The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia type I

Tortorelli, Silvia; Hahn, Sihoun; Cowan, Tina M.; Brewster, Thomas G.; Rinaldo, Piero; Matern, Dietrich

doi:10.1016/j.ymgme.2004.09.016

Cited by 52 publications

(50 citation statements)

References 21 publications

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“…The superior reactivity of DAABD-AE allowed for the use of urine without pretreatment, hence eliminated the extraction step. Compared with GC/MS, the MS/MS-based methods (Tortorelli et al 2005;Al-Dirbashi et al 2007) require simple sample preparation, less sample volume, and shorter analysis time and are thus in line with the current trend to develop MS/MS alternatives for classic biochemical analyses.…”

Section: Introductionmentioning

confidence: 75%

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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

Al-Dirbashi

Kölker

et al. 2010

J of Inher Metab Disea

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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.

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Section: Introductionmentioning

confidence: 75%

“…An approach to identify GA1 based on the analysis of C5DC in urine by MS/MS was also developed. In this method, acylcarnitines are treated with butanoic HCl and C5DC is monitored at m/z of 388 (Tortorelli et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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

Al-Dirbashi

Kölker

et al. 2010

J of Inher Metab Disea

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“…However, in recent years, urine acylcarnitine analysis has reemerged as a useful screening tool in some situations. 24 It appears to be of particular diagnostic value in the evaluation of patients with possible organic acidurias but inconclusive or minimally abnormal urine organic acid and plasma acylcarnitine profiles. In our IBD-deficient cohort, urine acylcarnitine analysis revealed an elevated C 4 -acylcarnitine excretion in all patients.…”

Section: Discussionmentioning

confidence: 99%

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Oglesbee¹,

Majumder

et al. 2007

Genetics in Medicine

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Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenasedeficient patients through newborn screening due to an elevation of C 4 -acylcarnitine in dried blood spots. Because C 4 -acylcarnitine represents both isobutyryl-and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C 4 -acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C 4 -acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase-and short-chain acyl-CoA dehydrogenase-deficient patients. Results: Quantification of C 4 -acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C 4 -acylcarnitine identified through newborn screening. Genet Med 2007:9(2):108-116.

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“…Other investigations for patient 2, at Children's Hospital of Eastern Ontario (CHEO), included analysis of dried urine spots for GA and 3HGA by a liquid chromatographytandem mass spectrometry (LC-MS/MS) assay (Al-Dirbashi et al 2011), with quantification of glutarylcarnitine (C5DC) and associated acylcarnitine ratios by MS/MS (Tortorelli et al 2005). Patient 3 also had urine acylglycine profiling performed at CHUS by LC-MS/MS (Bherer et al 2015).…”

Section: Metabolite Profiles In Urinementioning

confidence: 99%

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

et al. 2017

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Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally considered a likely "non-disease," but this is based on limited supporting information, with only nine individuals with GA3 described in the literature. Clinicians encountering a patient with GA3 therefore still face a dilemma of whether or not this should be dismissed as irrelevant.We have identified three unrelated Canadian patients with GA3. Two came to clinical attention because of symptoms, while the third was identified by a population urine-based newborn screening programme and has so far remained asymptomatic. We describe the clinical histories, biochemical characterisation and genotypes of these individuals. Examination of allele frequencies underlines the fact that GA3 is underdiagnosed. While one probable factor is that some GA3 patients remain asymptomatic, we highlight other plausible reasons whereby this diagnosis might be overlooked.Gastrointestinal disturbances were previously reported in some GA3 patients. In one of our patients, severe episodes of cyclic vomiting were the major problem. A trial of antibiotic treatment, to minimise bacterial GA production, was followed by significant clinical improvement.At present, there is insufficient evidence to define any specific clinical phenotype as attributable to GA3. However, we consider that it would be premature to assume that this condition is completely benign in all individuals at all times.

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The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia type I

Cited by 52 publications

References 21 publications

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

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

Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

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