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D-2-Hydroxyglutaric aciduria: Unravelling the biochemical pathway and the genetic defect

  • Metabolic Dissertation
  • Published:
Journal of Inherited Metabolic Disease

Summary

D-2-Hydroxyglutaric aciduria (D-2-HGA) is a neurometabolic inherited disorder first described in 1980. In the following years, it became clear that the clinical phenotype of the disease varies widely from severe neonatal to asymptomatic. However, the sparse biochemical knowledge made D-2-HGA a poorly understood disease. Much progress has been made in the last five years in various studies, revealing two human enzymes that play a role in the metabolism of D-2-hydroxyglutarate (D-2-HG): hydroxyacid-oxoacid transhydrogenase (HOT) and D-2-HG dehydrogenase. HOT is expected to be responsible for the formation of D-2-HG, while D-2-HG dehydrogenase converts D-2-HG into 2-ketoglutarate. We demonstrated pathogenic mutations in the D2HGD gene in patients with D-2-HGA, helping to unravel the primary defect causing D-2-HGA. However, in approximately 50% of the patients with D-2-HGA examined, no pathogenic mutations have yet been found.

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References

  • Achouri Y, Rider MH, Schaftingen EV, Robbi M (1997) Cloning, sequencing and expression of rat liver 3-phosphoglycerate dehydrogenase. Biochem J 323: 365–370.

    CAS  PubMed  Google Scholar 

  • Achouri Y, Noel G, Vertommen D, Rider MH, Veiga-Da-Cunha M, Van Schaftingen E (2004) Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J 381: 35–42.

    CAS  PubMed  Google Scholar 

  • Albers E, Gustafsson L, Niklasson C, Liden G (1998) Distribution of 14C-labelled carbon from glucose and glutamate during anaerobic growth of Saccharomyces cerevisiae. Microbiology 144: 683–690.

    Google Scholar 

  • Amiel J, de Lonlay P, Francannet C, et al (1999) Facial anomalies in D-2-hydroxyglutaric aciduria. Am J Med Genet 86: 124–129.

    Article  CAS  PubMed  Google Scholar 

  • Barth PG, Hoffmann GF, Jaeken J, et al (1992) L-2-Hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Annals of Neurology 32: 66–71.

    Article  CAS  PubMed  Google Scholar 

  • Bayar A, Acun C, Dursun A, et al (2005) Metaphyseal enchondrodysplasia with 2-hydroxy-glutaric aciduria: observation of a third case and further delineation. Clin Dysmorphol 14: 7–11.

    Article  PubMed  Google Scholar 

  • Buckel W (1980) The reversible dehydration of (R)-2-hydroxyglutarate to (E)-glutaconate. Eur J Biochem 106: 439–447.

    Article  CAS  PubMed  Google Scholar 

  • Chalmers RA, Lawson AM, Borud O (1977) Gas chromatographic and mass spectrometric studies on urinary organic acids in a patient with congenital lactic acidosis due to pyruvate decarboxylase deficiency. Clin Chim Acta 77: 117–124.

    Article  CAS  PubMed  Google Scholar 

  • Chalmers RA, Lawson AM, Watts RWE, et al (1980) D-2-Hydroxyglutaric aciduria: case report and biochemical studies. J Inherit Metab Dis 3: 11–15.

    Google Scholar 

  • Clarke NF, Andrews I, Carpenter K, Jakobs C, van der Knaap MS, Kirk EP (2003) D-2-Hydroxyglutaric aciduria: a case with an intermediate phenotype and prenatal diagnosis of two affected fetuses. Am J Med Genet A 120: 523–527.

    PubMed  Google Scholar 

  • Craigen WJ, Jakobs C, Sekul EA, et al (1994) D-2-Hydroxyglutaric aciduria in neonate with seizures and CNS dysfunction. Pediatr Neurol 10: 49–53.

    Article  CAS  PubMed  Google Scholar 

  • da Silva CG, Ribeiro CA, Leipnitz G, et al (2002) Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by D-2-hydroxyglutaric acid in vitro. Biochim Biophys Acta 1586: 81–91.

    CAS  PubMed  Google Scholar 

  • da Silva CG, Bueno AR, Schuck PF, et al (2003a) D-2-Hydroxyglutaric acid inhibits creatine kinase activity from cardiac and skeletal muscle of young rats. Eur J Clin Invest 10: 840–847.

    Google Scholar 

  • da Silva CG, Bueno AR, Rosa RB, et al (2003b) Inhibition of mitochondrial creatine kinase activity by D-2-hydroxyglutaric acid in cerebellum of young rats. Neurochem Res 28: 1329–1337.

    CAS  Google Scholar 

  • da Silva CG, Bueno AR, Schuck PF, et al (2004) Inhibition of creatine kinase activity from rat cerebral cortex by D-2-hydroxyglutaric acid in vitro. Neurochem Int 44: 45–52.

    CAS  PubMed  Google Scholar 

  • Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman. SK (1980) L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis 3: 109–112.

    Article  CAS  PubMed  Google Scholar 

  • Gibson KM, ten Brink HJ, Schor DSM, et al (1993a) Stable-isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias. Pediatr Res 34: 277–280.

    CAS  Google Scholar 

  • Gibson KM, Craigen W, Herman GE, Jakobs C (1993b) D-2-Hydroxyglutaric aciduria in a newborn with neurological abnormalities: a new neurometabolic disorder? J Inherit Metab Dis 16: 497–500.

    CAS  Google Scholar 

  • Goodman SI, McCabe ERB, Fennessey PV, Mace JW (1980) Multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II) with transient hypersarcosinemia and sarcosinuria; possible inherited deficiency of an electron transfer flavoprotein. Pediatr Res 14: 12–17.

    CAS  PubMed  Google Scholar 

  • Gregersen N, Ingerslev J, Rasmussen K (1977) Low molecular weight organic acids in the urine of the newborn. Acta Paediatr Scand 66: 85–89.

    CAS  PubMed  Google Scholar 

  • Hammerstedt RH, Swan PB, Henderson LM (1968) Degradation of 5-hydroxylysine in the rat and in the perfused liver. Arch Biochem Biophys 128: 243–251.

    Article  CAS  PubMed  Google Scholar 

  • Honey EM, van Rensburg M, Knoll DP, Mienie LJ, van de Werke I, Beighton P (2003) Spondyloenchondromatosis with D-2-hydroxyglutaric aciduria: a report of a second patient with this unusual combination. Clin Dysmorphol 12: 95–99.

    Google Scholar 

  • Kaufman EE, Nelson T, Fales HM, Levin DM (1988a) Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria. J Biol Chem 263: 16872–16879.

    CAS  Google Scholar 

  • Kaufman EE, Nelson T, Miller D, Stadlan N (1988b) Oxidation of gamma-hydroxybutyrate to succinic semialdehyde by a mitochondrial pyridine nucleotide-independent enzyme. J Neurochem 51: 1079–1084.

    CAS  Google Scholar 

  • Kolker S, Pawlak V, Ahlemeyer B, et al (2002) NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in D-2-hydroxyglutaric aciduria. Eur J Neurosci 16: 21–28.

    Article  PubMed  Google Scholar 

  • Kopchick JJ, Hartline RA (1979) alpha-Hydroxyglutarate as an intermediate in the catabolism of alpha-aminoadipate by Pseudomonas putida J Biol Chem 254: 3259–3263.

    Google Scholar 

  • Korman SH, Salomons GS, Gutman A, Brooks R, Jakobs C (2004) D-2-Hydroxyglutaric aciduria and glutaric aciduria type 1 in siblings: coincidence, or linked disorders? Neuropediatrics 35: 151–156.

    Article  CAS  PubMed  Google Scholar 

  • Kuhara T, Shinka T, Inoue Y, et al (1983) Studies of urinary organic acid profiles of a patient with dihydrolipoyl dehydrogenase deficiency. Clin Chim Acta 133: 133–140.

    CAS  PubMed  Google Scholar 

  • Kumps A, Duez P, Mardens Y (2002) Metabolic, nutritional, iatrogenic, and artifactual sources of urinary organic acids: a comprehensive table. Clin Chem 48: 708–717.

    CAS  PubMed  Google Scholar 

  • Latini A, Scussiato K, Rosa RB, et al (2003) D-2-Hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur J Neurosci 17: 2017–2022.

    Article  PubMed  Google Scholar 

  • Lindahl G, Lindstedt G, Lindstedt S (1967) Metabolism of 2-amino-5-hydroxyadipic acid in the rat. Arch Biochem Biophys 119: 347–352.

    Article  CAS  PubMed  Google Scholar 

  • Misra VK, Struys EA, O’Brien W, et al (2005) Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria monozygotic twins. Mol Genet Metab 86: 200–205.

    Article  CAS  PubMed  Google Scholar 

  • Muntau AC, Röschinger W, Merkenschlager A, et al (2000) Combined D-2- and L-2-hydroxyglutaric aciduria with neonatal onset encephalopathy: a third biochemical variant of 2-hydroxyglutaric aciduria? Neuropediatrics 31: 137–140.

    Article  CAS  PubMed  Google Scholar 

  • Nelson T, Kaufman EE (1994) Developmental time courses in the brain and kidney of two enzymes that oxidize gamma-hydroxybutyrate. Dev Neurosci 16: 352–358.

    CAS  PubMed  Google Scholar 

  • Przyrembel H, Wendel U, Becker K, et al (1976) Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clin Chim Acta 66: 227–239.

    Google Scholar 

  • Rashed MS, AlAmoudi M, Aboul-Enein HY (2000) Chiral liquid chromatography tandem mass spectrometry in the determination of the configuration of 2-hydroxyglutaric acid in urine. Biomed Chromatogr 14: 317–320.

    Article  CAS  PubMed  Google Scholar 

  • Read MH, Bonamy C, Laloum D, et al (2005) Clinical, biochemical, magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) findings in a fourth case of combined D- and L-hydroxyglutaric aciduria. J Inherit Metab Dis 28: 1149–1150.

    Article  PubMed  Google Scholar 

  • Rzem R, Veiga-da-Cunha M, Noel G, et al (2004) A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci USA 101: 16849–16854.

    Google Scholar 

  • Struys EA, Verhoeven NM, Brunengraber H, Jakobs C (2004a) Investigations by mass isotopomer analysis of the formation of D-2-hydroxyglutarate by cultured lymphoblasts from two patients with D-2-hydroxyglutaric aciduria. FEBS Lett 557: 115–120.

    Article  CAS  Google Scholar 

  • Struys EA, Jansen EEW, Verhoeven NM, Jakobs C (2004b) Measurement of urinary D- and L-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-L-tartaric anhydride. Clin Chem 50: 1391–1395.

    CAS  Google Scholar 

  • Struys EA, Salomons GS, Achouri Y, et al (2005a) Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet 76: 358–360.

    Article  CAS  Google Scholar 

  • Struys EA, Verhoeven NM, ten Brink HJ, Wickenhagen WV, Gibson KM, Jakobs C (2005b) Kinetic characterisation of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias. (2005b) J Inherit Metab Dis 28: 921–930.

    Google Scholar 

  • Struys EA, Korman SH, Salomons GS, et al (2005c) D-2-Hydroxyglutarate dehydrogenase mutations in phenotypically mild D-2-hydroxyglutaric aciduria. Ann Neurol. 58: 626–630.

    Article  CAS  Google Scholar 

  • Talkhani IS, Saklatvala J, Dwyer J (2000) D-2-Hydroxyglutaric aciduria in association with spondyloenchondromatosis. Skeletal Radiol 29: 289–292.

    Article  CAS  PubMed  Google Scholar 

  • Thompson JA, Miles BS, Fennessey PV (1977) Urinary organic acids quantitated by age groups in a healthy pediatric population. Clin Chem 23: 1734–1738.

    CAS  PubMed  Google Scholar 

  • Topcu M, Jobard F, Halliez S, et al (2004) L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13: 2803–2811.

    Article  CAS  PubMed  Google Scholar 

  • Tubbs PK, Greville GD (1961) The oxidation of D-alpha-hydroxy acids in animal tissues. Biochem J 81: 104–114.

    CAS  PubMed  Google Scholar 

  • Van Biervliet JP, Bruinvis L, van der Heiden C, et al (1977) Report of a patient with severe, chronic lactic acidaemia and pyruvate carboxylase deficiency. Dev Med Child Neurol 19: 392–401.

    Google Scholar 

  • van der Knaap MS, Jakobs C, Hoffmann GF, et al (1999a) D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity? Ann Neurol 45, 111–119.

    Article  CAS  Google Scholar 

  • van der Knaap MS, Jakobs C, Hoffmann GF, et al (1999b) D-2-Hydroxyglutaric aciduria: further clinical delineation. J Inherit Metab Dis 22: 404–413.

    Article  CAS  Google Scholar 

  • Wajner M, Vargas CR, Funayama C, et al (2002) D-2-Hydroxyglutaric aciduria in a patient with a severe clinical phenotype and unusual MRI findings. J Inherit Metab Dis 25: 28–34.

    Article  Google Scholar 

  • Wanders RJ, Mooyer P (1995) D-2-Hydroxyglutaric acidaemia: identification of a new enzyme, D-2-hydroxyglutarate dehydrogenase, localized in mitochondria. J Inherit Metab Dis 18: 194–196.

    CAS  PubMed  Google Scholar 

  • Wegener WS, Reeves HC, Ajl SJ (1968) Propionate metabolism. 3. Studies on the significance of the alpha-hydroxyglutarate pathway. Arch Biochem Biophys 123: 62–65.

    CAS  PubMed  Google Scholar 

  • Zhao G, Winkler ME (1996) A novel alpha-ketoglutarate reductase activity of the serA-encoded 3-phosphoglycerate dehydrogenase of Escherichia coli K-12 and its possible implications for human 2-hydroxyglutaric aciduria. J Bacteriol 178: 232–239.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. VU University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Eduard A. Struys

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  1. Eduard A. Struys
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Correspondence to Eduard A. Struys.

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Communicating editor: Verena Peters

Competing interests: None declared

This article is based on a Ph.D. thesis (Academisch Proefschrift) accepted by the Vrije Universiteit Amsterdam, The Netherlands. The Project was carried out under the supervision of Cornelis Jakobs, Gajja S. Salomons and Nanda M. Verhoeven.

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Struys, E.A. D-2-Hydroxyglutaric aciduria: Unravelling the biochemical pathway and the genetic defect. J Inherit Metab Dis 29, 21–29 (2006). https://doi.org/10.1007/s10545-006-0317-9

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  • DOI: https://doi.org/10.1007/s10545-006-0317-9

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