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
  • Adenosine Diphosphate/metabolism
  • Adenosine Triphosphate/metabolism
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromosome Mapping
  • Cloning, Molecular
  • Diet*
  • Disease Models, Animal
  • Embryo, Nonmammalian/physiology*
  • Fetal Death
  • Humans
  • Ketones/administration & dosage*
  • Ketones/therapeutic use
  • Lactates/metabolism
  • Molecular Sequence Data
  • Nervous System/embryology*
  • Nervous System Diseases/genetics
  • Nervous System Diseases/prevention & control
  • Pyruvate Dehydrogenase Complex/genetics*
  • Pyruvates/metabolism
  • Vision Disorders/genetics
  • Vision Disorders/prevention & control
  • Zebrafish/embryology*
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
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping