Systematic Diagnosis of Myopathy due to Muscle Glycogenosis

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Patients with skeletal muscle glycogenosis complain without exception of high fatigability and markedly lowered tolerance against muscular exercise. However, these are not specific for muscle glycogenosis; similar symptoms are often accompanied with other myopathies or even with simple fatigue. This study was undertaken in order to establish the method how to differentiate muscle glycogenosis from other myopathies and to diagnose muscle glycogenosis systematically. Since two types of muscle glycogenosis, phosphofructokinase deficiency and phosphorylase deficiency, have been so far reported, these two types constitute the main subject of this study. However, possibility is taken into account that there might exist an undescribed muscle glycogenosis based on the defect of another enzyme in the glycolytic pathway than phosphorylase and phosphofructokinase. Our data obtained from three patients with muscle phosphofructokinase deficiency and VB6-deficient rats with lowered activity of muscle phosphorylase indicate that the following procedures are suitable for systematic diagnosis of muscle glycogenosis. (1) Ischemic forearm exercise: In muscle phosphofructokinase deficiency, no elevation in blood lactate of the antecubital vein is observed in ischemic forearm exercise test, which was first designed by McArdle (1951) as a specific diagnostic method for McArdle's disease (muscle phosphorylase deficiency). Larner et al.(1961) found that venous lactate failed to increase after ischemic ex ercise also in limit dextrinosis (debranching enzyme deficiency). Therefore, it is reasonably presumed that an abnormal finding could be obtained by the test wherever the blocking step in the glycolytic chain may exist. Ischemic forearm exercise test should be considered as a screening method for muscle glycogenosis. Determination of the blocking step in the muscle glycolytic system is carried out by anaerobic glycolysis and determination of muscle glycogen and glycolytic intermediates. (2) Anaerobic glycolysis of muscle homogenates: Production of lactate in the materials from patients with muscle glycogenosis is very low in the presence of the substrates which are situated above the blocking step in the glycolytic pathway. Contrarily, addition of the substrates under the blocking step causes the production of lactate of the same or a higher degree as compared with normal muscles. (3) Determination of muscle glycogen and glycolytic intermediates: The glycolytic intermediates above the blocking step and glycogen are always increased markedly (in phosphofructokinase deficiency, hexose-monophosphates are accumlated about ten-fold higher than in normals), whereas those under the blocking step are decreased significantly. (4) Analysis of glycogen structure: If the above experiments show that the block is situated between glycogen and glucose-1-phosphate, further procedure is necessary to determine the defective enzyme, since both phosphorylase and debranching enzyme are involved in this process. β-Amylolysis of the deposited glycogen makes differential diagnosis possible. Normal structural glycogen is accumlated in phosphorylase deficiency and limit dextrin-like glycogen in debranching enzyme deficiency. Finally the assay of the enzyme activity gives the decisive typing of muscle glycogenosis
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Systematic Diagnosis of Myopathy due to Muscle Glycogenosis

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