Abstract
Summary: During the last decades, efforts have been made to elucidate the complex mechanisms underlying neuronal damage in glutaryl-CoA dehydrogenase deficiency. A combination of in vitro and in vivo investigations have facilitated the development of several hypotheses, including the probable pathogenic role of accumulating glutaric acid and 3-hydroxyglutaric acid. However, there are still many shortcomings that limit an evidence-based approach to treating this inborn error of metabolism. Major future goals should include generation of a suitable animal model for acute striatal necrosis, investigation of the formation, distribution and exact intra- and extracellular concentrations of accumulating metabolites, a deeper understanding of striatal vulnerability, and systematic investigation of effects on cerebral gene expression during development and of the modulatory role of inflammatory cytokines.
Similar content being viewed by others
REFERENCES
Bähr O, Mader I, Zschocke J, et al (2002)Adult onset glutaric aciduria typ I presenting with leukoencephalopathy.Neurology 59:1802-1804.
Brismar J, Ozand PT (1995)CT and MR of the brain in glutaric acidemia type I:a revi w of 59 published cases and a report of 5 new patients.Am J Neuroradiol 16:675-683.
Brouillet E, Jenkins BG, Hyman BT, et al (1993)Ag-dependent vulnerability of the striatum to th mitochondrial toxin 3-nitropropionic acid.J Neurochem 60:356-359.
Busquets C, Merinero B, Christensen E, et al (2000)Glutaryl-CoA dehydrogenas de ficiency in Spain:vidence of two groups of pati nts,genetically,and biochemically distinct.Pediatr Res 48:315-322.
de Mello CF, Kölker S, Ahlemeyer B, et al (2001)Intrastriatal administration of3-hydroxyglutaric acid induces convulsions and xcitotoxic l sions in rats.Brain Res 916:70-75.
Goodman SI, Norenberg MD, Shikes RH, et al (1977)Glutaric aciduria:biochemical andmorphological considerations.JPediatr 90:746-750.
Greene JG, Porter RH, Eller RV, Greenamyre JT (1993)Inhibition of succinat dehydrogenas by malonic acid produc s an 'excitotoxic 'l sion in rat striatum.J Neurochem 61:1151-1154.
Hewett SJ, Csernansky CA, Choi DW (1994)S lectiv potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS.Neuron 13:487-494.
Hoffmann GF, Athanassopoulos S, Burlina AB, et al (1996)Clinical course,early diagnosis,treatment,and prevention of disease in glutaryl-CoA dehydrogenas de ficiency. Neuropediatrics 27:115-123.
Ikonomidou C, Bosch F, Miksa M, et al (1999)Blockade of NMDA receptors and apoptotic neurodegeneration in th dev loping brain.Science 283:70-74.
Knerr I, Zschocke J, Trautmann U, et al (2002)Glutaric aciduria typ III:A distinctive non-disease?J Inherit Metab Dis 25:483-490.
Koeller DM, DiGuilio KA, Angeloni SV, et al (1995)Cloning,structure,and chromosome localization of the mouse glutaryl-CoA dehydrogenase g ne.Genomics 28:508-512.
Koeller DM, Woontner M, Crnic LS, et al (2002)Biochemical,pathologic and behavioral analysis of a mous mod l of glutaric acid mia typ I.Hum Mol Genet 11:347-357.
Kölker S, Ahlemeyer B, Krieglstein J, Hoffmann GF (2001)Contribution of reactiv oxygen speci s to 3-hydroxyglutarate neurotoxicity in primary neuronal cultures from chick mbryo telencephalons.Pediatr Res 50:76-82.
Kölker S, Köhr G, Ahlemeyer B, et al (2002)Ca 2 + and Na + dependenc of 3-hydroxyglutarate-induced excitotoxicity in primary neuronal cultures from chick embryo telencephalons.Pediatr Res 52:199-206.
Kölker S, Schor DSM, Feyh P, et al (2003)Glutaryl-CoA dehydrogenase de ficiency: region-speci fic analysis of organic acids and acylcarnitin s in post mort m brain predicts vulnerability of the putamen.Neuropediatrics 34:253-260.
Kölker S, Koeller DM, Sauer S, et al (2004)Excitotoxicity and bioenerg tics in glutaryl-CoA dehydrogenas de ficiency.JInheritMetabDis 27:805-812.
Latini A, Borba Rosa-R, Scussiato K, et al (2002)3-Hydroxyglutaric acid induces oxidative stress and decr ases the antioxidant defenses in cerebral cortex of young rats.Brain Res 956:367-373.
Leibel RL, Shih VE, Goodman SI, et al (1980)Glutaric acidemia:a metabolic disorder causing progr ssiv choreoathethosis.Neurology 30:1163-1168.
Liesert M, Zschocke J, Hoffmann GF, Muhlhauser N, Buckel W (1999)Biochemistry of glutaric aciduria typ I:activities of in vitro expressed wild-type and mutant cDNA ncoding human glutaryl-CoA dehydrogenase.J Inherit Metab Dis 22:256-258.
Lima TTF, Begnini J, de Bastiani J, et al (1998)Pharmacological evidence for GABAergic and glutamatergic involvem nt in the convulsant and behavioralffects of glutaric acid.Brain Res 802:55-60.
Mühlhausen C, Hoffmann GF, Strauss KA, et al (2004a)Maintenanc treatment of glutaryl-CoA dehydrogenase de fici ncy.J Inherit Metab Dis 27:885-892.
Mühlhausen C, Ergffn S, Strauss KA, et al (2004b)Vascular dysfunction as an additional pathom chanism in glutaric aciduria typ I.JInheritMetabDis 27:829-834.
McMillan TA, Gibson KM, Sweetman L, Meyers GS, Green R(1988)Conservation of central nervous syst m glutaryl-coenzyme A d hydrog nase in fruit-eating bats with glutaric aciduria and de ficient h patic glutaryl-coenzyme A d hydrog nase.JBiolChem 263:17258-17261.
Nansen EA, Jokel ES, Lobo MK, Micevych PE, Ariano MA, Levine MS (2000)Striatal ionotropic glutamat receptor ontog ny in the rat.Dev Neurosci 22:329-340.
Nishino H, Hida H, Kumazaki M, et al (2000)The striatum is the most vulnerabl region in the brain to mitochondrial n rgy compromis:a hypothesis to xplain its sp ci fic vulnerability.JNeurotrauma 17:251-260.
Porciúncula LO, Dal-Pizzol A, Coitinho AS, et al (2000)Inhibition of synaptosomal [3 H ]glutamat uptak and [3 H ]glutamat binding to plasma m mbranes from brain of young rats by glutaric acid in vitro. JNeurolSci 173:93-96.
Resink A, Villa M, Benke D, et al (1996)Characterization of agonist-induc d downregulation of NMDA receptors in cerebellar granule c ll cultures.J Neurochem 66:369-377.
Soffer D, Amir N, Elpeleg ON, et al (1992)Striatal deg n ration and spongy my linopathy in glutaric acid mia.JNeurolSci 107:199-204.
Stokk O, Goodman SI, Moe PG (1976)Inhibition of brain glutamat d carboxylase by glutarate,glutaconat, and b hydroxyglutarate:explanation of the symptoms in glutaric aciduria?Clin Chim Acta 66:411-415.
Strauss KA, Morton DH (2003)Type I glutaric aciduria,part 2:A model of acut striatal necrosis.Am J Med Genet 121C:53-70.
Strauss KA, Puffenberger EG, Robinson DL, Morton DH (2003)Typ I glutaric aciduria, part 1:Natural history of 77 patients.Am J Med Genet 121C:38-52.
Twomey EL, Naughten ER, Donoghuej VB, Ryan S (2003)Neuroimaging findings in glutaric aciduria type I.Pediatr Radiol 33:823-830.
Ullrich K, Flott-Rahmel B, SchluffP, et al (1999)Glutaric aciduria type I:pathomechanism of neurodegeneration.J Inherit Metab Dis 22:392-403.
Vamecq J, d Hoffmann E, van Hoof F (1985)Mitochondrial and p roxisomal m tabolism of glutaryl-CoA.Eur J Biochem 146:663-669.
Varadkar S, Surtees R (2004)Glutaric aciduria typ I and kynurenine pathway metabolites: a modi fied hypothesis.JInheritMetabDis 27:835-842.
Volpe JJ (2001)Hypoxic-ischemic encephalopathy:biochemical and physiological aspects.In: Volpe JJ,ed.Neurology of the Newborn, 4th ed.Philadelphia: WB Saunders,217-277.
Wallace DC, Lott MT, Brown MD, Kerstmann K (2001)Mitochondria and neuro-ophthalmological diseases.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 dn.New York: McGraw-Hill,2425-2512.
Woontner M, Crnic LS, Koeller DM (2000)Analysis of the xpression of murine glutaryl-CoA d hydrog nase:in vitro and in vivo studi s.Mol Genet Metab 69:116-122.
Yannicelli S, Rohr F, Warman ML(1994)Nutrition support for glutaric acidemia type I.Jam Diet Assoc 94:183-188.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
KÖlker, S., Strauss, K.A., Goodman, S.I. et al. Challenges for basic research in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27, 843–849 (2004). https://doi.org/10.1023/B:BOLI.0000045768.38073.22
Issue Date:
DOI: https://doi.org/10.1023/B:BOLI.0000045768.38073.22