Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics.

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 nuclearly 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.

Peripheral nerve vasculitis: immune characterization of the vascular lesions.

Quantitative immunohistochemical analyses were performed on 22 nerve biopsy specimens from patients with systemic vasculitis (n = 14) or isolated vasculitis of peripheral nerve (n = 8). In the vascular lesions the cellular infiltrates were composed primarily of T cells (71 +/- 18%; mean +/- SD) and macrophages (27 +/- 17%), and the majority of the T cells (65 +/- 20%) were cytotoxic/suppressor CD8 cells. B cells were seen in only 4 cases and constituted less than 2% of all cells. Natural killer cells and polymorphonuclear leukocytes were rare, and a leukocytoclastic response was not observed. Fourteen biopsy specimens had vascular deposits of immunoglobulins G and M and complement components C3 and C5b-9 membrane attack complex, while 4 had only the latter. The fact that the immunoglobulin and complement deposits were seen only in vessels that had corresponding intense cellular infiltrates suggests an important, but perhaps not primary, role for immune complexes in causing the vascular lesions. Statistical analysis revealed striking similarities in the lesions of patients with isolated nerve vasculitis and those with systemic vasculitides, suggesting a common pathogenic mechanism. Collectively, our observations suggest an important role for a T-cell-dependent cell-mediated process as a primary mechanism of vessel injury in peripheral nerve vasculitis.