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.
Competing interests: None declared
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Acknowledgements
We thank Dr. Barry Lewis and Mr. Lawrence Greed (Princess Margaret Hospital for Children, Perth) for supplying oxalate data and retrieving the newborn screening card from patient A and Ms. Avantika Mishra, Ms. Mary Eggington, Mr. Kai Mun Hong and Ms. Maggie Tan for performing analyses. A preliminary report of sections of this work was previously been presented at the SSIEM Annual 2012 Symposium, Birmingham (Pitt et al. 2012). Sections of this work were supported by the Victorian Government’s Operational Infrastructure Support Program.
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Communicated by: Rodney Pollitt, PhD
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Author Contributions
Ruth Belostotsky: performed mutation analysis, provided samples from the Israeli cohort, revised the manuscript
Frank Willis: clinically managed, organised samples and consent for patient A, revised the manuscript
Nicholas Tzanakos: performed dried blood spot analysis, revised the manuscript
Yaacov Frishberg: advised on study design, managed and provided data for the Israeli cohort, contributed to the manuscript
James Pitt: conceived, designed and supervised the study, wrote the manuscript, acts as guarantor
Funding Disclosure: None relevant to this research
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James Pitt, Ruth Belostotsky, Frank Willis, Nicholas Tzanakos and Yaacov Frishberg declare that they have no conflict of interest.
Ethical Approval
Control neonatal dried blood spots were analysed with the approval of the Royal Children’s Hospital Human Research Ethics Committee. This study was also approved by the Helsinki Committee of the Shaare Zedek Medical Center, Jerusalem, Israel.
Consent: Parental consent was obtained for testing the neonatal blood spot from patient A.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
Animal Rights: Not applicable, no animal experiments were performed
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Pitt, J.J., Willis, F., Tzanakos, N., Belostotsky, R., Frishberg, Y. (2014). 4-Hydroxyglutamate Is a Biomarker for Primary Hyperoxaluria Type 3. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 15. JIMD Reports, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_291
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DOI: https://doi.org/10.1007/8904_2013_291
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