Journal oj the Neurological Sciences, 102 ( 1991 ) 17-24 Elsevier JNS 03487 17 Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study Laurence A. Bindoff ~, Claude Desnuelle 2, Mark A. Birch-Machin 1, Jean-Francois Pellissier 3, Georges Serratrice 2, Charlotte Dravet 3, Michelle Bureau 3, Neil Howell 4 and Douglass M. Turnbull ~ ~ Division ~?[(Tinical Neuroscience and Human Metabolism Research Centre, University of Newcastle upon Tyne, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH (U.K.), 2Clinique des Maladies du SystOme Nerveux, CHU La Timone, 13385 Marseille Cedex 5 (France), 3Centre Saint Paul, 300 Bd. de Sainte Marguerite, 13009 Marseille (France), 4Department of Radiation Therapy, Biology Division, UniversiO' of Texas Medical Branch at Galveston, TX 77550-2780 (U.S.A.) (Received 15 June, 1990) (Revised, received 22 October, 1990) (Accepted 25 October, 1990) Key words." Respiratory chain; Mitochondrial encephalopathy; Mitochondrial DNA Summary We describe a young man with a progressive neurological disorder including myoclonus, mental retardation, muscle weakness and a mitochondrial myopathy (myoclonus epilepsy and ragged red fibres - MERRF). Multiple abnormalities of the mitochondrial respiratory chain in skeletal muscle are shown by direct measurement of the flux through the individual complexes, low-temperature redox spectroscopy and decreased immunodetectable subunits of complexes I and IV by immunoblotting. No abnormality of mitochondrial DNA was found. This is the first report of combined defects of complexes I, III and IV as a cause of this clinical syndrome. However, we propose that the occurrence of multiple respiratory chain defects may be more common than previously recognised and that this particular combination of defects, involving complexes I, III and IV, may be the predominant biochemical abnormality in MERRF. Introduction There is increasing interest in the multisystem diseases caused by defects of mitochondrial function. Such dis- orders are associated with a variety of clinical syndromes with little apparent correlation between clinical expression and biochemical defect. Many authors believe that the over- lap between the clinical syndromes is too great to permit clear distinction ; these have tended to employ generic terms such as mitochondrial myopathy (Petty et al. 1986) or mito- chondrial encephalomyopathy (Schapira etal. 1977; Pavlakis et al. 1988). Others have recognised a constancy of clinical associations and accepted classifications such as Kearns-Sayre syndrome (Rowland et al. 1983), Leigh's dis- ease (Leigh, 1951), mitochondrial encephalopathy lactic Correspondence to." D.M. Turnbull, MD, Division of Clinical Neuroscience, University of Newcastle upon Tyne, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K. Telephone: 091 222 6000 Ext. 7051: Fax: 091 222 7424. acidosis and stroke (MELAS; Pavlakis et al. 1984), and myoclonus epilepsy with ragged red fibres (MERRF; Fukuhara et al. 1980). Myoclonic epilepsy associated with abnormalities of skeletal muscle was first described by Tsairis et al. (1973). The acronym myoclonus epilepsy with ragged red fibres (MERRF) was suggested by Fukuhara (1983) when review- ing 8 additional cases. There have now been reports of over 30 patients with clinical features compatible with MERRF. Relatively few have been characterised biochemically, and in those who have been studied, no consistent abnormality has been associated with this clinical syndrome. We describe a patient with myoclonic epilepsy, mental retardation, ataxia, hearing loss and skeletal muscle involve- ment, in whom we have demonstrated multiple defects (complexes I, III and IV) of the mitochondrial respiratory chain. We suggest that multiple defects of the respiratory chain may be more common than previously recognised and that the combined defects of complexes I, Ill and IV may be the predominant biochemical abnormality causing MERRF. 0022-510X/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)