Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1782

Article

Keyser, Britta¹  Glatzel, Markus²  Stellmer, Franziska¹  Kortmann, Bastian¹  Lukacs, Zoltan¹  Koelker, Stefan³  Sauer, Sven W.³  Muschol, Nicole¹  Herdering, Wilhelm⁴  Thiem, Joachim⁵  Goodman, Stephen I.⁶  Koeller, David M.⁷  Ullrich, Kurt¹  Braulke, Thomas¹  Muehlhausen, Chris¹ 

[1] Univ Med Ctr Hamburg Eppendorf, Dept Biochem, Childrens Hosp, D-20246 Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Dept Neuropathol, D-20246 Hamburg, Germany

[3] Univ Childrens Hosp Heidelberg, Div Inherited Metab Dis, Dept Gen Pediat, D-69120 Heidelberg, Germany

[4] Univ Hamburg, Inst Inorgan & Appl Chem, D-20146 Hamburg, Germany

[5] Univ Hamburg, Inst Organ Chem, D-20146 Hamburg, Germany

[6] Univ Colorado, Hlth Sci Ctr Fitzsimons, Dept Pediat, Denver, CO 80220 USA

[7] Oregon Hlth & Sci Univ, Dept Pediat, CDRC, Portland, OR 97239 USA

关键词: radiolabeled metabolite;    glutaric aciduria type 1;    mouse model;    metabolite distribution;    glutaryl-CoA dehydrogenase deficiency;    metabolic crisis;   

DOI  :  10.1016/j.bbadis.2008.02.008

来源: Elsevier

【 摘 要 】

Glutaric aciduria type 1 (GA1) is caused by the deficiency of glutaryl-CoA dehydrogenase (GCDH). Affected patients are prone to the development of encephalopathic crises during an early time window with destruction of striatal neurons and a subsequent irreversible movement disorder. 3-Hydroxyglutaric acid (30HGA) accumulates in tissues and body fluids of GA1 patients and has been shown to mediate toxic effects on neuronal as well as endothelial cells. Injection of (H-3)-labeled into 6 week-old Gcdh(-/-) mice, a model of GAL revealed a low recovery in kidney, liver, or brain tissue that did not differ from control mice. Significant amounts of 30HGA were found to be excreted via the intestinal tract. Exposure of Gcdh(-/-) mice to a high protein diet led to an encephalopathic crisis, vacuolization in the brain, and death after 4-5 days. Under these conditions, high amounts of injected H-3-30HGA were found in kidneys of Gcdh(-/-) mice, whereas the radioactivity recovered in brain and blood was reduced. The data demonstrate that under conditions mimicking encephalopathic crises the blood-brain barrier appears to remain intact. (C) 2008 Elsevier B.V. All rights reserved.

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