D-2-Hydroxyglutaric aciduria: Biochemical marker or clinical disease entity?

Knaap, Marjo S. van der; Jakobs, Cornelis; Hoffmann, Georg F.; Nyhan, William L.; Renier, W.O.; Smeitink, J.A.M.; Catsman‐Berrevoets, Coriene E.; Hjalmarson, Ola; Vallance, Hilary; Sugita, Katsuo; Bowe, Constance M.; Herrin, John T.; Craigen, William J.; Buist, Neil R. M.; Brookfield, D. S. K.; Chalmers, R. A.

doi:10.1002/1531-8249(199901)45:1<111::aid-art17>3.0.co;2-n

Cited by 78 publications

(66 citation statements)

References 52 publications

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“…Cardiomyopathy requiring treatment is frequently observed in type II D2HGA patients (Kranendijk et al 2010b(Kranendijk et al , 2012. Although 2HG levels fluctuate in the same individuals (van der Knaap et al 1999), patients who have IDH2 mutations generally have twofold to eightfold higher 2HG levels than those who have mutations in D2HGDH (Kranendijk et al 2010a).…”

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D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

et al. 2014

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Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2 R140Q and IDH2 R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2 R140Q -expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2 R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.

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D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

et al. 2014

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“…Additional biochemical abnormalities include increased l-lysine in the CSF of L-2-HGA patients (9,10 ), regularly increased urinary Krebs cycle intermediates (especially succinate, 2-ketoglutarate, and citrate) in D-2-HGA (3,4 ), and increased excretion of 2-ketoglutarate in D/L-2-HGA (7 ).…”

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confidence: 99%

Disease-related Metabolites in Culture Medium of Fibroblasts from Patients with d-2-Hydroxyglutaric Aciduria, l-2-Hydroxyglutaric Aciduria, and Combined d/l-2-Hydroxyglutaric Aciduria

et al. 2003

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Background: d-2-Hydroxyglutaric aciduria (D-2-HGA), l-2-hydroxyglutaric aciduria (L-2-HGA), and the combined d/l-2-hydroxyglutaric aciduria (D/L-2-HGA) are poorly understood organic acidurias. To investigate the usefulness of cultured human skin fibroblasts for both diagnostic and research purposes, we measured disease-related metabolites in the cell culture medium. Methods: We measured d-2-hydroxyglutarate (D-2-HG), l-2-hydroxyglutarate (L-2-HG), succinate, 2-ketoglutarate, and citrate in fibroblast cell medium by stable-isotope-dilution gas chromatography–mass spectrometry and glutamine, glutamic acid, and lysine with an amino acid analyzer. We used six cell lines from patients with D-2-HGA, two from patients with L-2-HGA, three from patients with D/L-2-HGA, and seven control cell lines. Culture medium was analyzed after a 96-h incubation period. Results: Culture media from cell lines from D-2-HGA patients contained D-2-HG at concentrations 5- to 30-fold higher than media from controls, whereas the concentration of L-2-HG in media was not increased. Media from L-2-HGA cell lines showed a fivefold increase in L-2-HG compared with controls. Media containing fibroblasts from D/L-2-HGA patients contained moderately increased amounts of both D-2-HG and L-2-HG. For all cell lines, succinate concentrations in the blank medium were higher than after 96 h of incubation with the exception of two of three D/L-2-HGA cell lines. Media of D-2-HGA cell lines had 2-ketoglutarate concentrations that were 40% of that for controls. Glutamic acid concentrations in media of these cell lines were 60% lower than in controls. Conclusions: Cell culture media from fibroblasts from patients with D-2-HGA, L-2-HGA, or D/L-2-HGA contain increased amounts the corresponding 2-HGs, demonstrating the suitability of fibroblasts for both diagnosis of and research concerning 2-HGAs.

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“…Increased urinary excretion of L-2 hydroxyglutaric acid, typical MRI findings, and L2HGDH gen mutation established the L2HGA diagnosis. To our knowledge, there are no previous reports of a patient with DCM and L2HGA; however, patients with DCM and D-2 hydroxyglutaric aciduria (D2HGA) have been discussed (4,5).…”

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confidence: 99%

A child with L-2 hydroxyglutaric aciduria presenting with dilated cardiomyopathy: Coincidence or a new syndrome?

Işıkay¹,

Ceylaner²,

Karacan³

2013

Anadolu Kardiyol Derg

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D-2-Hydroxyglutaric aciduria: Biochemical marker or clinical disease entity?

Cited by 78 publications

References 52 publications

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice

Disease-related Metabolites in Culture Medium of Fibroblasts from Patients with d-2-Hydroxyglutaric Aciduria, l-2-Hydroxyglutaric Aciduria, and Combined d/l-2-Hydroxyglutaric Aciduria

A child with L-2 hydroxyglutaric aciduria presenting with dilated cardiomyopathy: Coincidence or a new syndrome?

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