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Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism

  • SSIEM Symposium 2007
  • Published:
Journal of Inherited Metabolic Disease

Summary

Inherited disorders of amino and organic acid metabolism have a high cumulative frequency, and despite heterogeneous aetiology and varying clinical presentation, the manifestation of neurological disease is common. It has been demonstrated for some of these diseases that accumulating pathological metabolites are directly involved in the manifestation of neurological disease. Various pathomechanisms have been suggested in different in vitro and in vivo models including an impairment of brain energy metabolism, an imbalance of excitatory and inhibitory neurotransmission, altered transport across the blood–brain barrier and between glial cells and neurons, impairment of myelination and disturbed neuronal efflux of metabolic water. This review summarizes recent knowledge on pathomechanisms involved in phenylketonuria, glutaric aciduria type I, succinic semialdehyde dehydrogenase deficiency and aspartoacylase deficiency with examples, highlighting general as well as disease-specific concepts and their putative impact on treatment.

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Abbreviations

CD:

Canavan–van Bogaert–Bertrand disease

CNS:

central nervous system

GA I:

glutaric aciduria type I

IEM:

inborn error of metabolism

LNAA:

large neutral amino acid

NAA:

N-acetyl-l-aspartate

OAD:

organic aciduria

PKU:

phenylketonuria

SSADH:

succinic semialdehyde dehydrogenase

TCA cycle:

tricarboxylic acid cycle

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Authors and Affiliations

  1. Department of General Pediatrics, Division of Inherited Metabolic Disease, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 153, D-69120, Heidelberg, Germany

    S. Kölker, S. W. Sauer, G. F. Hoffmann, I. Müller, M. A. Morath & J. G. Okun

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  1. S. Kölker
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  2. S. W. Sauer
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  3. G. F. Hoffmann
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  4. I. Müller
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Correspondence to S. Kölker.

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Communicating editor: Michael Gibson

Competing interests: None declared

References to electronic databases: Phenylketonuria: OMIM #261600. Glutaric aciduria type I: OMIM #231670. Succinic semialdehyde dehydrogenase deficiency: OMIM #271980. Aspartoacylase disease (Canavan–van Bogaert–Bertrand disease): OMIM #271900. Phenylalanine hydroxylase: EC 1.14.16.1. Glutaryl-CoA dehydrogenase: EC 1.3.99.7. Succinic semialdehyde dehydrogenase: EC 1.2.1.16. Aspartoacylase: EC 3.5.1.15.

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Kölker, S., Sauer, S.W., Hoffmann, G.F. et al. Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. J Inherit Metab Dis 31, 194–204 (2008). https://doi.org/10.1007/s10545-008-0823-z

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  • DOI: https://doi.org/10.1007/s10545-008-0823-z

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