Attacks Of Myoglobinuria Research Articles

Exercise‐induced cramp, myoglobinuria, and tubular aggregates in phosphoglycerate mutase deficiency

We report two patients in whom phosphoglycerate mutase (PGAM) deficiency was associated with the triad of exercise-induced cramps, recurrent myoglobinuria, and tubular aggregates in the muscle biopsy. Serum creatine kinase (CK) levels were elevated between attacks of myoglobinuria. Forearm ischemic exercise tests produced subnormal increases of venous lactate. Muscle biopsies showed subsarcolemmal tubular aggregates in type 2 fibers. Muscle PGAM activities were markedly decreased (3% of the normal mean) and molecular genetic studies showed that both patients were homozygous for a described missense mutation (W78X). A review of 15 cases with tubular aggregates in the muscle biopsies from our laboratory and 15 cases with PGAM deficiency described in the literature showed that this clinicopathological triad is highly suggestive of PGAM deficiency.

Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA.

The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy. We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene. We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (from nucleotide 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All the point mutations involved the substitution of adenine for guanine, but all were in different locations. The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance.

Molecular heterogeneity of McArdle disease

McArdle disease (McKusick 23260) is a rare form of metabolic myopathy due to the lack of glycogen phosphorylase activity in muscle. This disease, genetically transmitted as an autosomal recessive character, is clinically characterized by weakness, cramps and attacks of myoglobinuria. Glycogen phosphorylase isoenzymes (muscle, liver and brain types) show a specific tissue distribution, so that the defect is limited to skeletal muscle.

Serum carnitine. An index of muscle destruction in man.

Carnitine was identified as a constituent of normal human serum by reaction with a specific enzyme and by thin-layer chromatography. A spectrophotometric enzymatic assay was adapted for use with human serum, based upon the liberation of coenzyme A from acetylcoenzyme A in the presence of carnitine and carnitine acetyltransferase. Normal human serum contains 2.3μmols to 7.0μmols/100ml. Serum content increased to 33.4μmols/100 ml during attacks of myoglobinuria but was not increased in patients with Duchenne dystrophy, liver disease, uremia, or acute myocardial infarction.

Myoglobin and muscular dystrophy. Electrophoretic and immunochemical study.

THE muscular dystrophies are inherited diseases, presumably due to abnormality of a protein which is either completely lacking or so altered by genetic defect that it is functionally inadequate. There is no satisfactory clue to the nature of this fault, but there has been difference of opinion regarding the state of myoglobin. In 1961, Whorton and his associates^1,2first reported that the absorption spectrum of myoglobin from dystrophic muscle is abnormal in the range of visible light, implying an abnormality of structure. Soon afterwards, Miyoshi et al³reported that they found no spectral abnormality in the visible range, but that there were differences in the absorption of ultraviolet light. At about the same time, Kossman et al⁴and Benoit^5,6described rapidly migrating forms of myoglobin in starch gel electrophoresis of urine during attacks of myoglobinuria; they suggested that these were either abnormal forms of the