Skip to main content
SpringerLink
Log in

Current concepts in organic acidurias: understanding intra- and extracerebral disease manifestation

  • SSIEM Symposium 2012
  • Published:
Journal of Inherited Metabolic Disease

Abstract

This review focuses on the pathophysiology of organic acidurias (OADs), in particular, OADs caused by deficient amino acid metabolism. OADs are termed classical if patients present with acute metabolic decompensation and multiorgan dysfunction or cerebral if patients predominantly present with neurological symptoms but without metabolic crises. In both groups, however, the brain is the major target. The high energy demand of the brain, the gate-keeping function of the blood–brain barrier, a high lipid content, vulnerable neuronal subpopulations, and glutamatergic neurotransmission all make the brain particularly vulnerable against mitochondrial dysfunction, oxidative stress, and excitotoxicity. In fact, toxic metabolites in OADs are thought to cause secondary impairment of energy metabolism; some of these toxic metabolites are trapped in the brain. In contrast to cerebral OADs, patients with classical OADs have an increased risk of multiorgan dysfunction. The lack of the anaplerotic propionate pathway, synergistic inhibition of energy metabolism by toxic metabolites, and multiple oxidative phosphorylation (OXPHOS) deficiency may best explain the involvement of organs with a high energy demand. Intriguingly, late-onset organ dysfunction may manifest even under metabolically stable conditions. This might be explained by chronic mitochondrial DNA depletion, increased production of reactive oxygen species, and altered gene expression due to histone modification. In conclusion, pathomechanisms underlying the acute disease manifestation in OADs, with a particular focus on the brain, are partially understood. More work is required to predict the risk and to elucidate the mechanism of late-onset organ dysfunction, extracerebral disease manifestation, and tumorigenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1
Fig. 2

Similar content being viewed by others

Abbreviations

BBB:

Blood–brain barrier

mtDNA:

Mitochondrial DNA

OAD(s):

organic aciduria(s)

ROS:

Reactive oxygen species

TCA:

Tricarboxylic acid cycle

References

  • Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98:641–653

    Article  PubMed  CAS  Google Scholar 

  • Baumgartner D, Scholl-Bürgi S, Sass JO et al (2007) Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidema. J Pediatr 150:192–197

    Article  PubMed  Google Scholar 

  • Bayley JP, Devilee P (2010) Warburg tumours and the mechanism of mitochondrial tumour suppressor genes. Barking up at the right tree? Curr Opin Genet Dev 20:324–329

    Article  PubMed  CAS  Google Scholar 

  • Baysal BE, Ferrell RE, Willett-Brozick JE et al (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851

    Article  PubMed  CAS  Google Scholar 

  • Braissant O (2012) Creatine and guanidinoacetate transport at blood–brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis 35:655–664

    Article  PubMed  CAS  Google Scholar 

  • Brock M, Buckel W (2004) On the mechanism of action of the antifungal agent propionate. Propionyl-CoA inhibits glucose metabolism in Aspergillus nidulans. Eur J Biochem 271:3227–3241

    Article  PubMed  CAS  Google Scholar 

  • Brunengraber H, Roe CR (2006) Anaplerotic molecules: current and future. J Inherit Metab Dis 29:327–331

    Article  PubMed  Google Scholar 

  • Burlina AP, Danieli D, Malfa F et al (2012) Glutaric aciduria type I and glioma: first report in a young adult patient. J Inherit Metab Dis 35(Suppl 1):S58, abstract

    Google Scholar 

  • Chandler RJ, Venditti CP (2012) Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA). Mol Genet Metab 107:617–619

    Article  PubMed  CAS  Google Scholar 

  • Chandler RJ, Zerfas PM, Shanske S et al (2009) Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J 23:1252–1261

    Article  PubMed  CAS  Google Scholar 

  • Chapman KA, Summar ML, Enns GM (2012) Propionic acidemia: to liver transplant or not to liver transplant? Pediatr Transpl 16:209–210

    Article  Google Scholar 

  • Cheema-Dhadli S, Leznoff CC, Halperin ML (1975) Effect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduria. Pediatr Res 9:905–908

    PubMed  CAS  Google Scholar 

  • Chowdbury R, Yeoh KK, Tian YM et al (2012) The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 12:463–469

    Article  Google Scholar 

  • Cosson MA, Touati G, Lacaille F et al (2008) Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria. Mol Genet Metab 95:107–109

    Article  PubMed  CAS  Google Scholar 

  • Coude FX, Sweetman L, Nyhan WL (1979) Inhibition of propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest 64:1544–1551

    Article  PubMed  CAS  Google Scholar 

  • Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  PubMed  CAS  Google Scholar 

  • Danhauser K, Sauer SW, Haack TB et al (2012) DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. Am J Hum Genet 91:1082–1087

    Article  PubMed  CAS  Google Scholar 

  • Davison JE, Davies NP, Wilson M et al (2011) MR spectroscopy-based brain metabolite profiling in propionic acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation. Orphanet J Rare Dis 6:19

    Article  PubMed  Google Scholar 

  • De Keyzer Y, Valayannopoulos V, Benoist JF et al (2009) Multiple OXPHOS deficiency in liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95

    Article  PubMed  Google Scholar 

  • Dewar D, Underhill SM, Goldberg MP (2003) Oligodendrocytes and ischemic brain injury. J Cereb Blood Flow Metab 23:263–274

    Article  PubMed  Google Scholar 

  • Di Lisa F, Menabo R, Barbato R, Siliprandi N (1994) Contrasting effects of propionate and propionyl-L-carnitine on energy-linked processes in ischemic hearts. Am J Physiol 267:H455–461

    PubMed  Google Scholar 

  • Elpeleg O, Miller C, Hershkovitz E et al (2005) Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 76:1081–1086

    Article  PubMed  CAS  Google Scholar 

  • Harting I, Neumaier-Probst E, Seitz A et al (2009) Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain 132:1764–1782

    Article  PubMed  Google Scholar 

  • Hassel B, Brathe A, Petersen D (2002) Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate. J Neurochem 82:410–419

    Article  PubMed  CAS  Google Scholar 

  • Hayasaka K, Metoki K, Satoh T et al (1982) Comparison of cytosolic and mitochondrial enzyme alterations in the livers of propionic and methylmalonic acidemia: a reduction of cytochrome c oxidase activity. Tohoku J Exp Med 137:329–334

    Article  PubMed  CAS  Google Scholar 

  • Heringer J, Boy NPS, Ensenauer R et al (2010) Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 68:743–52

    Article  PubMed  Google Scholar 

  • Hoffmann GF, Kölker S (2010) Protein-dependent inborn errors of metabolism. In: Warrel DA, Cox TM, Firth JD (eds) Oxford Textbook of Medicine, 5th edn. Oxford University Press, Oxford, pp 1559–1595

    Chapter  Google Scholar 

  • Hoffmann GF, Kölker S (2011) Cerebral organic acid disorders and other disorders of lysine catabolism. In: Saudubray JM, van den Berghe G, Walter JH (eds) Inborn Metabolic Diseases, 5th edn. Springer, Berlin, pp 333–347

    Google Scholar 

  • Hoppel CL, Tandler B, Fujioka H, Riva A (2009) Dynamic organization of mitochondria in human heart and in myocardial disease. Int J Biochem Cell Biol 41:1949–1956

    Article  PubMed  CAS  Google Scholar 

  • Hörster F, Baumgartner MR, Viardot C et al (2007) Long-term outcome in methylmalonic aciduria is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res 62:225–230

    Article  PubMed  Google Scholar 

  • Hörster F, Garbade SF, Zwickler T et al (2009) Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis 32:630–639

    Article  PubMed  Google Scholar 

  • Kaelin WG Jr (2009) SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell 16:180–182

    Article  PubMed  CAS  Google Scholar 

  • Kasahara M, Sakamoto S, Kanazawa H et al (2012) Living-donor liver transplantation for propionic academia. Pediatr Transplant 16:230–234

    Article  PubMed  CAS  Google Scholar 

  • Koeller DM, Woontner M, Crnic LS et al (2002) Biochemical, pathologic and behavioral analysis of a mouse model of glutaric academia type I. Hum Mol Genet 11:347–357

    Article  PubMed  CAS  Google Scholar 

  • Kölker S, Köhr G, Ahlemeyer B et al (2002) Ca2+ and Na+ dependence Of 3-hydroxyglutarate-induced excitotoxicity in primary neuronal cultures from chick embryo telencephalons. Pediatr Res 52:199–206

    PubMed  Google Scholar 

  • Kölker S, Schwab M, Hörster F et al (2003) Methylmalonic acid, a biochemical hallmark of methylmalonic aciduria but no inhibitor of mitochondrial respiratory chain. J Biol Chem 278:47388–47393

    Article  PubMed  Google Scholar 

  • Kölker S, Koeller DM, Okun JG, Hoffmann GF (2004) Pathomechanisms of neurodegeneration in glutaryl-CoA dehydrogenase deficiency. Ann Neurol 55:7–12

    Article  PubMed  Google Scholar 

  • Kölker S, Sauer SW, Surtees RA, Leonard JV (2006a) The aetiology of neurological complications of organic acidaemias—A role for the blood–brain barrier. J Inherit Metab Dis 29:701–704

    Article  Google Scholar 

  • Kölker S, Garbade SF, Greenberg CR et al (2006b) Natural history, outcome and therapeutic efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59:840–847

    Article  Google Scholar 

  • Kölker S, Christensen E, Leonard JV et al (2011) Diagnosis and management of glutaric aciduria type I - revised recommendations. J Inherit Metab Dis 34:677–94

    Article  PubMed  Google Scholar 

  • Kölker S, Boy SP, Heringer J et al (2012) Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I—a decade of experience. Mol Genet Metab 107:72–80

    Article  PubMed  Google Scholar 

  • Komatsuzaki S, Sakamoto O, Fuse N, Uematsu M, Matsubara Y, Ohura T (2012) Clinical reasoning: a young man with progressive subcortical lesions and optic nerve atrophy. Neurology 79:e63–68

    Article  PubMed  Google Scholar 

  • Kossoff EH, Zupec-Kania BA, Amark PE et al (2009) Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia 50:304–317

    Article  PubMed  Google Scholar 

  • Krähenbühl S, Chang M, Brass EP, Hoppel CL (1991) Decreased activities of ubiquinol:ferricytochrome c oxidoreductase (complex III) and ferrocytochrome c oxygen oxidoreductase (complex IV) in liver mitochondria from rats with hydroxycobalamin[c-lactam]-induced methylmalonic aciduria. J Biol Chem 266:20998–21003

    PubMed  Google Scholar 

  • Kranendijk M, Struys EA, Salomons GS, van der Knaap MS, Jakobs C (2012a) Progress in understanding D-2-hydroxyglutaric acidurias. J Inherit Metab Dis 35:571–587

    Article  CAS  Google Scholar 

  • Kranendijk M, Struys EA, van Schaftingen E et al (2012b) IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:336

    Article  Google Scholar 

  • Külkens S, Harting I, Sauer S et al (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64:2142–2144

    Article  PubMed  Google Scholar 

  • Kyllerman M, Skjeldal O, Christensen E et al (2004) Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1. Eur J Paediatr Neurol 8:121–129

    Article  PubMed  Google Scholar 

  • Lamp J, Keyser B, Koeller DM, Ullrich K, Braulke T, Mühlhausen C (2011) Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem 285:17777–17784

    Article  Google Scholar 

  • Marquard J, el Scheich T, Klee D et al (2011) Chronic pancreatitis in branched-chain organic acidurias—a case of methylmalonic aciduria and an overview of the literature. Eur J Pediatr 170:241–245

    Article  PubMed  Google Scholar 

  • Meyburg J, Hoffmann GF (2005) Liver transplantation for inborn errors of metabolism. Transplantation 80(Suppl 1):S135–137

    Article  PubMed  Google Scholar 

  • Mirandola SR, Melo DR, Schuck PF, Ferreira GC, Wajner M, Castilho RF (2008) Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake. J Inherit Metab Dis 31:44–54

    Article  PubMed  CAS  Google Scholar 

  • Mitchell IJ, Cooper AJ, Griffiths MR (1999) The selective vulnerability of striatopallidal neurons. Prog Neurobiol 59:691–719

    Article  PubMed  CAS  Google Scholar 

  • Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I (2008) Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab 94:4–15

    Article  PubMed  CAS  Google Scholar 

  • Morath MA, Okun JG, Müller IB et al (2008) Neurodegeneration and chronic renal failure in methylmalonic aciduria—a pathophysiological approach. J Inherit Metab Dis 31:35–43

    Article  PubMed  CAS  Google Scholar 

  • Moroni I, Bugiani M, D’Incerti L et al (2004) L-2-hydroxyglutaric aciduria and brain malignant tumours: a predisposing condition ? Neurology 62:1882–1884

    Article  PubMed  CAS  Google Scholar 

  • Neumaier-Probst E, Harting I, Seitz A, Ding C, Kölker S (2004) Neuroradiological findings in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27:869–876

    Article  PubMed  CAS  Google Scholar 

  • Nguyen NHT, Morland C, Gonzalez SV et al (2007) Propionate increases neuronal histone acetylation, but is metabolized oxidatively via glia. Relevance for propionic acidemia. J Neurochem 101:806–814

    Article  PubMed  CAS  Google Scholar 

  • Nyhan WL, Barshop BA, Ozand PT (2005a) Propionic acidemia. In: Nyhan WL, Barshop BA, Ozand PT (eds) Atlas of metabolic diseases, 2nd edn. Hodder Education, London, pp 8–17

    Google Scholar 

  • Nyhan WL, Barshop BA, Ozand PT (2005b) Methylmalonic acidemia. In: Nyhan WL, Barshop BA, Ozand PT (eds) Atlas of metabolic diseases, 2nd edn. Hodder Education, London, pp 18–29

    Google Scholar 

  • O’Shea CJ, Sloan JL, Wiggs EA et al (2012) Neurocognitive phenotype of isolated methylmalonic aciduria. Pediatrics 129:e1541

    Article  PubMed  Google Scholar 

  • Oberholzer VG, Levin B, Burgess A, Young WF (1967) Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child 42:482–504

    Article  Google Scholar 

  • Ohtsuki S (2004) New aspects of the blood–brain barrier transporters: its physiological roles in the central nervous system. Biol Pharm Bull 27:1489–1496

    Article  PubMed  CAS  Google Scholar 

  • Okun JG, Hörster F, Farkas LM et al (2002) Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity. J Biol Chem 277:14674–14680

    PubMed  CAS  Google Scholar 

  • Ostergaard E, Hansen FJ, Sorensen N et al (2007) Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 130:853–861

    Article  PubMed  Google Scholar 

  • Pardridge WM (1998) Blood–brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 23:635–644

    Article  PubMed  CAS  Google Scholar 

  • Pearl PL, Gibson KM, Acosta MT et al (2003) Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 60:1413–1417

    Article  PubMed  CAS  Google Scholar 

  • Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32:1152–1566

    Article  PubMed  CAS  Google Scholar 

  • Pena L, Franks J, Chapman KA et al (2011) Natural history of propionic acidemia. Mol Genet Metab 105:5–9

    Article  PubMed  Google Scholar 

  • Prada CE, Al Jasmi F, Kirk EP et al (2011) Cardiac disease in methylmalonic acidemia. J Pediatr 159:862–864

    Article  PubMed  Google Scholar 

  • Reitman ZJ, Yan H (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102:932–941

    Article  PubMed  CAS  Google Scholar 

  • Romano S, Valayannopoulos V, Touati G et al (2010) Cardiomyopathies in propionic aciduria are reversible after liver transplantation. J Pediatr 156:128–134

    Article  PubMed  Google Scholar 

  • Rothman SM, Olney JW (1995) Excitotoxicity and the NMDA receptor—still lethal after eight years. Trends Neurosci 18:57–58

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Okun JG, Schwab MA et al (2005) Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency, a role for glutaryl-coenzyme A. J Biol Chem 280:21830–21836

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Okun JG, Fricker G et al (2006) Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood–brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97:899–910

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Okun JG, Hoffmann GF, Kölker S, Morath MA (2008) Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism. Biochim Biophys Acta 1777:1276–1282

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Opp S, Haarmann A, Okun JG, Kölker S, Morath MA (2010a) Long-term exposure of human proximal tubule cells to hydroxycobalamin[c-lactam] as a possible model to study renal disease in methylmalonic acidurias. J Inherit Metab Dis 32:720–727

    Article  Google Scholar 

  • Sauer SW, Opp S, Mahringer A et al (2010b) Glutaric aciduria type I and methylmalonic aciduria: stimulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood–brain barrier and the choroid plexus. Biochem Biophys Acta 1802:551–560

    Google Scholar 

  • Sauer SW, Opp S, Hoffmann GF, Koeller DM, Okun JG, Kölker S (2011) Therapeutic modulation of cerebral L-lysine metabolism in a mouse model for glutaric aciduria type I. Brain 134:157–70

    Article  PubMed  Google Scholar 

  • Schousboe A, Westergaard N, Waagepetersen HS, Larsson OM, Barken IJ, Sonnewald U (1997) Trafficking between glia and neurons of TCA cycle intermediates and related metabolites. Glia 21:99–105

    Article  PubMed  CAS  Google Scholar 

  • Schwab MA, Sauer SW, Okun JG et al (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398:107–112

    Article  PubMed  CAS  Google Scholar 

  • Segel R, Anikster Y, Zevin S et al (2011) A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab 103:203–206

    Article  PubMed  CAS  Google Scholar 

  • Sokoloff L (1960) The metabolism of the central nervous system in vivo. In: Field J, Magoun HW, Hall VE (eds) Handbook of Physiology, Sect 1, vol II. Raven, New York, pp 161–168

    Google Scholar 

  • Steenweg ME, Salomons GS, Yapici Z et al (2009) L-2-hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology 251:856–865

    Article  PubMed  Google Scholar 

  • Steenweg ME, Jakobs C, Errami A et al (2010) Am overview on L-2-hydroxyglutarate dehydrogenase gene variants (L2HGDH): a genotype-phenotype study. Hum Mutat 31:380–390

    Article  PubMed  CAS  Google Scholar 

  • Strauss KA, Donnelly P, Wintermark M (2010) Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain 133:76–92

    Article  PubMed  Google Scholar 

  • Strauss KA, Brumbaugh J, Duffy A et al (2011) Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: focus on cerebral amino acid influx. Mol Genet Metab 104:93–106

    Article  PubMed  CAS  Google Scholar 

  • Sumegi B, Podanyi B, Forgo P, Kover KE (1995) Metabolism of [3-13C]pyruvate and [3-13C]propionate in normal ischaemic rat heart in vivo: 1H- and 13C-NMR studies. Biochem J 312:75–61

    PubMed  CAS  Google Scholar 

  • Sutton VR, Chapman KA, Gropman AL et al (2012) Chronic management and health supervision of individuals with propionic acidemia. Mol Genet Metab 105:26–33

    Article  PubMed  CAS  Google Scholar 

  • Topcu M, Aydin OF, Yalcinkaya C et al (2005) L-2-hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr 47:1–7

    PubMed  Google Scholar 

  • Traber G, Baumgartner MR, Schwarz U, Pangalu A, Donath MY, Landau K (2011) Subacute bilateral visual loss in methylmalonic acidemia. J Neuroophthalmol 31:344–346

    Article  PubMed  Google Scholar 

  • Wajner M, Goodmann SI (2011) Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. J Bioenerg Biomembr 43:31–38

    Article  PubMed  CAS  Google Scholar 

  • Williams Z, Hurley PE, Altiparmak UE et al (2009) Late onset optic neuropathy in methymalonic and propionic acidemia. Am J Ophthalmol 147:929–933

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Yang H, Liu Y et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30

    Article  PubMed  CAS  Google Scholar 

  • Yodoya E (2006) Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary cultured cerebral astrocytes and neurons. J Neurochem 97:162–173

    Article  PubMed  CAS  Google Scholar 

  • Zinnanti WJ, Lazovic J, Housman C et al (2007) Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest 117:3258–3270

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements and funding

Cited studies conducted by the Heidelberg team are supported by grants from the German Research Community (to S. W. S.), Kindness for Kids Foundation, Munich, Germany (to SK), and the European Union(project E-IMD) in the framework of the Health Programme 2008–2013 (to SK). The authors declare no conflict of interest and confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Division of Inherited Metabolic Diseases, Centre for Child and Adolescent Medicine, Clinic I, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Stefan Kölker, Peter Burgard, Sven W. Sauer & Jürgen G. Okun

Authors
  1. Stefan Kölker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Burgard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sven W. Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jürgen G. Okun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan Kölker.

Additional information

Communicated by: Gregory Enns

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kölker, S., Burgard, P., Sauer, S.W. et al. Current concepts in organic acidurias: understanding intra- and extracerebral disease manifestation. J Inherit Metab Dis 36, 635–644 (2013). https://doi.org/10.1007/s10545-013-9600-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-013-9600-8

Keywords

Search

Navigation