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1 Department of Clinical Chemistry, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
aAddress correspondence to this author at: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Fax 31-20-4440305; e-mail N.Verhoeven{at}VUMC.NL.
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.
The following articles in journals at HighWire Press have cited this article:
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  M. Seijo-Martinez, C. Navarro, M. Castro del Rio, O. Vila, M. Puig, A. Ribes, and M. Butron L-2-Hydroxyglutaric Aciduria: Clinical, Neuroimaging, and Neuropathological Findings Arch Neurol, April 1, 2005; 62(4): 666 - 670. [Abstract] [Full Text] [PDF]
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 I. Moroni, M. Bugiani, L. D'Incerti, C. Maccagnano, M. Rimoldi, L. Bissola, B. Pollo, G. Finocchiaro, and G. Uziel L-2-hydroxyglutaric aciduria and brain malignant tumors: A predisposing condition? Neurology, May 25, 2004; 62(10): 1882 - 1884. [Abstract] [Full Text] [PDF]
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