevated. Thus, our study indicates that biallelic SLC34A1 and SLC34A3 carriers show distinct, albeit overlapping phenotypes, with the latter having an increased risk of CKD in adulthood. Phosphate treatment may promote kidney phosphate loss and enhance 1,25(OH)<sub>2</sub>D synthesis via increased PTH production.

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Journal
Kidney International
Published
2024-10-24
DOI
https://doi.org/10.1016/j.kint.2024.08.035
Citations
20
Primary Topic
Amino Acid Enzymes and Metabolism
Type
article
Field-Weighted Citation Impact
5.90

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article

Presentation and outcome in carriers of pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter NPT 2a and 2c

Laura Espinosa, Marc R. Liliën, Priyanka Khandelwal, Jeremy Allgrove et al.
20 citations
Kidney International
Amino Acid Enzymes and Metabolism
5.90
article

Presentation and outcome in carriers of pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter NPT 2a and 2c

Laura Espinosa, Marc R. Liliën, Priyanka Khandelwal, Jeremy Allgrove, Mehmet Eltan, Justine Bacchetta, Marc Fila, Felix Lechner, Martine Besouw, Marcin Zaniew, Maria Szczepańska, Corinna Grasemann, Svetlana Papizh, Dieter Haffner, Dirk Schnabel, Juan David González-Rodríguez, Francesco Emma, Lena Brunkhorst, İbrahim Gökçe, Mandy G. Keijzer‐Veen, Przemysław Sikora, Elisabeth A. M. Cornelissen, Serap Turan, Milan Chromek, Helge Martens, Thomas J. Neuhaus, Max Brunkhorst
article en
20 citations

Abstract

Pathogenic variants in SLC34A1 and SLC34A3 encoding sodium-phosphate transporter 2a and 2c are rare causes of phosphate wasting. Since data on presentation and outcomes are scarce, we collected clinical, biochemical and genetic data via an online questionnaire and the support of European professional organizations. One hundred thirteen patients (86% children) from 90 families and 17 countries with pathogenic or likely pathogenic variants in SLC34A1 or SLC34A3 and a median follow-up of three years were analyzed. Biallelic SLC34A1 variant carriers showed polyuria, failure to thrive, vomiting, constipation, hypercalcemia and nephrocalcinosis in infancy, while biallelic SLC34A3 carriers presented in childhood or even adulthood with rickets/osteomalacia and/or osteopenia/osteoporosis, hypophosphatemia and, less frequently, nephrocalcinosis, while the prevalences of kidney stones were comparable. Adult biallelic SLC34A3 carriers had a six-fold increase chronic kidney disease (CKD) prevalence compared to the general population. All biallelic variant carriers shared a common biochemical pattern including elevated 1,25(OH)<sub>2</sub>D and alkaline phosphatase levels, suppressed parathyroid hormone (PTH), and hypercalciuria. Heterozygous carriers showed similar but less pronounced phenotypes. In biallelic SLC34A1 carriers, an attenuation of clinical features was observed after infancy, independent of treatment. Phosphate treatment was given in 55% of patients, median duration two years, and resulted in significant reduction, although not normalization, of alkaline phosphatase and of hypercalciuria but an increase in PTH levels, while 1,25(OH)<sub>2</sub>D levels remained elevated. Thus, our study indicates that biallelic SLC34A1 and SLC34A3 carriers show distinct, albeit overlapping phenotypes, with the latter having an increased risk of CKD in adulthood. Phosphate treatment may promote kidney phosphate loss and enhance 1,25(OH)<sub>2</sub>D synthesis via increased PTH production.

Kidney InternationalVol. 107(1)
Medical University of Lublin (PL), University Medical Center Groningen (NL), Karolinska University Hospital (SE), Radboud University Nijmegen (NL), Inserm (FR), Medical University of Silesia (PL), University of Groningen (NL), Great Ormond Street Hospital (GB), Hospital Universitario La Paz (ES), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), Pirogov Russian National Research Medical University (RU), Medizinische Hochschule Hannover (DE), Hospices Civils de Lyon (FR), University of Teacher Education Lucerne (CH), Bambino Gesù Children's Hospital (IT), Santa Lucía University General Hospital (ES), Kernkraftwerk Gundremmingen (DE), Hôpital Arnaud de Villeneuve (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Wilhelmina Children's Hospital (NL), University College London (GB), University of Zielona Góra (PL), All India Institute of Medical Sciences (IN), Marmara University (TR), Charité - Universitätsmedizin Berlin (DE), Ruhr University Bochum (DE)
Deutsche Forschungsgemeinschaft, European Rare Kidney Disease Reference Network
Openalex Percentile: Top 3%
Amino Acid Enzymes and Metabolism
5.90
DOIOpen Access PDFOpenAlex
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