Priyanka Khandelwal1, Vijay Prakash Mathur2, Sumantra Raut1, Thenral S Geetha3, Sandhya Nair3, Pankaj Hari1, Aditi Sinha4, Arvind Bagga1. 1. Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India. 2. Center for Dental Education and Research, All India Institute of Medical Sciences, New Delhi, India. 3. Medgenome Labs, Bommasandra, Bangalore, India. 4. Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India. aditisinhaaiims@gmail.com.
Abstract
BACKGROUND: Distal renal tubular acidosis (RTA) is typically caused by defects in ATP6V0A4, ATP6V1B1, and SLC4A1, accounting for 60-80% of patients. Genes recently implicated include FOXI1, ATP6V1C2, and WDR72, of which WDR72 is associated with dental enamel defects. METHODS: We describe 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Distal tubular acidification was evaluated by furosemide-fludrocortisone test, urine-to-blood PCO2 gradient and fractional excretion of bicarbonate. Exome sequencing was performed using a panel of genes implicated in human disease. RESULTS: Patients had polyuria, hypokalemia, hypercalciuria, and nephrocalcinosis, but metabolic acidosis varied in severity. Although all patients acidified urine to pH < 5.3 during furosemide-fludrocortisone test, urine-to-blood PCO2 gradient was < 20 mmHg during bicarbonate loading. All patients had transient proximal tubular dysfunction with urinary losses of phosphate and beta-2-microglobulin, and generalized aminoaciduria. Homozygous pathogenic truncating variants in WDR72 was detected in all probands. CONCLUSION: Patients with WDR72 mutations show mild rate-dependent distal RTA with variable metabolic acidosis, and intact ability to acidify the urine on provocative testing. Concomitant proximal tubular dysfunction may be present. Mutations in WDR72 should be considered in patients with suspected distal RTA, especially if associated with dental defects.
BACKGROUND: Distal renal tubular acidosis (RTA) is typically caused by defects in ATP6V0A4, ATP6V1B1, and SLC4A1, accounting for 60-80% of patients. Genes recently implicated include FOXI1, ATP6V1C2, and WDR72, of which WDR72 is associated with dental enamel defects. METHODS: We describe 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Distal tubular acidification was evaluated by furosemide-fludrocortisone test, urine-to-blood PCO2 gradient and fractional excretion of bicarbonate. Exome sequencing was performed using a panel of genes implicated in human disease. RESULTS: Patients had polyuria, hypokalemia, hypercalciuria, and nephrocalcinosis, but metabolic acidosis varied in severity. Although all patients acidified urine to pH < 5.3 during furosemide-fludrocortisone test, urine-to-blood PCO2 gradient was < 20 mmHg during bicarbonate loading. All patients had transient proximal tubular dysfunction with urinary losses of phosphate and beta-2-microglobulin, and generalized aminoaciduria. Homozygous pathogenic truncating variants in WDR72 was detected in all probands. CONCLUSION: Patients with WDR72 mutations show mild rate-dependent distal RTA with variable metabolic acidosis, and intact ability to acidify the urine on provocative testing. Concomitant proximal tubular dysfunction may be present. Mutations in WDR72 should be considered in patients with suspected distal RTA, especially if associated with dental defects.
Authors: Christina B Joseph; Marta Mariniello; Ayumi Yoshifuji; Guglielmo Schiano; Jennifer Lake; Jonathan Marten; Anne Richmond; Jennifer E Huffman; Archie Campbell; Sarah E Harris; Stephan Troyanov; Massimiliano Cocca; Antonietta Robino; Sébastien Thériault; Kai-Uwe Eckardt; Matthias Wuttke; Yurong Cheng; Tanguy Corre; Ivana Kolcic; Corrinda Black; Vanessa Bruat; Maria Pina Concas; Cinzia Sala; Stefanie Aeschbacher; Franz Schaefer; Sven Bergmann; Harry Campbell; Matthias Olden; Ozren Polasek; David J Porteous; Ian J Deary; Francois Madore; Philip Awadalla; Giorgia Girotto; Sheila Ulivi; David Conen; Elke Wuehl; Eric Olinger; James F Wilson; Murielle Bochud; Anna Köttgen; Caroline Hayward; Olivier Devuyst Journal: J Am Soc Nephrol Date: 2022-03 Impact factor: 10.121