Muscle pyruvate kinase deficiency: glycogen storage disease or mitochondrial myopathy?

Defects of muscle glycogen metabolism are well documented causes of metabolic myopathy, presenting with a spectrum of symptoms which show some relationship to the position of defective enzyme within the glycolytic pathway. We present three women with metabolic myopathic conditions which show some features associated with a glycogen storage disease and some features of a mitochondrial defect. Muscle histochemistry and electron microscopy showed only minor and non-specific changes. However biochemical analysis of muscle biopsies in these three cases revealed a defect in glycolysis at the level of pyruvate kinase (PK), a defect as yet undescribed. Further investigation of the enzyme's properties, revealed that the residual muscle PK activity was due to the muscle (M1) isoform.

Muscle phosphoglycerate mutase deficiency: a study of a family with metabolic myopathy.

Muscle phosphoglycerate mutase deficiency results in a myopathic condition characterised by repeated cramps, possible myoglobinuria and muscle pain. We present a family with muscle phosphoglycerate mutase (PGaM) deficiency, mild glycogen storage and some exertional myalgia. Investigations of muscle biopsy tissue showed a residual PGaM activity in muscle due to a small amount of brain isoenzyme. The enzyme was also measured in blood cells and a full investigation of muscle metabolism was also carried out. Electron microscopy revealed mitochondria with similar morphological features in two patients investigated.

Mitochondrial myopathy associated with sudden death in young adults and a novel mutation in the mitochondrial DNA leucine transfer RNA(UUR) gene.

A family exhibited maternal inheritance of a variable syndrome comprising ocular, neck and proximal upper limb weakness, psychiatric features, and sudden death. Of 15 definitely or probably affected individuals, 7 had died in early adult life, probably of respiratory failure. A novel point mutation of mitochondrial DNA, in a transfer RNA gene at position 3251, was detected in all living affected family members.

Peripheral nerve protein glycation and muscle fructolysis: evidence of abnormal carbohydrate metabolism in ALS.

Conversion of glucose to fructose via sorbitol depends upon the enzymes aldose reductase and sorbitol dehydrogenase and is called the polyol pathway. It is particularly active in muscle from patients with X-linked muscular dystrophies (15). This investigation shows enhanced metabolism of glucose to fructose in muscle from patients with ALS. Evidence is also presented showing increased activities of ketohexokinase and F-1-P splitting aldolase, which suggests that further metabolism of fructose may occur via a fructolytic pathway. Investigation of protein glycation, by an adapted fructosamine assay, in post mortem muscle, sural nerve and blood indicates that there is an increased concentration of glucose in muscle and nerve in the period prior to sampling, but blood glucose concentrations were within normal limits. The implications of fructolysis and the relationship of altered glucose metabolism in ALS are discussed.

A new metabolic muscle disease due to abnormal hexokinase activity.

A 34 year old man presented with an 8 year history of mild muscle pain and stiffness on exertion especially in the cold. Clinical examination was normal. Apart from a mild persistent leucocytosis, his routine investigations were normal including creatine kinase activity, electromyography and nerve conduction studies. An ischaemic exercise test produced a slow and incomplete rise in lactate. Histological examination showed non-specific myopathic changes in some quadriceps femoris muscle fibres. Investigation of muscle metabolism by spectrofluorometric analysis of muscle enzyme activity and by muscle fibre incubation studies revealed a severe defect in glucose phosphorylation, associated with an electrophoretically abnormal hexokinase. Further metabolic studies suggest that the block in glucose metabolism is by-passed via an enhanced phosphorylation of fructose by the abnormal hexokinase.