Cerebral Organic Acidurias

  • Stefan KölkerEmail author
  • Eduard A. Struys
  • Marjo S. van der Knaap
  • Cornelis Jakobs


A group of organic acidurias, including Canavan disease (N-acetylaspartic aciduria), glutaric aciduria type I, l-2-hydroxylgutaric aciduria and d-2-hydroxyglutaric aciduria types I and II, are characterised by a predominantly or even exclusively neurological presentation and have therefore been termed ‘cerebral’. Frequent neurological symptoms are motor and/or mental retardation or regression, extrapyramidal movement disorders and epilepsy. These symptoms are the result of acute and/or chronic pathological changes in various brain regions including grey matter (cortex, basal ganglia, cerebellum) and white matter (periventricular and subcortical). Unlike ‘classic’ organic acidurias (e.g. propionic and methylmalonic aciduria), acute metabolic decompensations with hyperammonemia, metabolic acidosis and elevated concentrations of lactate and ketone bodies are uncommon for cerebral organic acidurias. Biochemically, these diseases are characterised by accumulation of characteristic organic acids, mostly dicarboxylic acids, in body fluids. At high concentrations some of these may become neurotoxic. Since the blood–brain barrier has a low transport capacity for dicarboxylic acids, cerebral accumulation of dicarboxylic acids is facilitated. Impairment of brain energy metabolism is suggested to play a central role in the pathophysiology of this disease group. Metabolic treatment initiated in neonatally diagnosed patients with glutaric aciduria type I has significantly improved the neurological outcome, whereas current treatment strategies for the other cerebral organic acidurias are ineffective.


Glutaric Aciduria Type Canavan Disease Carnitine Supplementation Metabolic Treatment ASPA Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Assadi M, Janson C, Wan DJ et al (2010) Lithium citrate reduces excessive intracerebral N-acetylaspartate in Canavan disease. Eur J Paediatr Neurol 14:354–359PubMedCrossRefGoogle Scholar
  2. Gitiaux C, Roze E, Kinugawa K et al (2008) Spectrum of movement disorders associated with glutaric aciduria type 1: a study of 16 patients. Mov Disord 23:2392–2397PubMedCrossRefGoogle Scholar
  3. Harting I, Neumaier-Probst E, Seitz A et al (2009) Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain 132:1764–1782PubMedCrossRefGoogle Scholar
  4. Heringer J, Boy SPN, Ensenauer R et al (2010) Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 68:743–752PubMedCrossRefGoogle Scholar
  5. Kölker S, Garbade S, Greenberg CR et al (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59:840–847PubMedCrossRefGoogle Scholar
  6. Kölker S, Christensen E, Leonard JV et al (2011) Diagnosis and management of glutaric aciduria type I – revised recommendations. J Inherit Metab Dis 34:677–694PubMedCentralPubMedCrossRefGoogle Scholar
  7. Kranendijk M, Struys EA, Van Schaftingen E et al (2010) IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:336PubMedCrossRefGoogle Scholar
  8. Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C (2012) Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis 35(4):571–587PubMedCentralPubMedCrossRefGoogle Scholar
  9. Leone P, Janson CG, Bilanuk L et al (2000) Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 48:27–38PubMedCrossRefGoogle Scholar
  10. Matalon R, Michals K, Kaul R (1995) Canavan disease: from spongy degeneration to molecular analysis. J Pediatr 127:511–517PubMedCrossRefGoogle Scholar
  11. 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 constitutes a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97:899–910PubMedCrossRefGoogle Scholar
  12. Segel R, Anikster Y, Zevin S et al (2011) A safety trial of high glucose triacetate for Canavan disease. Mol Genet Metab 103:203–206PubMedCrossRefGoogle Scholar
  13. Steenweg ME, Salomons GS, Yapici Z et al (2009) L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology 2009(251):856–865CrossRefGoogle Scholar
  14. Steenweg ME, Jakobs C, Errami A et al (2010) An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study. Hum Mutat 31:380–390PubMedCrossRefGoogle Scholar
  15. Struys EA, Verhoeven NM, Brunengraber H et al (2004) 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(1–3):115–120PubMedCrossRefGoogle Scholar
  16. Struys EA, Salomons GS, Achouri Y et al (2005) Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet 76:358–360PubMedCentralPubMedCrossRefGoogle Scholar
  17. Van Schaftingen E, Rzem R, Veiga-da-Cunha M (2009) L-2-hydroxyglutaric aciduria, a disorder of metabolite repair. J Inherit Metab Dis 32:135–142PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Stefan Kölker
    • 1
    Email author
  • Eduard A. Struys
    • 2
  • Marjo S. van der Knaap
    • 3
  • Cornelis Jakobs
    • 4
  1. 1.Division of Inborn Metabolic Diseases, Department of General PediatricsUniversity Children’s HospitalHeidelbergGermany
  2. 2.Metabolic Unit, Clinical ChemistryVUmc Medical CenterAmsterdamThe Netherlands
  3. 3.Department of Child Neurology, Neuroscience Campus AmsterdamVU University Medical CenterAmsterdamThe Netherlands
  4. 4.Department of Clinical Chemistry, PK 1X 014VU University Medical Center AmsterdamAmsterdamThe Netherlands

Personalised recommendations