Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect

Wortmann, Saskia B.; Kluijtmans, Leo A. J.; Sequeira, Sílvia; Wevers, Ron A.; Morava, Éva

doi:10.1007/8904_2014_309

Cited by 17 publications

(12 citation statements)

References 15 publications

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“…The so-called classical MGTA is a leucine catabolism disorder caused by deficiency of 3-methylglutaconyl-CoA hydratase, which leads to the accumulation of 3-methylglutaconic acid and of its hydrogenated derivative 3MGA. The other five subtypes described so far (Barth syndrome, MEGDEL syndrome, Costeff syndrome, DNAJC19 defect and TMEM70 defect) are considered secondary MGTA once the biochemical deffects in these disorders remain unknown [8,9]. H owever, mitochondrial dysfunction is thought to be a common characteristic of all types of MGTA [10].…”

Section: Isolation Of Brain Synaptosomesmentioning

confidence: 96%

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

et al. 2016

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3-Methylglutaric acid (3MGA) is an organic acid that accumulates in various organic acidemias whose patients present neurodegeneration events in children coursing with metabolic acidurias. Limited evidence describes the toxic mechanisms elicited by 3MGA in the brain. Herein, we explored the effects of 3MGA on different toxic endpoints in synaptosomal and mitochondrial-enriched fractions of adult rat brains to provide novel information on early mechanisms evoked by this metabolite. At 1 and 5 mM concentration, 3MGA increased lipid peroxidation, but decreased mitochondrial function only at 5 mM concentration. Despite less intense effects were obtained at 1 mM concentration, its co-administration with the kynurenine pathway (KP) metabolite and N-methyl-D-aspartate receptor (NMDAr) agonist, quinolinic acid (QUIN, 50 and 100 µM), produced toxic synergism on markers of oxidative stress and mitochondrial function. The toxicity of 3MGA per se (5 mM) was prevented by the cannabinoid receptor agonist WIN55,212-2 and the NMDAr antagonist kynurenic acid (KYNA), suggesting cannabinoid and glutamatergic components in the 3MGA pattern of toxicity. The synergic model (3MGA + QUIN) was also sensitive to KYNA and the antioxidant S-allylcysteine, but not to the nitric oxide synthase inhibitor L-nitroarginine methyl ester. These findings suggest various underlying mechanisms involved in the neurotoxicity of 3MGA that may possibly contribute to the neurodegeneration observed in acidemias.

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Section: Isolation Of Brain Synaptosomesmentioning

confidence: 96%

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

et al. 2016

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“…Unlike primary 3MGC aciduria, no leucine pathway enzyme deficiencies exist in secondary 3MGC aciduria. Moreover, leucine loading has little effect on the amount of 3MGC acid excreted in urine 3 . These features indicate that secondary 3MGC aciduria arises from an alternate biosynthetic route.…”

Section: Introductionmentioning

confidence: 92%

“…In leucine metabolism, AUH catalyzes hydration of trans ‐3MGC CoA to ( S )‐HMG CoA while HMG CoA lyase cleaves ( S )‐HMG CoA to acetoacetate plus acetyl CoA. When either of these enzymes is deficient, leucine administration results in increased urinary excretion of 3MGC acid 3 . Normally, during leucine catabolism the pathway intermediate 3‐methylcrotonyl CoA is carboxylated to form trans ‐3MGC CoA which is hydrated to HMG CoA by AUH.…”

Section: Introductionmentioning

confidence: 99%

Isomerization of trans‐3‐methylglutaconic acid

et al. 2020

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3‐Methylglutaconic (3MGC) aciduria is a common phenotypic feature of a growing number of inborn errors of metabolism. “Primary” 3MGC aciduria is caused by deficiencies in leucine pathway enzymes while “secondary” 3MGC aciduria results from inborn errors of metabolism that impact mitochondrial energy production. The metabolic precursor of 3MGC acid is trans‐3MGC CoA, an intermediate in the leucine catabolism pathway. Gas chromatography‐mass spectrometry (GC‐MS) analysis of commercially available trans‐3MGC acid yielded a mixture of cis and trans isomers while 1H‐NMR spectroscopy of trans‐3MGC acid at 25°C provided no evidence for the cis isomer. When trans‐3MGC acid was incubated under conditions used for sample derivatization prior to GC‐MS (but with no trimethylsilane added), 1H‐NMR spectroscopy provided evidence of trans to cis isomerization. Incubation of trans‐3MGC acid at 37°C resulted in time‐dependent isomerization to cis‐3MGC acid. Cis‐3MGC acid behaved in a similar manner except that, under identical incubation conditions, less isomerization occurred. In agreement with these experimental results, molecular modeling studies provided evidence that the energy minimized structure of cis‐3MGC acid is 4 kJ/mol more stable than that for trans‐3MGC acid. Once generated in vivo, trans‐3MGC acid is proposed to isomerize via a mechanism involving π electron delocalization with formation of a resonance structure that permits bond rotation. The data presented are consistent with the occurrence of both diastereomers in urine samples of subjects with 3MGC aciduria.

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“…A leucine-loading test was performed as described by Wortmann et al 9 No significant increase in 3-MGA-uria was seen after leucine loading, virtually excluding 3-methylglutaconyl-CoA hydratase deficiency (AUH) defect (►Table 1).…”

Section: Case Reportmentioning

confidence: 99%

MEGDEL Syndrome: Expanding the Phenotype and New Mutations

et al. 2017

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Abstract3-MEthylGlutaconic aciduria, Deafness, Encephalopathy, neuroradiological evidence of Leigh-like disease (MEGDEL syndrome) was initially described in four children with additional features of defective oxidative phosphorylation. Loss of functional variants in the SERAC1 gene was later reported in relation with this disorder of phospholipid remodeling. We describe a girl born after a pregnancy complicated by intrauterine growth retardation. In the neonatal period, she presented hypotonia, lethargy, weak reflexes, transient hypoglycemia, and elevated transaminases. Magnetic resonance imaging (MRI) performed at 12 days of life showed bilateral basal ganglia alterations suggestive of Leigh syndrome. She progressed with failure to thrive, severe delay of developmental milestones, axial hypotonia, spastic tetraparesis and dystonic movements. Investigations disclosed hyperlactacidemia, and the urinary organic acids revealed high levels mainly of 3-methylglutaconic acid. Muscle biopsy showed decreased activity of several complexes of the respiratory chain. Compound heterozygosity for two previously unreported variants in SERAC1 leads to the diagnosis of MEGDEL syndrome. Unlike other patients, this child presents very early MRI alterations and manifests no deafness.

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Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect

Abstract: Currently, six inborn errors of metabolism with 3-

Cited by 17 publications

References 15 publications

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging Mechanisms

Isomerization of trans‐3‐methylglutaconic acid

MEGDEL Syndrome: Expanding the Phenotype and New Mutations

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