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. 2015:15:1-6.
doi: 10.1007/8904_2013_291. Epub 2014 Feb 22.

4-hydroxyglutamate is a biomarker for primary hyperoxaluria type 3

James J Pitt  1 , Frank Willis, Nicholas Tzanakos, Ruth Belostotsky, Yaacov Frishberg
Affiliations

4-hydroxyglutamate is a biomarker for primary hyperoxaluria type 3

James J Pitt et al. JIMD Rep. 2015.

Abstract

Primary hyperoxaluria type 3 (PH3) is a recently identified inborn error of 4-hydroxyproline metabolism causing kidney stone disease. Diagnosis to date has relied on mutation detection. The excretion of 4-hydroxyglutamate (4OHGlu) was investigated in controls and a cohort of nine patients with PH3 and their parents using flow injection tandem mass spectrometry. 4OHGlu was stable in acidified urine samples and was not influenced by diet. Its measurement was readily incorporated into an existing multi-analyte panel for comprehensive screening for inborn errors of metabolism. There was a steady decline with age in 4OHGlu levels, expressed as μmol/mmol of creatinine, in controls. Levels in patients with PH3 ranged from 6.5 to 98 μmol/mmol of creatinine and were all significantly increased when compared to age-matched controls (<4.2). Levels in eight parents (obligatory carriers of the corresponding mutation) were moderately, but significantly increased, ranging from 0.6 to 2.5 (age-matched controls <1.4, p = 0.03). Urine 4OHGlu screening was used to prospectively diagnose PH3 in an 18-month-old boy with calcium oxalate kidney stone disease associated with hyperoxaluria. 4OHGlu was also increased in a stored newborn screening dried blood spot sample from this child (37 μmol/L, controls <2.53). 4OHGlu testing provides a robust and high-throughput biochemical screen for PH3.

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Figures

Fig. 1
Fig. 1
Metabolic pathway for 4-hydroxyproline showing the enzymatic block in primary hyperoxaluria type 3 and the proposed metabolic re-routing mechanism. Enzymes are as follows: 1 aspartate aminotransferase, 2 4-hydroxy-2-oxo-glutarate aldolase, 3 unidentified aldolase, 4 lactate dehydrogenase. Principal PH3 urine metabolites that exit the cell are underlined
Fig. 2
Fig. 2
Response of urinary 4-hydroxyglutamate and 4-hydroxyproline levels (μmol/mmol of creatinine) to gelatine loading (20 g at 0 h) in an adult control
Fig. 3
Fig. 3
Urine 4-hydroxyglutamate levels (y-axis, μmol/mmol of creatinine, log scale) vs age (x-axis in years). Samples from patient A are connected by lines
See this image and copyright information in PMC

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