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Deficiency of pyruvate dehydrogenase complex (PDHC) in Leigh's disease fibroblasts

An abnormality in lipoamide dehydrogenase affecting PDHC activation

Department of Neurology, Cornell University Medical College, Burke Rehabilitation Center, White Plains, NY (Drs. Hinman, Sheu, and Blass, and Ms. Baker)
Department of Medicine, Cornell University Medical College, New York, NY. (Dr. Kim)

Several groups have reported abnormalities of the pyruvate dehydrogenase complex (PDHC) in cultured cells or other tissues from patients with Leigh's disease (subacute necrotizing encephalomyelopathy). We therefore undertook studies to elucidate the molecular basis of the defect of PDHC in cultured skin fibroblasts from two patients with Leigh's disease. The deficit of total PDHC activity in homogenates of Leigh's disease fibroblasts could be restored by adding exogenous lipoamide dehydrogenase (LAD, E₃), the third component of PDHC. The LAD in these Leigh's disease cells had a markedly reduced ability (< 20% of normal LAD) to reconstitute with other PDHC components to form active enzyme complex. A polyclonal antibody to pig heart LAD inhibited LAD activity in control cells more efficiently than in Leigh's disease cells. Other mitochondrial enzyme activities and growth of these two Leigh's disease cells appeared normal. These results suggest that the deficiency of PDHC in these two patients with Leigh's disease was due to a structural abnormality of the LAD component of PDHC.

Address correspondence and reprint requests to Dr. Hinman, Medical Research Division, Lederle Laboratories, Pearl River, NY 10965.

Supported in part by the Will Rogers Institute and the Winifred Masterson Burk Relief Foundation, and grants from NIH (NS15125 and AG03853), March of Dimes Birth Defect Foundation (#6-406), and the Muscular Dystrophy Foundation.

A preliminary report of part of this work appears as an abstract (Clin Res 1984; 32: 492A).

Received September 30, 1987. Accepted for publication in final form June 22, 1988.

This article has been cited by other articles:

				M. L. Grunnet, E. L. Zalneraitis, B. S. Russman, and M. C. Barwick Juvenile Leigh's Encephalomyelopathy With Peripheral Neuropathy, Myopathy, and Cardiomyopathy J Child Neurol, April 1, 1991; 6(2): 159 - 163. [Abstract] [PDF]