Sensitivity and specificity of free and total glutaric acid and 3‐hydroxyglutaric acid measurements by stable‐isotope dilution assays for the diagnosis of glutaric aciduria type I

BackgroundWithout neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment.ResultsNo late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients.ConclusionsWhile clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users.

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“…Two biochemical phenotypes, low and high excretors, have been defined based on urinary excretion of GA [1]. …”

Section: Introductionmentioning

confidence: 99%

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Boy

Heringer

Brackmann

et al. 2017

Orphanet J Rare Dis

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“…Patient HK showed large amounts of GA in urine and was thought to be a high excretor of GA [1], while the amounts of GA in the other patients decreased later in infancy. In GA 1 patients, 3HGA in urine is thought to be disease-specific and the only diagnostic metabolite [3].…”

Section: Discussionmentioning

confidence: 94%

“…The accumulation of glutaryl-CoA leads elevated levels of 3HGA, GA, and glutarylcarnitine in body fluids [1,2]. Although the exact mechanism of the formation of 3HGA is not known, 3HGA accumulation in the central nervous system is thought to be a possible cause of neurological deterioration with focal striatal necrosis in infancy [4].…”

Section: Discussionmentioning

confidence: 99%

“…It is unnecessary to use ammonia as a reagent gas, which is difficult to regulate in the laboratory. Although we adopted a convenient solvent extraction method in which the recovery of 3HGA was about 50%, some increment in sensitivity can be obtained if solid-phase extraction is used [1]. Indeed, we derivatized urease-treated urine specimens without the extraction process and were able to perform the sensitive analysis using an aliquot of control urine containing levels as low as 0.01 mg Cr.…”

Section: Discussionmentioning

confidence: 99%

“…The deficiency of GCDH in the metabolism of lysine, hydroxylysine, and tryptophan leads to the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3HGA), glutaconic acid [1], and glutarylcarnitine [2] in body fluids. The clinical picture of this disease features abrupt neurological deterioration with focal striatal necrosis in infancy, often after infectious illnesses [3].…”

Section: Introductionmentioning

confidence: 99%

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Stable-isotope dilution gas chromatography–mass spectrometric measurement of 3-hydroxyglutaric acid, glutaric acid and related metabolites in body fluids of patients with glutaric aciduria type 1 found in newborn screening

Shigematsu¹,

Hata²,

Tanaka³

et al. 2005

Journal of Chromatography B

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We developed a simple and sensitive stable-isotope dilution method for the quantification of 3-hydroxyglutaric acid (3HGA) and glutaric acid (GA) in body fluids. In our method, tert-butyldimethylsilyl (tBDMS) derivatives of 3HGA and GA were measured with a conventional electron-impact ionization (EI) mode in gas chromatography-mass spectrometry (GC-MS). The control values for 3HGA in nmol/ml were 0.15+/-0.08 (serum; n=10) and 0.07+/-0.03 (CSF; n=10). In addition, glutarylcarnitine and free carnitine were quantified by electrospray tandem mass spectrometry. Using these methods, we monitored 3HGA, GA, and glutarylcarnitine in the body fluids of three patients with glutaric aciduria type 1 found during newborn screening. None of the patients had experienced neurological strokes, which are possibly caused by the accumulation of 3HGA, at 15-24 months of age under a disease-specific treatment, including carnitine supplementation. Our data showed that 3HGA levels were relatively high in some serum samples with lower glutarylcarnitine and carnitine levels, suggesting that carnitine supplementation may play a role in preventing the accumulation of 3HGA in patients with this disease.

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Pathomechanisms of neurodegeneration in glutaryl‐CoA dehydrogenase deficiency

Kölker

Koeller

Okun

et al. 2003

Annals of Neurology

112

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Glutaryl-CoA dehydrogenase deficiency is an inherited organic aciduria with predominantly neurological presentation. Biochemically, it is characterized by an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3-hydroxyglutaric acid. If untreated, acute striatal degeneration is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. The mechanism underlying these acute encephalopathic crises has been partially elucidated using in vitro and in vivo models. 3-Hydroxyglutaric and glutaric acids share structural similarities with the main excitatory amino acid glutamate and are considered to play an important role in the pathophysiology of this disease. 3-Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N-methyl-D-aspartate receptors. Furthermore, glutaric and 3-hydroxyglutaric acids indirectly modulate glutamatergic and GABAergic neurotransmission, resulting in an imbalance of excitatory and inhibitory neurotransmission. It also has been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine-stimulated nitric oxide production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation-dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability to 3-hydroxyglutaric and glutaric acid toxicity.

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Sensitivity and specificity of free and total glutaric acid and 3‐hydroxyglutaric acid measurements by stable‐isotope dilution assays for the diagnosis of glutaric aciduria type I

Cited by 123 publications

References 22 publications

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Stable-isotope dilution gas chromatography–mass spectrometric measurement of 3-hydroxyglutaric acid, glutaric acid and related metabolites in body fluids of patients with glutaric aciduria type 1 found in newborn screening

Pathomechanisms of neurodegeneration in glutaryl‐CoA dehydrogenase deficiency

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