title: Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I.
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.
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, OR 97201, USA. koellerd@ohsu.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.forename: Linda S
authors.initials: LS
authors.lastname: Crnic
authors.forename: Bette
authors.initials: B
authors.lastname: Kleinschmidt-DeMasters
authors.forename: Janet
authors.initials: J
authors.lastname: Stephens
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Hunt
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood* / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D018390:Gene Targeting; D005977:Glutarates / Q000097:blood*; D050770:Glutaryl-CoA Dehydrogenase; D006801:Humans; D051379:Mice; D010088:Oxidoreductases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010641:Phenotype
chemical_list: D005977:Glutarates; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid