CHRONIC PROGRESSIVE MYOPATHY WITH MYOGLOBINURIA: DEMONSTRATION OF A GLYCOGENOLYTIC DEFECT IN THE MUSCLE*

Abstract

Clinical manifestations and laboratory investigations of a 54-year-old male patient who had suffered for the past 35 years from chronic, progressive myopathy are reported. The outstanding feature of this patient was his inability to perform moderate degrees of muscular exercise, even over short periods of time, whereas minimal muscular work was tolerated almost without limitations. Moderate exercise of a few seconds'' duration resulted in prolonged, painful cramps of the involved muscle groups, associated with tissue necrosis and transient myoglobinuria. Exercise and ischemic exercise, sufficient in extent to produce a cramp, failed to result in the expected rise in venous lactate concentration. This finding suggested a defect involving the glycolytic mechanism in the muscle. Glycogen content of the muscle was found to be increased approximately 5 times; in spite of this, incubation of muscle homog-enate produced 4 times less lactate than control preparations. This defect could be corrected by addition of crystalline phosphorylase. With glucose-1-phosphate as substrate, lactate formation in the patient''s muscle was comparable to that of control preparations. These observations suggested that the disturbance involved the phosphorylase system, which catalyzes the breakdown of glycogen to glucose-1-phosphate. In the patient''s muscle, phosphorylase activity was found to be absent, even in the presence of adenylic acid or after preincuba-tion of tissue with epinephrine. Treatment of the patient with epineph-rine or glucagon resulted in hyperglycemia and increased serum lactate levels, associated with marked reduction in serum phosphorus. Infusion of glucose and insulin produced increased venous lactate concentration and reduced serum levels of phosphorus and non-esterified fatty acids. Associated with this was a marked increase in exercise tolerance. These findings indicate a defect in the phosphorylase system of the muscle, which precludes breakdown of glycogen and eliminates anaerobic glycogenolysis as a source of energy for muscular contraction. Muscular work is limited by the energy which can be derived from nutrients diffusing from the blood into the muscle cell. Contraction beyond these limits results in cramps, muscle necrosis and myoglobinuria.