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Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry

Accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3HGA) in body fluids is the biochemical hallmark of type 1 glutaric aciduria (GA1), a disorder characterized by acute striatal degeneration and a subsequent dystonia. To date, methods for quantification of 3HGA are mainly based on stable...

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Main Authors: Al-Dirbashi, Osama Y. (Author) , Kölker, Stefan (Author) , Ng, Dione (Author) , Fisher, Lawrence (Author) , Rupar, Tony (Author) , Lepage, Nathalie (Author) , Rashed, Mohamed S. (Author) , Santa, Tomofumi (Author) , Goodman, Stephen I. (Author) , Geraghty, Michael T. (Author) , Zschocke, Johannes (Author) , Christensen, Ernst (Author) , Hoffmann, Georg F. (Author) , Chakraborty, Pranesh (Author)
Format: Article (Journal)
Language:English
Published: 2011
In: Journal of inherited metabolic disease
Year: 2011, Volume: 34, Issue: 1, Pages: 173-180
ISSN:1573-2665
DOI:10.1007/s10545-010-9223-2
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s10545-010-9223-2
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1007/s10545-010-9223-2
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Author Notes:Osama Y. Al-Dirbashi, Stefan Kölker, Dione Ng, Lawrence Fisher, Tony Rupar, Nathalie Lepage, Mohamed S. Rashed, Tomofumi Santa, Stephen I. Goodman, Michael T. Geraghty, Johannes Zschocke, Ernst Christensen, Georg F. Hoffmann, Pranesh Chakraborty
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Summary:Accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3HGA) in body fluids is the biochemical hallmark of type 1 glutaric aciduria (GA1), a disorder characterized by acute striatal degeneration and a subsequent dystonia. To date, methods for quantification of 3HGA are mainly based on stable isotope dilution gas chromatography mass spectrometry (GC-MS) and require extensive sample preparation. Here we describe a simple liquid chromatography tandem MS (LC-MS/MS) method to quantify this important metabolite in dried urine spots (DUS). This method is based on derivatization with 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE). Derivatization was adopted to improve the chromatographic and mass spectrometric properties of the studied analytes. Derivatization was performed directly on a 3.2-mm disc of DUS as a sample without extraction. Sample mixture was heated at 60°C for 45 min, and 5 μl of the reaction solution was analyzed by LC-MS/MS. Reference ranges obtained were in excellent agreement with the literature. The method was applied retrospectively for the analysis of DUS samples from established low- and high-excreter GA1 patients as well as controls (n = 100). Comparison of results obtained versus those obtained by GC-MS was satisfactory (n = 14). In populations with a high risk of GA1, this approach will be useful as a primary screening method for high- or low-excreter variants. In these populations, however, DUS analysis should not be implemented before completing a parallel comparative study with the standard screening method (i.e., molecular testing). In addition, follow-up DUS GA and 3HGA testing of babies with elevated dried blood spot C5DC acylcarnitines will be useful as a first-tier diagnostic test, thus reducing the number of cases requiring enzymatic and molecular analyses to establish or refute the diagnosis of GA1.
Item Description:First published: 27 October 2010
Gesehen am 28.02.2022
Physical Description:Online Resource
ISSN:1573-2665
DOI:10.1007/s10545-010-9223-2

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