L‐2‐Hydroxyglutaric aciduria: an inborn error of metabolism?
Abstract
A 5‐year‐old boy, excreting large amounts of 2‐hydroxyglutaric acid in the urine (3.3–7.6 mmol/l), is described. The patient presented with psychomotor retardation and dystrophy. His skeletal age was delayed. The EEG was not well differentiated; it resembled that observed in 2‐year‐old children. There was a severe anaemia, which reacted well to iron supplements. The 2‐hydroxyglutaric acid was found to have the l ‐configuration, as analysed by capillary gas chromatography of the O ‐acetylated di‐(‐)‐2‐butyl ester derivative. The relation of l ‐2‐hydroxyglutarate excretion to known metabolic pathways is discussed.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
D-2-HG produced by mIDH1/2 drives a CpG island methylator phenotype in glioma and ICC tumours to promote tumorigenesis.
“D-2-HG produced by mIDH1/2 has been shown to drive a CpG island methylator phenotype (G-CIMP) in both glioma and ICC tumours to promote tumorigenesis, and has also been found to occupy the active site of histone demethylases thereby increasing histone methylation in primary gliomas121,123-125.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [121]
D-2-HG occupies the active site of histone demethylases, increasing histone methylation in primary gliomas.
“D-2-HG produced by mIDH1/2 has been shown to drive a CpG island methylator phenotype (G-CIMP) in both glioma and ICC tumours to promote tumorigenesis, and has also been found to occupy the active site of histone demethylases thereby increasing histone methylation in primary gliomas121,123-125.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [121]
D-2-HG acts as a competitive inhibitor of α-KGDDs including TET family and JMJD family.
“As with succinate and fumarate, D-2-HG acts as a competitive inhibitor of α-KGDDs including, but not limited to, the TET family and JMJD family of DNA and histone demethylases, respectively121,22.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [121]
The IC50 of D-2-HG toward KDM family members is in the low micromolar range (24-106 μM).
“Although the IC50 of D-2-HG toward KDM family members is in the low micromolar range (24-106 μM), it can also inhibit FIH and PHD2, with IC50 values of 1.5 and 7.3 mM, respectively121.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [121]
D-2-HG inhibits FIH and PHD2 with IC50 values of 1.5 and 7.3 mM, respectively.
“Although the IC50 of D-2-HG toward KDM family members is in the low micromolar range (24-106 μM), it can also inhibit FIH and PHD2, with IC50 values of 1.5 and 7.3 mM, respectively121.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [121]
D-2-HG inhibits α-KG-dependent ALKBH2 and ALKBH3, DNA damage repair enzymes that detoxify 1-methyladenine and 3-methylcytosine lesions.
“D-2-HG has been shown to inhibit α-KG-dependent alkylation repair homologs, ALKBH2 and ALKBH3, critical DNA damage repair enzymes that detoxify 1-methyladenine (1 mA) and 3-methlycytosine (3mC) lesions in DNA derived from alkylating agents121,131.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [121]
Cites
Gerwig, G. J., Kamerling, J. P., & Vliegenthart, J. F. G. (1978) · Carbohydrate Research · doi:10.1016/s0008-6215(00)80881-2 · Cited by 862 · see citing works
Self-citationWilliams, H. E., & Smith, L. H. (1968) · New England Journal of Medicine · doi:10.1056/nejm196802012780502 · Cited by 181 · see citing works
D‐2‐hydroxyglutaric aciduria: Case report and biochemical studies
Chalmers, R. A., Lawson, A. M., Watts, R. W. E., Tavill, A. S., Kamerling, J. P., Hey, E., & Ogilvie, D. (1980) · Journal of Inherited Metabolic Disease · doi:10.1007/bf02312516 · Cited by 135 · see citing works
Self-citationDeficiency of 2-oxo-glutarate: glyoxylate carboligase activity in primary hyperoxaluria.
Koch, J., Stokstad, E. L. R., Williams, H. E., et al. (1967) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.57.4.1123 · Cited by 66 · see citing works
Kamerling, J. P., Gerwig, G. J., Vliegenthart, J. F. G., Durán, M., Ketting, D., & Wadman, S. K. (1977) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)81817-4 · Cited by 59 · see citing works
Self-citationKamerling, J. P., Durán, M., Bruinvis, L., et al. (1977) · Clinica Chimica Acta · doi:10.1016/0009-8981(77)90246-7 · Cited by 50 · see citing works
Self-citationd ‐GLYCERIC‐ACIDAEMIA AND NON‐KETOTIC HYPERGLYCINEMIA
Brandt, N. J., Rasmussen, K. D., Brandt, S., et al. (1976) · Acta Paediatrica · doi:10.1111/j.1651-2227.1976.tb04401.x · Cited by 47 · see citing works
D-Glyceric acidemia in a patient with chronic metabolic acedosis
Wadman, S. K., Durán, M., Ketting, D., et al. (1976) · Clinica Chimica Acta · doi:10.1016/0009-8981(76)90099-1 · Cited by 46 · see citing works
Self-citationThe oxidation of l(−)α-hydroxyglutaric acid in animal tissues
Weil‐Malherbe, H. (1937) · Biochemical Journal · doi:10.1042/bj0312080 · Cited by 43 · see citing works
d-lactic aciduria, an inborn error of metabolism?
Durán, M., Biervliet, J. P. G. M. V., Kamerling, J. P., et al. (1977) · Clinica Chimica Acta · doi:10.1016/0009-8981(77)90297-2 · Cited by 40 · see citing works
Self-citationγδ-Dioxovalerate as a substrate for the glyoxalase enzyme system
Jerzykowski, T., Winter, R., & Matuszewski, W. (1973) · Biochemical Journal · doi:10.1042/bj1350713 · Cited by 35 · see citing works
Metabolism of 2-amino-5-hydroxyadipic acid in the rat
Lindahl, G., Lindstedt, G., & Lindstedt, S. (1967) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(67)90463-8 · Cited by 32 · see citing works
Studies on the metabolism of lysine and 5-hydroxylysine
Lindstedt, S., Lindstedt, G., & Mitoma, C. (1967) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(67)90462-6 · Cited by 17 · see citing works
CHALMERS, R. A., Watts, R. W. E., & Lawson, A. M. (1977) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/000456327701400134 · Cited by 17 · see citing works
Kopchick, J. J., & Hartline, R. A. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50753-5 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Oldham, W. M., Clish, C. B., Yang, Y., & Loscalzo, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.021 · Cited by 364 · see citing works
“Two enantiomers of 2HG, L and D, have been associated with separate, rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012).”
Progress in understanding 2‐hydroxyglutaric acidurias
Kranendijk, M., Struys, E. A., Salomons, G. S., Van der Knaap, M. S., & Jakobs, C. (2012) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-012-9462-5 · Cited by 292 · see citing works
Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
Ye, D., Guan, K.-L., & Xiong, Y. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2017.12.005 · Cited by 242 · see citing works
IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
de Botton, S., Mondesir, J., Willekens, C., & Touat, M. (2016) · Journal of Blood Medicine · doi:10.2147/jbm.s70716 · Cited by 220 · see citing works
Rzem, R., Veiga-da-Cunha, M., Noël, G., Goffette, S., Nassogne, M.-C., Tabarki, B., Schöller, C., Marquardt, T., Vikkula, M., & Van Schaftingen, E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404840101 · Cited by 195 · see citing works
Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review
Aghili, M., Zahedi, F., & Rafiee, E. (2009) · Journal of Neuro-Oncology · doi:10.1007/s11060-008-9706-2 · Cited by 159 · see citing works
D‐2‐hydroxyglutaric aciduria: Case report and biochemical studies
Chalmers, R. A., Lawson, A. M., Watts, R. W. E., Tavill, A. S., Kamerling, J. P., Hey, E., & Ogilvie, D. (1980) · Journal of Inherited Metabolic Disease · doi:10.1007/bf02312516 · Cited by 135 · see citing works
Self-citationTopçu, M., Jobard, F., Halliez, S., Coskun, T., Yalçinkayal, C., Gerceker, F. O., Wanders, R. J. A., Prud'homme, J.-F., Lathrop, M., Özguc, M., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh300 · Cited by 133 · see citing works
L-2-hydroxyglutaric aciduria and brain malignant tumors: A predisposing condition?
Moroni, I., Bugiani, M., D’Incerti, L., Maccagnano, C., Rimoldi, M., Bissola, L., Pollo, B., Finocchiaro, G., & Uziel, G. (2004) · Neurology · doi:10.1212/01.wnl.0000125335.21381.87 · Cited by 118 · see citing works
- Authors
- Duran, M., Kamerling, J. P., Bakker, H. D., van Gennip, A. H., & Wadman, S. K.
- Affiliations
- University Children's Hospital ‘Het Wilhelmina Kinderziekenhuis’ Nieuwe Gracht 137 Utrecht The Netherlands
- Utrecht University (NL)
- Emma Kinderziekenhuis (NL)
- Emma Children's Hospital Spinozastraat 51 Amsterdam The Netherlands
- Wilhelmina Children's Hospital (NL)
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 1980-12
- Volume
- 3
- Issue
- 1
- Pages
- 109-112
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- OpenAlex
- W2000639840
- Cited by
- 226
- References
- 15
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 10 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 5 · 2016: 13 · 2015: 8 · 2014: 10 · 2013: 6 · 2012: 7
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- L-2-hydroxyglutaric aciduria, 2-hydroxyglutarate, inborn errors of metabolism, psychomotor retardation, dystrophy, anemia, iron supplementation, L-configuration, capillary gas chromatography, metabolic pathways
- MeSH terms
- Child, Preschool, Glutarates, Humans, Hydroxy Acids, Ketoglutaric Acids, Male, Metabolism, Inborn Errors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
