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Myoclonic epilepsy and ragged‐red fibers with cytochrome oxidase deficiency: Neuropathology, biochemistry, and molecular genetics
Author(s) -
Lombes Anne,
Mendell Jerry R.,
Nakase Hirofumi,
Barohn Richard J.,
Bonilla Eduardo,
Zeviani Massimo,
Yates Allan J.,
Omerza Jennifer,
Gales Tracy L.,
Nakahara Keichi,
Rizzuto Rosario,
Engel W. King,
Dimauro Salvatore
Publication year - 1989
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410260104
Subject(s) - cytochrome c oxidase , biology , microbiology and biotechnology , dentate nucleus , inferior olivary nucleus , cerebellum , myoclonic epilepsy , gliosis , mitochondrion , protein subunit , biochemistry , endocrinology , gene , epilepsy , neuroscience
A 36‐year‐old man with myoclonic epilepsy and ragged‐red fibers (MERRF) died after more than 18 years of follow‐up study. He was 1 of 3 affected siblings and the offspring of an affected mother, suggesting maternal transmission. At autopsy, there was neuronal loss and gliosis in the dentate nucleus of the cerebellum and in the inferior olivary nucleus. Skeletal muscle showed ragged‐red fibers, and paracrystalline inclusions in mitochondria by electron microscopy. Biochemical analysis showed a generalized partial defect of cytochrome c oxidase (COX) in mitochondria isolated from all tissues, including brain, heart, skeletal muscle, kidney, and liver. The Michaelis constant (Km) for cytochrome c was abnormally low, suggesting a defect of the mitochondrially encoded subunit II of COX. Immunological studies (enzyme‐linked immunosorbent assay, dot‐blot, Western blot, and immunohistochemistry) showed that the holoenzyme was decreased but subunit II was decreased more than the holocomplex or the nucleary encoded subunit IV. However, Northern and Southern blots showed that the gene for subunit II, as well as the genes for subunits I, III, IV, and VIII, were of normal size and were normally transcribed. A point mutation or a small deletion of mitochondrial DNA, probably affecting the COX‐II gene, may be responsible for the COX deficiency in this case of MERRF.