Quantification of glutaric and 3-hydroxyglutaric acids in urine of glutaric acidemia type I patients by HPLC with intramolecular excimer-forming fluorescence derivatization

Al-Dirbashi, Osama Y.; Jacob, Mohan V.; Al-Amoudi, Mohamed; Al-Kahtani, Khalid; Al-Odaib, Ahmed; El-Badaoui, Fahad; Rashed, Mohamed S.

doi:10.1016/j.cccn.2005.03.048

Cited by 16 publications

(21 citation statements)

References 21 publications

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“…GA1 markers are excreted in urine at low yet detectable levels in healthy individuals. On the other hand, it is not uncommon that 3HGA and GA in patients are increased to more than two and three orders of magnitude, respectively (Baric et al 1999;Christensen et al 2004;Al-Dirbashi et al 2005, 2007. With these wide ranges in mind, we set our calibrators to cover physiological and pathological concentration (2-5,000 μmol/L) to maximize the diagnostic utility of the assay.…”

Section: Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 98%

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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“…The introduction of MS/MS into neonatal screening has enabled the screening of conditions that might otherwise have been missed, and thus believed to be extremely rare [3,4]. This technique has significantly improved the efficacy of neonatal screening programs, demonstrating the importance of early identification and treatment of infants with disorders that would otherwise go unrecognized, before irreversible clinical damage occurs [5,6].…”

Section: Discussionmentioning

confidence: 99%

Screening for inborn errors of metabolism in high-risk children: a 3-year pilot study in Zhejiang Province, China

et al. 2012

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BackgroundTandem mass spectrometry (MS/MS) has been available in China for 8 years. This technique makes it possible to screen for a wide range of previously unscreened inborn errors of metabolism (IEM) using a single test. This 3-year pilot study investigated the screening, diagnosis, treatment and outcomes of IEM in symptomatic infants and children.MethodsAll children encountered in the Newborn Screening Center of Zhejiang Province during a 3-year period with symptoms suspicious for IEM were screened for metabolic diseases. Dried blood spots were collected and analyzed by tandem mass spectrometry. The diagnoses were further confirmed by clinical symptoms and biochemical analysis. Neonatal intrahepatic cholestasis caused by citrin deficiency, ornithine transcarbamylase deficiency and primary carnitine deficiency were confirmed by DNA analysis.ResultsA total of 11,060 symptomatic patients (6,720 boys, 4,340 girls) with a median age of 28.8 months (range: 0.04-168.2 months) were screened. Among these, 62 were diagnosed with IEM, with a detection rate of 0.56%. Thirty-five were males and 27 females and the median age was 3.55 months (range 0.07-143.9 months). Of the 62 patients, 27 (43.5%) had aminoacidemias, 26 (41.9%) had organic acidemias and nine (14.5%) had fatty acid oxidation disorders.ConclusionsBecause most symptomatic patients are diagnosed at an older age, mental retardation and motor delay are difficult to reverse. Additionally, poor medication compliance reduces the efficacy of treatment. More extensive newborn screening is thus imperative for ensuring early diagnosis and enhancing the treatment efficacy of IEM.

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“…A positive MS/MS screening result should be confirmed by one or more alternative techniques, including a sensitive method for quantitative determination of GA and 3-OH-GA in urine or blood such as GC/MS (Al-Dirbashi et al 2005; Baric et al 1999; Shigematsu et al 2005), mutation analysis of the GCDH gene, and/or GCDH enzyme analysis (Christensen 1983; Goodman et al 1998). A normal urine or blood 3-OH-GA level will make the diagnosis unlikely, whereas an elevated urine or blood level of 3-OH-GA should be followed by mutation analysis and start of treatment.…”

Section: Diagnostic Proceduresmentioning

confidence: 99%

Diagnosis and management of glutaric aciduria type I – revised recommendations

Kölker

Christensen²,

Leonard

et al. 2011

J of Inher Metab Disea

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238

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Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-011-9289-5) contains supplementary material, which is available to authorized users.

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Quantification of glutaric and 3-hydroxyglutaric acids in urine of glutaric acidemia type I patients by HPLC with intramolecular excimer-forming fluorescence derivatization

Cited by 16 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

Screening for inborn errors of metabolism in high-risk children: a 3-year pilot study in Zhejiang Province, China

Diagnosis and management of glutaric aciduria type I – revised recommendations

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