Neuropediatrics 2003; 34(5): 253-260
DOI: 10.1055/s-2003-43261
Original Article

Georg Thieme Verlag Stuttgart · New York

Glutaryl-CoA Dehydrogenase Deficiency: Region-Specific Analysis of Organic Acids and Acylcarnitines in post mortem Brain Predicts Vulnerability of the Putamen

S. Kölker 1 , G. F. Hoffmann 1 , D. S. M. Schor 2 , P. Feyh 1 , L. Wagner 3 , I. Jeffrey 4 , M. Pourfarzam 5 , J. G. Okun 1 , J. Zschocke 1 , I. Baric 6 , M. D. Bain 7 , C. Jakobs 2 , R. A. Chalmers 7
  • 1University Children's Hospital, Division of Metabolic and Endocrine Diseases, Heidelberg, Germany
  • 2Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
  • 3Department of Neuropediatrics and Metabolic Diseases, University Children's Hospital, Marburg, Germany
  • 4Department of Histopathology, St George's Hospital, London, United Kingdom
  • 5Department of Child Health, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
  • 6Department of Paediatrics, University Hospital Center, Zagreb, Croatia
  • 7Paediatric Metabolism Unit, Department of Child Health, St. George's Hospital Medical School, University of London, London, United Kingdom
Further Information

Publication History

Received: March 25, 2003

Accepted after Revision: July 27, 2003

Publication Date:
04 November 2003 (online)

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.

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Prof. Dr. Georg F. Hoffmann

Division of Metabolic and Endocrine Disease
University Children's Hospital

Im Neuenheimer Feld 150

69120 Heidelberg

Germany

Email: Georg_Hoffmann@med.uni-heidelberg.de

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