Journal of Inherited Metabolic Disease

, Volume 29, Issue 5, pp 612–619 | Cite as

Infant mice with glutaric acidaemia type I have increased vulnerability to 3-nitropropionic acid toxicity

  • K. B. Bjugstad
  • L. S. Crnic
  • S. I. Goodman
  • C. R. Freed
Original Article


Glutaric acidaemia type I (GA I) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH) and is characterized clinically by striatal degeneration that almost always occurs in early childhood. A murine knockout model of GA I has the organic aciduria seen in the human disorder, but this model does not develop striatal degeneration spontaneously. 3-Nitropropionic acid (3NP), a succinic dehydrogenase inhibitor with specificity for the striatum, was investigated as a potential initiator of striatal degeneration in GCDH-deficient mice. This study shows that GCDH-deficient mouse pups are more susceptible to 3NP than their wild-type littermates, and that all mouse pups are more sensitive to 3NP as infants than as adolescents and adults. Increased sensitivity to 3NP early in life may model the developmental window for the striatal damage observed in human GA I.



3-hydroxyglutaric acid


3-nitropropionic acid


glutaric acidaemia type I


glutaric acid


glutaryl-CoA dehydrogenase


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Al-Essa M, Bakheet S, Patay Z, et al (1998) 18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in glutaric aciduria type 1: clinical and MRI correlations. Brain Dev 20: 295–301.PubMedCrossRefGoogle Scholar
  2. Alexi T, Hughes PE, Knusel B, Tobin AJ (1998a) Metabolic compromise with systemic 3-nitropropionic acid produces striatal apoptosis in Sprague-Dawley rats but not in BALB/c ByJ mice. Exp Neurol 153: 74–93.CrossRefGoogle Scholar
  3. Alexi T, Hughes PE, Faull RLM, William CE (1998b) 3-Nitropropionic acid’s lethal triplet: cooperative pathways of neurodegeneration. NeuroReport 9, R57–R64.Google Scholar
  4. Beal MF, Ferrante RJ, Henshaw R, et al (1995) 3-Nitropropionic acid neurotoxicity is attenuated in copper/zinc superoxide dismutase transgenic mice. J Neurochem 65: 919–922.PubMedCrossRefGoogle Scholar
  5. Bjugstad KB, Goodman SI, Freed CR (2000) Age of symptom onset predicts severity of motor impairment and clinical outcome of glutaric acidemia type 1. J Pediatr 137: 681–686.PubMedCrossRefGoogle Scholar
  6. Bjugstad KB, Zawada WM, Goodman SI, Freed CR (2001) IGF-1 and bFGF reduce glutaric and 3-hydroxyglutaric acid toxicity in striatal cultures. J Inherit Metab Dis 24: 631–647.PubMedCrossRefGoogle Scholar
  7. Bogdanov MB, Ferrante RJ, Kuemmerle S, Klivenyi P, Beal MF (1998a) Increased vulnerability to 3-nitropropionic acid in an animal model of Huntington’s disease. J Neurochem 71: 2642–2644.CrossRefGoogle Scholar
  8. Bogdanov MB, Ramos LE, Xu Z, Beal MF (1998b) Elevated ‘hydroxyl radical’ generation in vivo in an animal model of amylotrophic lateral sclerosis. J Neurochem 71: 1321–1324.CrossRefGoogle Scholar
  9. Bogdanov MB, Ferrante RJ, Mueller G, Ramos LE, Martinou JC, Beal MF (1999) Oxidative stress is attenuated in mice overexpressing BCL-2. Neurosci Lett 262: 33–36.PubMedCrossRefGoogle Scholar
  10. Brouillet E, Jenkins BG, Hyman BT, et al (1993) Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitroproprionic acid. J Neurochem 60: 356–359.PubMedGoogle Scholar
  11. Chyi T, Chang C (1999) Temporal evolution of 3-nitropropionic acid-induced neurodegeneration in the rat brain by T2-weighted, diffusion-weighted, and perfusion magnetic resonance imaging. Neuroscience 92: 1035–1041.PubMedCrossRefGoogle Scholar
  12. De Mello CF, Kolker S, Ahlemeyer B, et al (2001) Intrastriatal administration of 3-hydroxyglutaric acid induces convulsion and excitotoxic lesions in rats. Brain Res 916: 70–75.PubMedCrossRefGoogle Scholar
  13. Flott-Rahmel B, Falter C, Schluff P, et al (1997) Nerve cell lesions caused by 3-hydroxyglutaric acid. A possible mechanism for neurodegeneration in glutaric acidaemia I. J Inherit Metab Dis, 20: 387–390.PubMedCrossRefGoogle Scholar
  14. Fox WM (1965) Reflex-ontogeny and behavioral development of the mouse. Animal Behav 13: 234–241.CrossRefGoogle Scholar
  15. Funk, CB, Prasad AN, Frosk P, et al (2005) Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain 128: 711–722.PubMedCrossRefGoogle Scholar
  16. Goodman SI, Biery BJ (1996) Glutaric acidemia (type 1) Ment Retard Dev Disabil Res Rev 2: 155–159.Google Scholar
  17. Goodman SI, Frerman FE (2001) Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2195–2204.Google Scholar
  18. Goodman SI, Kohlhoff JG (1975) Glutaric aciduria: inherited deficiency of glutaryl- CoA dehydrogenase activity. Biochem Med 13, 138–40.Google Scholar
  19. Goodman SI, Markey SP, Moe PG, Miles BS, Teng CC (1975) Glutaric aciduria: A ‘new’ disorder of amino acid metabolism. Biochem Med 12: 12–21.PubMedCrossRefGoogle Scholar
  20. Gould DH, Gustine DL (1982) Basal ganglia degeneration, myelin alterations, and enzyme inhibition induced in mice by the plant toxin 3-nitropropanoic acid. Neuropathol Appl Neurobiol 8: 377–393.PubMedGoogle Scholar
  21. Hamrick SEG, Ferriero DM (2003) The injury response in the term newborn brain: Can we neuroprotect? Curr Opin Neurol 16: 147–154.PubMedCrossRefGoogle Scholar
  22. Haworth JC, Booth FA, Chudley AE, et al (1991) Phenotypic variability in glutaric aciduria type 1: report of fourteen cases in five Canadian Indian kindreds. J Pediatr 118: 52–58.Google Scholar
  23. Herlenius E, Lagercrantz H (2004) Development of neurotransmitter systems during critical periods. Exp Neurol 190, s8–s21.Google Scholar
  24. Hoffmann GF, Trefz FK, Barth PG, et al (1991) Macrocephaly: an important indication for organic acid analysis. J Inherit Metab Dis 14: 329–332.PubMedCrossRefGoogle Scholar
  25. Holme E, Kyllerman M, Lindstedt S (1989) Early prenatal diagnosis in two pregnancies at risk for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 12: 280–282.PubMedGoogle Scholar
  26. Johnson M, Perry RH, Piggott MA, et al (1996) Glutamate receptor binding in the human hippocampus and adjacent cortex during development and aging. Neurobiol Aging 17: 639–651.PubMedCrossRefGoogle Scholar
  27. Kim GW, Copin JC, Kawase M, et al (2000) Excitotoxicity is required for induction of oxidative stress and apoptosis in mouse striatum by the mitochondrial toxin, 3-nitropropionic acid. J Cereb Blood Flow Metab 20: 119–129.PubMedCrossRefGoogle Scholar
  28. Kimura S, Hara M, Nezu A, Osaka H, Yamazaki S, Saitoh K (1994) Two cases of glutaric aciduria type 1: clinical and neuropathological findings. J Neurol Sci 123: 38–43.PubMedCrossRefGoogle Scholar
  29. Koeller DM, Woontner M, Crnic LS, et al (2002) Biochemical, pathologic, and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet 11: 347–357.PubMedCrossRefGoogle Scholar
  30. Kolker S, Ahlemeyer B, Krieglstein J, Hoffmann GF (1999) 3-Hydroxyglutaric and glutaric acids are neurotic through NMDA receptors in vitro. J Inherit Metab Dis, 22: 259–262.PubMedGoogle Scholar
  31. Kolker S, Ahlemeyer B, Krieglstein J, Hoffman GF (2000) Maturation-dependent neurotoxicity of 3-hydroxyglutaric and glutaric acids in vitro: a new pathophysiologic approach to glutaryl-coA dehydrogenase deficiency. Pediatr Res 47: 495–503.PubMedGoogle Scholar
  32. Kolker S, Ahlemeyer B, Krieglstein J, Hoffmann GF (2001) Contribution of reactive oxygen species to 3-hydroxyglutarate neurotoxicity in primary neuronal cultures from chick embryo telencephalons. Pediatr Res 50: 76–82.PubMedGoogle Scholar
  33. Kolker S, Kohr G, Ahlemeyer B, et al (2002) Ca2+ and Na+ dependence of 3-hydroxyglutarate-induced excitoxicity in primary neuronal cultures from chick embryo telencephalons. Pediatr Res 52: 199–206.PubMedCrossRefGoogle Scholar
  34. Kolker S, Koeller DM, Okun JG, Hoffmann GF (2004) Pathomechanisms of neurodegeneration in glutaryl-coA dehydrogenase deficiency. Ann Neurol 55: 7–12.PubMedCrossRefGoogle Scholar
  35. Kyllerman M, Steen G (1977) Intermittently progressive dyskinetic syndrome in glutaric aciduria. Neuropediatrics 8: 397–404.CrossRefGoogle Scholar
  36. Kyllerman M, Skjeldal OH, Lundberg M, et al (1994) Dystonia and dyskinesia in glutaric aciduria type 1: clinical heterogeneity and therapeutic considerations. Mov Disord 9: 22–30.PubMedCrossRefGoogle Scholar
  37. Latini A, Borba Rosa R, Scussiato K, Llesuy S, Bello-Klein A, Wajner M (2002) 3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defenses the antioxidant defenses in cerebral cortex of young rats. Brain Res 956: 367–373.PubMedCrossRefGoogle Scholar
  38. Latini A, Scussiato K, Leipnitz G, Dutra-Filho CS, Wajner M (2005) Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum. J Inherit Metab Dis 28: 57–67.PubMedCrossRefGoogle Scholar
  39. Lau WK, Lui PW, Wong CK, Chan YS, Yung KK (2003) Differential expression of N-methyl-D-aspartate receptor subunit messenger ribonucleic acids and immunoreactivity in the rat neostriatum during postnatal development. Neurochem Int 43: 47–65.PubMedCrossRefGoogle Scholar
  40. Laurie DJ, Seeburg PH (1994) Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J Neurosci 14: 3180–3194.PubMedGoogle Scholar
  41. Lea PM IV, Faden AI (2001) Traumatic brain injury: Developmental differences in glutamate receptor response and the impact on treatment. Ment Retard Dev Dis Res Rev 7: 235–248.CrossRefGoogle Scholar
  42. Lund TM, Christensen E, Kristensen AS, Schousboe A, Lund AM (2004) On the neurotoxicity of glutaric, 3-hydroxyglutaric, and trans-glutaconic acids in glutaric acidemia type 1. J Neurosci Res 77: 143–147.PubMedCrossRefGoogle Scholar
  43. Palmer C, Menzies SL, Roberts RL, Pavlick G, Connor JR (1999) Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat. J Neurosci Res 56: 60–71.PubMedCrossRefGoogle Scholar
  44. Peeters C, van Bel F (2001) Pharmacotherapeutical reduction of post-hypoxic-ischemic brain injury in the newborn. Biol Neonate 79: 274–280.PubMedCrossRefGoogle Scholar
  45. Sanchez-Cabente M, Massieu L (1999) Transient inhibition of glutamate uptake in vivo induces neurodegeneration when energy metabolism is impaired. J Neurochem 72: 129–138.CrossRefGoogle Scholar
  46. Stokke O, Goodman SI, Moe PG (1976) Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and β-hydroxyglutarate: explanation of the symptoms in the glutaric aciduria? Clin Chim Acta 66: 411–415.PubMedCrossRefGoogle Scholar
  47. Strauss KA, Morton DH (2003) Type I glutaric aciduria, part 2: a model of acute striatal necrosis. Am J Med Genet Part C (Semin Med Genet) 121C: 53–70.CrossRefGoogle Scholar
  48. Stutchfield P, Edwards MA, Gray RGF, Crawley P, Green A (1985) Glutaric aciduria type 1 misdiagnosed as Leigh’s encephalopathy and cerebral palsy. Dev Med Child Neurol 27: 514–521.PubMedCrossRefGoogle Scholar
  49. Ullrich K, Flott-Rahmel B, Schluff. P, et al (1999) Glutaric aciduria type I: pathomechanisms of neurodegeneration. J Inherit Metab Dis 22: 392–403.PubMedCrossRefGoogle Scholar
  50. Urbanska EM, Blaszczak P, Saran T, Kleinrok Z, Turski WA (1998) Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice. Eur J Pharmacol 359: 55–58.PubMedCrossRefGoogle Scholar
  51. Virmani A, Gaetani F, Binienda Z (2005) Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors MPTP, methamphetamine. Ann NY Acad Sci 1 053: 183–191.Google Scholar
  52. Woeffle J, Kreft B, Emons D, Haverkamp F (1996) Subdural hemorrhage as an initial sign of glutaric aciduria type 1: a diagnostic pitfall. Pediatr Radiol 26: 779–781.CrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  • K. B. Bjugstad
    • 1
  • L. S. Crnic
    • 2
  • S. I. Goodman
    • 2
  • C. R. Freed
    • 3
  1. 1.Department PsychiatryUniversity of Colorado Health Sciences CenterDenverUSA
  2. 2.Department PediatricsUniversity of Colorado Health Sciences CenterDenverUSA
  3. 3.Department Medicine and Division of Clinical PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA

Personalised recommendations