3-Methylglutaconic aciduria type I redefined

Wortmann, S. B.; Kremer, Berry; Graham, Alison; Willemsen, M.A.A.P.; Loupatty, Ference J.; Hogg, Sarah; Engelke, Udo F. H.; Kluijtmans, Leo A. J.; Wanders, R. J. A.; Illsinger, Sabine; Wilcken, Bridget; Cruysberg, J.R.M.; Das, Anibh M.; Morava, Éva; Wevers, R.A.

doi:10.1212/wnl.0b013e3181f39a8a

Cited by 48 publications

(18 citation statements)

References 12 publications

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“…Elevated urinary excretion of 3-MGA (3-MGAuria) was first described in patients with 3-methylglutaconylCoA hydratase deficiency (former type I, AUH, MIM ID: #250950), a defect of leucin catabolism leading to a late onset leukoencephalop-athy (Wortmann et al 2010b).…”

Section: Introductionmentioning

confidence: 99%

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Wortmann

Kluijtmans

Rodenburg

et al. 2013

J of Inher Metab Disea

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Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven,

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Section: Introductionmentioning

confidence: 99%

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

Wortmann

Kluijtmans

Rodenburg

et al. 2013

J of Inher Metab Disea

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“…H owever, mitochondrial dysfunction is thought to be a common characteristic of all types of MGTA [10]. Clinical features of the primary MGTA are nonspecific and variable, ranging from minimal to severe symptoms and brain abnormalities that include delayed speech, dementia, progressive leukoencephalopathy and ataxia [10,11]. Psychomotor retardation, microcephaly and progressive neurological impairment with spasticity and seizures have also been reported in several patients [12,13].…”

Section: Isolation Of Brain Synaptosomesmentioning

confidence: 99%

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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“…Methylglutaconyl CoA hydratase (EC 4.2.1.18) is one such deficiency, which appeared likely to be benign (Ly et al 2003). Recently, there is evidence to suggest that it may be associated with adult-onset leukoencephalopathy (Wortmann et al 2010). It is not yet clear whether early treatment would be helpful.…”

Section: Possibility Of Late Effects Previously Unrecognisedmentioning

confidence: 99%

Expanded newborn screening: reducing harm, assessing benefit

Wilcken

2010

J of Inher Metab Disea

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Achieving the goals of newborn screening is, as for any screening, a balancing act: getting the maximum benefit from screening while producing the minimum harm. The advent of "expanded" newborn screening, with a large number of disorders detectable using a single test, has also posed problems, not new, but now more obvious. One is the finding of many more cases by screening, the extra cases being largely patients who have attenuated phenotypes and may remain asymptomatic for many years, even throughout life. These may or may not require active management in the short term, but do need lifelong awareness. Additionally, disorders have been included that are now thought benign or largely so. Babies risk being unnecessarily medicalized. Assessing outcome has also proved difficult because of the rarity of some disorders and the impracticality of randomized controlled trials. The requirements for valid studies include the need for case definitions, comparable comparison groups and probably assessment on a whole-population basis. An Australia-wide study of tandem mass spectrometry newborn screening involving 2 million screened and unscreened babies has demonstrated benefits overall to screened patients at age 6 years. The study was too small to provide conclusions for individual disorders other than for medium-chain acyl-CoA dehydrogenase deficiency.

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3-Methylglutaconic aciduria type I redefined

Cited by 48 publications

References 12 publications

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

3‐Methylglutaconic aciduria—lessons from 50 genes and 977 patients

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

Expanded newborn screening: reducing harm, assessing benefit

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