The objectives of this study were to describe the course of two forms of an hereditary syndrome characterised by congenital cataract, mitochondrial myopathy of heart and skeletal muscle and lactic acidosis. We also sought to determine clinical, physicochemical and histopathological data which might allow early distinction between the two forms. We compared the ages at which clinical and physicochemical signs appeared in 16 patients. In 5 patients, enzyme-histochemical and ultrastructural data of skeletal muscle were available and muscle fibre composition analysed morphometrically. In any particular family only one form of the syndrome occurred. Amongst the patients who did not survive (range 14-34 years) 4 patients died in the neonatal period and 7 died at a median age of 23 years. The median age of the survivors was 19 years (range 15-42 years). Outflow obstruction of the left ventricle was noted in four deceased patients at variable times prior to death. The other deceased patients were not examined, but the cause of death was invariably heart failure. In none of the surviving patients was outflow obstruction noted. Enzyme-histochemical and ultrastructural findings were not specific for the course of the disease. In one biopsy, taken at the age of 3.5 months from a patient who survived, strong lipid accumulation was noted. Morphometric analysis showed proliferation of the mitochondria in muscle fibres, which increased during the course of the disease.

A six day old boy died from an hereditary hypertrophic cardiomyopathy which was associated with mitochondrial myopathy of skeletal muscle, congenital cataract and lactic acidosis. In heart and skeletal muscle identical mitochondrial abnormalities were found: paucity and abnormal arrangement of cristae, formation and extrusion of vesicle-like structures and crystalline inclusions in the matrix compartment. Electron-cytochemistry revealed that only part of the mitochondria reacted positively for cytochrome oxidase activity. Morphometric analysis indicated that the cardiomegaly was due to cellular hypertrophy, which might be caused by an increase in the mitochondrial mass. The cardiac hypertrophy in this syndrome can be classified histopathologically as mitochondrial hypertrophic cardiomyopathy.

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Muscle biopsies from 17 children with exercise intolerance and other miscellaneous symptoms and signs showed changes in mitochondrial content. The patients could not be classified according to known criteria. The histopathological changes were quantified by morphometric analysis and the clinical data were statistically analysed to detect intercorrelations. After a mean follow up period of 6.8 years (range 0.5-13.6), patients were re-examined and the course of the disease was determined. No clinical entity could be established. None of the patients showed aggravation of the exercise intolerance, but 71% noted no improvement. An increased volume density of peripheral mitochondria was shown in 59%. Based on clinical history, histopathological changes and course we suggest that some of these patients suffer from a yet unknown disturbance in energy metabolism. Recognition of these patients is important for appropriate counselling.

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