Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen

Neuropediatrics. 2003 Jun;34(5):253-60. doi: 10.1055/s-2003-43261.

Abstract

The neurometabolic disorder glutaryl-CoA dehydrogenase (GCDH) deficiency is biochemically characterised by an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid, and glutarylcarnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, in particular the putamen. 3-hydroxyglutaric acid is considered the major neurotoxin in this disease. There are only preliminary data concerning glutaric acid concentrations in the brains of affected children and the distribution of 3-hydroxyglutaric acid and glutarylcarnitine has not been described. In the present study, we investigated post mortem the distribution of 3-hydroxyglutaric and glutaric acids as well as glutarylcarnitine in 14 different brain regions, internal organs, and body fluids (urine, plasma, cerebrospinal fluid) in a 14-year-old boy. 3-Hydroxyglutaric acid showed the highest concentration (62 nmol/g protein) in the putamen among all brain areas investigated. The glutarylcarnitine concentration was also highest in the putamen (7.1 nmol/g protein). We suggest that the regional-specific differences in the relative concentrations of 3-hydroxyglutaric acid contribute to the pattern of neuronal damage in this disease. These results provide an explanatory basis for the high vulnerability of the putamen in this disease, adding to the strong corticostriatal glutamatergic input into the putamen and the high excitotoxic susceptibility of neostriatal medium spiny neurons.

Publication types

  • Case Reports

MeSH terms

  • Acidosis / metabolism
  • Acute Disease
  • Adolescent
  • Anticonvulsants / therapeutic use
  • Atrophy / pathology
  • Brain / enzymology
  • Brain / metabolism*
  • Carnitine* / analogs & derivatives*
  • Carnitine* / blood
  • Carnitine* / cerebrospinal fluid
  • Carnitine* / metabolism*
  • Carnitine* / urine
  • DNA Mutational Analysis
  • Fatal Outcome
  • Gas Chromatography-Mass Spectrometry
  • Gene Expression / genetics
  • Glutarates* / blood
  • Glutarates* / cerebrospinal fluid
  • Glutarates* / urine
  • Glutaryl-CoA Dehydrogenase
  • Humans
  • Male
  • Muscle Hypotonia / diagnosis
  • Muscle Hypotonia / drug therapy
  • Muscle Hypotonia / metabolism
  • N-Methylaspartate / metabolism*
  • Oxidoreductases Acting on CH-CH Group Donors / deficiency*
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Point Mutation / genetics
  • Putamen / metabolism*
  • Putamen / pathology*
  • Spasm / drug therapy
  • Spasm / metabolism
  • Vigabatrin / therapeutic use

Substances

  • 3-hydroxyglutaric acid
  • Anticonvulsants
  • Glutarates
  • acylcarnitine
  • glutarylcarnitine
  • N-Methylaspartate
  • Oxidoreductases Acting on CH-CH Group Donors
  • Glutaryl-CoA Dehydrogenase
  • Vigabatrin
  • glutaric acid
  • Carnitine