Organic Acid and Acylcarnitine Profiles of Glutaric Aciduria Type I

Matsumoto, Masahiro; Matsumoto, Isamu; Shinka, Toshikatsu; Kuhara, Tomiko; Imamura, Hiroaki; Shimao, Satoshi; Okada, Takenori

doi:10.1111/j.1442-200x.1990.tb00787.x

Cited by 11 publications

(3 citation statements)

References 14 publications

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“…Glutaryl-CoA inhibited the E2k subunit of KGDHc, but did not affect the E1k or E3 subunits. KGDHc inhibition in patients with GCDH deficiency is supported by the presence of increased urinary excretion of ␣-ketoglutarate, in particular during metabolic decompensation (37). 2 In comparison to KGDHc, PDHc activity was less affected by glutarylCoA.…”

Section: Reduction Of Flux Through Tca Cycle Via Inhibition Of Kgdhc Bymentioning

confidence: 99%

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Sauer

Okun

Schwab

et al. 2005

Journal of Biological Chemistry

111

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Inherited deficiency of glutaryl-CoA dehydrogenase results in an accumulation of glutaryl-CoA, glutaric, and 3-hydroxyglutaric acids. If untreated, most patients suffer an acute encephalopathic crisis and, subsequently, acute striatal damage being precipitated by febrile infectious diseases during a vulnerable period of brain development (age 3 and 36 months). It has been suggested before that some of these organic acids may induce excitotoxic cell damage, however, the relevance of bioenergetic impairment is not yet understood. The major aim of our study was to investigate respiratory chain, tricarboxylic acid cycle, and fatty acid oxidation in this disease using purified single enzymes and tissue homogenates from Gcdh-deficient and wild-type mice. In purified enzymes, glutaryl-CoA but not glutaric or 3-hydroxyglutaric induced an uncompetitive inhibition of ␣-ketoglutarate dehydrogenase complex activity. Notably, reduced activity of ␣-ketoglutarate dehydrogenase activity has recently been demonstrated in other neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases. In contrast to ␣-ketoglutarate dehydrogenase complex, no direct inhibition of glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid was found in other enzymes tested. In Gcdh-deficient mice, respiratory chain and tricarboxylic acid activities remained widely unaffected, virtually excluding regulatory changes in these enzymes. However, hepatic activity of very long-chain acyl-CoA dehydrogenase was decreased and concentrations of long-chain acylcarnitines increased in the bile of these mice, which suggested disturbed oxidation of long-chain fatty acids. In conclusion, our results demonstrate that bioenergetic impairment may play an important role in the pathomechanisms underlying neurodegenerative changes in glutaryl-CoA dehydrogenase deficiency.

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Section: Reduction Of Flux Through Tca Cycle Via Inhibition Of Kgdhc Bymentioning

confidence: 99%

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Sauer

Okun

Schwab

et al. 2005

Journal of Biological Chemistry

111

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“…We speculate that mitochondrial adipoyl-CoA is derived from adipoylcarnitine that may be produced by peroxisomal β-oxidation of long-chain dicarboxylic acids [33]. Adipic acid excretion is also elevated in GA1 [32,34,35] and urine levels increased even more with SUGCT deficiency. It is currently unknown why adipic acid excretion is increased in GA1.…”

Section: Discussionmentioning

confidence: 92%

Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains

Leandro

Bender

Dodatko

et al. 2021

Molecular Genetics and Metabolism

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“…In some conditions, the presence of just one acylcarnitine species can be sufficient to suggest an inborn error (such as the presence of glutarylcarnitine in glutaric aciduria3). Conversely, the absence of glutarylcarnitine does not exclude the possible diagnosis, as the gold standard for this condition is enzyme analysis.…”

Section: Indications/validationsmentioning

confidence: 99%

How to use acylcarnitine profiles to help diagnose inborn errors of metabolism

Santra

Hendriksz

2010

Archives of Disease in Childhood - Education and Practice

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Inborn errors of metabolism are a heterogeneous group of conditions which frequently cause diagnostic diffi culties due to their wide range of presenting features. Because many of these disorders overlap considerably in their presentation, a clinical suspicion of metabolic disease often leads to the taking of a "fi rst line metabolic screen", which will typically include all or a combination of the following:▶ blood for ammonia and lactate measurement ▶ urine for organic acid analysis ± glycosaminoglycans ▶ blood for amino acids ▶ blood for acylcarnitine analysis. This article is intended to aid the non-metabolic specialist in understanding the method and rationale for measuring acylcarnitines when investigating children with suspected inborn errors of metabolism and help one appreciate what it does, and more importantly does not, tell about a patient. It is not intended to be a substitute for close communication with one's local metabolic laboratory! BIOCHEMICAL BASISCarnitine is a small intracellular molecule, which facilitates the transport of larger molecules,

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Organic Acid and Acylcarnitine Profiles of Glutaric Aciduria Type I

Cited by 11 publications

References 14 publications

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Glutaric aciduria type 3 is a naturally occurring biochemical trait in inbred mice of 129 substrains

How to use acylcarnitine profiles to help diagnose inborn errors of metabolism

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