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

S. Kölker; G. F. Hoffmann; D. S. M. Schor; P. Feyh; L. Wagner; I. Jeffrey; M. Pourfarzam; J. G. Okun; J. Zschocke; I. Baric; M. D. Bain; C. Jakobs; R. A. Chalmers

doi:10.1055/s-2003-43261

Neuropediatrics, Table of Contents

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. Kölker¹ , G. F. Hoffmann¹ , D. S. M. Schor² , P. Feyh¹ , L. Wagner³ , I. Jeffrey⁴ , M. Pourfarzam⁵ , J. G. Okun¹ , J. Zschocke¹ , I. Baric⁶ , M. D. Bain⁷ , C. Jakobs² , R. A. Chalmers⁷

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

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.

Key words

Glutaryl-CoA dehydrogenase - organic acids - acylcarnitines - putamen

Full Text

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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