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

Hum Mol Genet. 2002 Feb 15;11(4):347-57. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / blood*
  • Amino Acid Metabolism, Inborn Errors / genetics
  • Animals
  • Behavior, Animal
  • Brain / metabolism
  • Corpus Striatum / metabolism
  • Corpus Striatum / ultrastructure
  • Disease Models, Animal
  • Gene Targeting
  • Glutarates / blood*
  • Glutaryl-CoA Dehydrogenase
  • Humans
  • Mice
  • Oxidoreductases / deficiency*
  • Oxidoreductases / genetics
  • Oxidoreductases / physiology
  • Oxidoreductases Acting on CH-CH Group Donors*
  • Phenotype


  • Glutarates
  • Oxidoreductases
  • Oxidoreductases Acting on CH-CH Group Donors
  • Glutaryl-CoA Dehydrogenase
  • glutaric acid