PUBLICATION

A zebrafish model for pyruvate dehydrogenase deficiency: Rescue of neurological dysfunction and embryonic lethality using a ketogenic diet

Authors
Taylor, M.R., Hurley, J.B., Van Epps, H.A., and Brockerhoff, S.E.
ID
ZDB-PUB-040319-7
Date
2004
Source
Proceedings of the National Academy of Sciences of the United States of America   101(13): 4584-4589 (Journal)
Registered Authors
Brockerhoff, Susan, Hurley, James B., Taylor, Michael, Van Epps, Heather
Keywords
none
MeSH Terms
  • Chromosome Mapping
  • Fetal Death
  • Animals
  • Molecular Sequence Data
  • Pyruvate Dehydrogenase Complex/genetics*
  • Adenosine Triphosphate/metabolism
  • Disease Models, Animal
  • Humans
  • Amino Acid Sequence
  • Lactates/metabolism
  • Cloning, Molecular
  • Diet*
  • Zebrafish/embryology*
  • Embryo, Nonmammalian/physiology*
  • Nervous System Diseases/genetics
  • Nervous System Diseases/prevention & control
  • Pyruvates/metabolism
  • Nervous System/embryology*
  • Vision Disorders/genetics
  • Vision Disorders/prevention & control
  • Base Sequence
  • Ketones/administration & dosage*
  • Ketones/therapeutic use
  • Adenosine Diphosphate/metabolism
(all 24)
PubMed
15070761 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Defects in the pyruvate dehydrogenase (PDH) complex result in severe neurological dysfunction, congenital lactic acidosis, growth retardation, and early death. Current treatments for PDH deficiency are administered postnatally and are generally unsuccessful. Because many patients with this disease are born with irreversible defects, a model system for the development of effective pre- and postnatal therapies would be of great value. In a behavioral genetic screen aimed to identify zebrafish with visual function defects, we previously isolated two alleles of the recessive lethal mutant no optokinetic response a (noa). Here we report that noa is deficient for dihydrolipoamide S-acetyltransferase (Dlat), the PDH E2 subunit, and exhibits phenotypes similar to human patients with PDH deficiency. To rescue the deficiency, we added ketogenic substrates to the water in which the embryos develop. This treatment successfully restored vision, promoted feeding behavior, reduced lactic acidosis, and increased survival. Our study demonstrates an approach for establishing effective therapies for PDH deficiency and other congenital diseases that affect early embryonic development.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a13
    Point Mutation
    m631
      Point Mutation
      1 - 2 of 2
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      Human Disease / Model
      Sequence Targeting Reagents
      No data available
      Fish
      1 - 2 of 2
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      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      No data available
      Mapping
      Entity Type Entity Symbol Location
      ESTfc14f10Chr: 21 Details
      ESTfc47a05Chr: 21 Details
      Featurea13Chr: 21 Details
      GENEzbtb16aChr: 21 Details
      STSchunp69Chr: 21 Details
      1 - 5 of 5
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