Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type 1

David Koeller, Michael Woontner, Linda S. Crnic, Bette Kleinschmidt-Demasters, Janet Stephens, Edgar L. Hunt, Stephen I. Goodman

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Abstract

Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of amino acid metabolism resulting from a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients accumulate glutaric acid (GA) and 3-OH glutaric acid (3-OHGA) in their blood, urine and CSF. Clinically, GA-I is characterized by macrocephaly, progressive dystonia and dyskinesia. Degeneration of the caudate and putamen of the basal ganglia, widening of the Sylvian fissures, fronto-temporal atrophy and severe spongiform change in the white matter are also commonly observed. In this report we describe the phenotype of a mouse model of GA-I generated via targeted deletion of the Gcdh gene in embryonic stem cells. The Gcdh-/- mice have a biochemical phenotype very similar to human GA-I patients, including elevations of GA and 3-OHGA at levels similar to those seen in GA-I patients. The affected mice have a mild motor deficit but do not develop the progressive dystonia seen in human patients. Pathologically, the Gcdh-/- mice have a diffuse spongiform myelinopathy similar to that seen in GA-I patients. However, unlike in human patients, there is no evidence of neuron loss or astrogliosis in the striatum. Subjecting the Gcdh-/- mice to a metabolic stress, which often precipitates an encephalopathic crisis and the development of dystonia in GA-I patients, failed to have any neurologic effect on the mice. We hypothesize that the lack of similarity in regards to the neurologic phenotype and striatal pathology of GA-I patients, as compared with the Gcdh-/- mice, is due to intrinsic differences between the striata of mice and men.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalHuman Molecular Genetics
Volume11
Issue number4
StatePublished - Feb 15 2002

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Dystonia
Phenotype
Nervous System
Megalencephaly
Glutaric Acidemia I
Corpus Striatum
Physiological Stress
Putamen
Dyskinesias
Gene Deletion
Embryonic Stem Cells
Basal Ganglia
Atrophy
Urine
Pathology
Neurons
Amino Acids
glutaric acid

ASJC Scopus subject areas

  • Genetics

Cite this

Koeller, D., Woontner, M., Crnic, L. S., Kleinschmidt-Demasters, B., Stephens, J., Hunt, E. L., & Goodman, S. I. (2002). Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type 1. Human Molecular Genetics, 11(4), 347-357.

Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type 1. / Koeller, David; Woontner, Michael; Crnic, Linda S.; Kleinschmidt-Demasters, Bette; Stephens, Janet; Hunt, Edgar L.; Goodman, Stephen I.

In: Human Molecular Genetics, Vol. 11, No. 4, 15.02.2002, p. 347-357.

Research output: Contribution to journalArticle

Koeller, D, Woontner, M, Crnic, LS, Kleinschmidt-Demasters, B, Stephens, J, Hunt, EL & Goodman, SI 2002, 'Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type 1', Human Molecular Genetics, vol. 11, no. 4, pp. 347-357.
Koeller D, Woontner M, Crnic LS, Kleinschmidt-Demasters B, Stephens J, Hunt EL et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type 1. Human Molecular Genetics. 2002 Feb 15;11(4):347-357.
Koeller, David ; Woontner, Michael ; Crnic, Linda S. ; Kleinschmidt-Demasters, Bette ; Stephens, Janet ; Hunt, Edgar L. ; Goodman, Stephen I. / Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type 1. In: Human Molecular Genetics. 2002 ; Vol. 11, No. 4. pp. 347-357.
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