Infant mice with glutaric acidaemia type I have increased vulnerability to 3‐nitropropionic acid toxicity

Summary Glutaric acidaemia type I (GA I) is an inborn error of metabolism caused by a deficiency of glutaryl‐CoA dehydrogenase (GCDH) and is characterized clinically by striatal degeneration that almost always occurs in early childhood. A murine knockout model of GA I has the organic aciduria seen i...

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Bibliographic Details
Published inJournal of inherited metabolic disease Vol. 29; no. 5; pp. 612 - 619
Main Authors Bjugstad, K. B., Crnic, L. S., Goodman, S. I., Freed, C. R.
Format Journal Article
LanguageEnglish
Published Dordrecht Kluwer Academic Publishers 01.10.2006
Springer
Blackwell Publishing Ltd
Subjects
Animals
Animals, Newborn
Biological and medical sciences
Brain - pathology
Brain Diseases, Metabolic, Inborn - metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
General aspects
Glutarates - metabolism
Glutarates - urine
Humans
Medical genetics
Medical sciences
Metabolic diseases
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neurodegenerative Diseases - pathology
Nitro Compounds - pharmacology
Nitro Compounds - toxicity
Propionates - pharmacology
Propionates - toxicity
Nutrition
Toxicity
Rodentia
Metabolic diseases
Vulnerability
Young animal
Acidemia
Genetic disease
Vertebrata
Type
Mammalia
Acids
Mouse
Genetics
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Summary:Summary Glutaric acidaemia type I (GA I) is an inborn error of metabolism caused by a deficiency of glutaryl‐CoA dehydrogenase (GCDH) and is characterized clinically by striatal degeneration that almost always occurs in early childhood. A murine knockout model of GA I has the organic aciduria seen in the human disorder, but this model does not develop striatal degeneration spontaneously. 3‐Nitropropionic acid (3NP), a succinic dehydrogenase inhibitor with specificity for the striatum, was investigated as a potential initiator of striatal degeneration in GCDH‐deficient mice. This study shows that GCDH‐deficient mouse pups are more susceptible to 3NP than their wild‐type littermates, and that all mouse pups are more sensitive to 3NP as infants than as adolescents and adults. Increased sensitivity to 3NP early in life may model the developmental window for the striatal damage observed in human GA I.
Bibliography:Competing interests: None declared
Communicating editor: Georg Hoffmann
ObjectType-Article-1
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ISSN:0141-8955
1573-2665
DOI:10.1007/s10545-006-0102-9