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Previous Volume 341:1037-1044 September 30, 1999 Number 14 Next

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ABSTRACT

Background The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy.

Methods We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene.

Results We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (nucleotides 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All the point mutations involved the substitution of adenine for guanine, but all were in different locations.

Conclusions The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance.

Source Information

From the H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Department of Neurology, Columbia College of Physicians and Surgeons, New York (A.L.A., C.B., K.T., F.P., E.B., S.D.); Centre d'Investigacions en Bioquimica i Biologia Molecular, Hospitals Vall d'Hebron, Barcelona, Spain (A.L.A.); the Institute of Neurology, University College London, London (M.G.H., J.M.-H.); Neurologischen Universitaetsklinik, Universitaetsklinikum Carl Gustav Carus der Technischen Universitat Dresden, Dresden, Germany (H.R.); the Department of Pediatrics, Istituto G. Gaslini, Universitá di Genova, Genova, Italy (C.B.); the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md. (A.S.P.); the Department of Biochemistry, Uppsala Universitet, Uppsala, Sweden (S.I.); and the Department of Laboratory Medicine, Ottawa Hospital, Ottawa, Ont., Canada (B.L.). Other authors were Sara Shanske, Ph.D., and Carolyn M. Sue, M.D., H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Department of Neurology, Columbia College of Physicians and Surgeons, New York; Teeratorn Pulkes, M.D., Asra Siddiqui, M.R.C.P., John B. Clark, Ph.D., and John Land, Ph.D., the Institute of Neurology, University College London, London; Momi Iwata, Ph.D., the Department of Biochemistry, Uppsala Universitet, Uppsala, Sweden; and Jochen Schaefer, M.D., Neurologischen Universitaetsklinik, Universitaetsklinikum Carl Gustav Carus der Technischen Universitat Dresden, Dresden, Germany.

Address reprint requests to Dr. DiMauro at 4-420 College of Physicians & Surgeons, 630 W. 168th St., New York, NY 10032, or at sd12{at}columbia.edu.

Full Text of this Article

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Mitochondrial Disease in Patients with Exercise Intolerance
Vladutiu G. D., Tabone E., Miró OÒs., Grav J. M., Casademont J., Andreu A., DiMauro S., Griggs R. C., Karpati G.
Extract | Full Text  
N Engl J Med 2000; 342:438-440, Feb 10, 2000. Correspondence

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