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Human Molecular Genetics, 2002, Vol. 11, No. 4 347-357
© 2002 Oxford University Press

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

David M. Koeller1,+, Michael Woontner2, Linda S. Crnic2,3, Bette Kleinschmidt-DeMasters4,5, Janet Stephens5, Edgar L. Hunt5 and Stephen I. Goodman2

1Departments of Pediatrics and Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA, and 2Department of Pediatrics, 3Department of Psychiatry, 4Department of Neurology and 5Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262, USA

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.

+ To whom correspondence should be addressed. Tel: +1 503 494 2783; Fax: +1 503 494 2781; Email: koellerd@ohsu.edu


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