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

• Published in: Human molecular genetics 2002-02, Vol.11 (4), p.347-357
• Main Authors: KOELLER, David M, WOONTNER, Michael, CRNIC, Linda S, KLEINSCHMIDT-DEMASTERS, Bette, STEPHENS, Janet, HUNT, Edgar L, GOODMAN, Stephen I
• Format: Article
• Language: English
• Subjects: Amino Acid Metabolism, Inborn Errors - blood; Amino Acid Metabolism, Inborn Errors - genetics; Animals; Behavior, Animal; Biological and medical sciences; Brain - metabolism; Classical genetics, quantitative genetics, hybrids; Corpus Striatum - metabolism; Corpus Striatum - ultrastructure; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Gcdh gene; Gene Targeting; Genetics of eukaryotes. Biological and molecular evolution; Glutarates - blood; glutaric acidemia; Glutaryl-CoA Dehydrogenase; Humans; Mice; Oxidoreductases - deficiency; Oxidoreductases - genetics; Oxidoreductases - physiology; Oxidoreductases Acting on CH-CH Group Donors; Phenotype; Vertebrata
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/11.4.347

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.