Journal of Inherited Metabolic Disease

, Volume 36, Issue 4, pp 635–644 | Cite as

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

  • Stefan Kölker
  • Peter Burgard
  • Sven W. Sauer
  • Jürgen G. Okun
SSIEM Symposium 2012


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.


Premature Ovarian Failure Metabolic Decompensation Glutaric Aciduria Type Canavan Disease Organic Aciduria 
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.



Blood–brain barrier


Mitochondrial DNA


organic aciduria(s)


Reactive oxygen species


Tricarboxylic acid cycle


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



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Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Stefan Kölker
    • 1
  • Peter Burgard
    • 1
  • Sven W. Sauer
    • 1
  • Jürgen G. Okun
    • 1
  1. 1.Department of General Pediatrics, Division of Inherited Metabolic DiseasesCentre for Child and Adolescent Medicine, Clinic I, University Hospital HeidelbergHeidelbergGermany

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