Muscle biopsies from four infants with fatal myopathy and four with benign myopathy were examined using biochemical, histochemical and immunohistochemical techniques in the Departments of Neurology, Pathology and Genetics, Columbia University, New York; Universita Cattolica del Sacro Cuore, Rome, Italy; and Fachbereich Chemie, Philipps-Universitat, Marburg, Germany. At early stages the clinical picture failed to provide clues for differential diagnosis; both fatal and benign myopathies presented with hypotonia, generalized weakness, lactic acidosis, failure to thrive and severe respiratory insufficiency, often requiring assisted ventilation. Patients with benign myopathy gain strength and show an increase in the number of fibers with COX (cytochrome c oxidase) deficient activity. In contrast, patients with fatal myopathy die before one year of age and muscle histochemistry shows no increase in the number of fibers with COX activity. The subunit composition of COX was studied directly on frozen muscle sections using immunologic probes. The fatal type was characterized by absence of the nuclear DNA-encoded subunit VIIa,b of COX while in the benign myopathy both VIIa,b and the mitochondrial DNA-encoded subunit II were absent. From a practical standpoint, immunohistochemistry of COX-II should suffice for differential diagnosis because this subunit was present in the fatal myopathy but absent in the early stages of the benign myopathy. 
COMMENT. The diagnosis of COX-deficient myopathies of infancy relies on histochemical and biochemical evaluation of COX activities in muscle biopsies. These tests fail to distinguish the fatal and benign phenotypes at early stages because both show lack of COX activity. COX is a complex enzyme composed of 13 subunits with three larger subunits (I, II and III) which are synthesized in the mitochondria and the ten smaller subunits manufactured in the cytoplasm. COX VIIa,b is absent in the fatal myopathy and both COX-II and COX VIIa,b are absent in the early stages of benign myopathy. Thus, the immunohistochemistry of COX-II is sufficient for the differential diagnosis.