Muscle phosphorylase deficiency

D-1) Muscle phosphorylase deficiency (Type V GSD McArdle s Disease). Liver phosphorylase is normal, but muscle phosphorylase is deficient. The patient cannot break down muscle glycogen and experiences muscle cramps and weakness with exercise. Muscle biopsy may confirm the enzyme defect. There is no significant rise in lactate in an ischemic exercise test. Magnetic resonance spectroscopy may be useful in diagnosing changes in muscle metabolic function. 

The answer is c. (Murray, pp 199-207. Scriver, pp 1521-1552. Sack, pp 121-138. Wilson, pp 287-317.) Muscle phosphorylase deficiency leads to a glycogen storage disease [McArdles disease (232600)] and, in young adults, an inability to do strenuous physical work because of muscular cramps resulting from ischemia. The compromised phosphorylation of muscle glycogen characteristic of McArdle s disease compels the muscles to rely on auxiliary energy sources such as free fatty acids and ambient glu-... 

Table 15.12. Glycogen storage disease type 5 (muscle phosphorylase deficiency)...

Engel WK, Byerman BJ, Williams HE. (1963) Late-onset type of skeletal muscle phosphorylase deficiency a new familial variety of completely and partially affected subjects. New Engl J Med 268, 135-137. 

In 1965 Japanese workers [128] identified a deficiency in muscle of phosphofructokinase, another glycolytic enzyme the symptoms were quite similar to those of muscle phosphorylase deficiency. The enzyme was also low in erythrocytes. Inheritance is probably autosomal recessive and a small number of other cases have since been reported. A late-onset muscle disorder in two brothers associated with a low activity of phosphohexoseisomerase in the muscle has been reported in another Japanese family [129]. 

TypeV Myophosphorylase deficiency, McArdle s syndrome Absence of muscle phosphorylase Diminished exercise tolerance muscles have abnormally high glycogen content (2.5-4.1%). Little or no lactate in blood after exercise. 

Phosphorylase deficiency (McArdle s disease, glycogenosis type V) is an autosomal recessive myopathy caused by a genetic defect of the muscle isoenzyme of glycogen phosphorylase (Fig. 42-1). Intolerance of strenuous exercise is present from childhood, but usually onset is in adolescence, with cramps after exercise [1, 5]. Myoglobinuria occurs in about one-half of patients. If they avoid intense exercise, most patients can live normal lives however, about one-third of them develop some degree of fixed weakness, usually as a late-onset manifestation of the disease. In a few patients, weakness rather than exercise-related cramps and myoglobinuria characterizes the clinical picture. 

Glycogen phosphorylase deficiency in muscle gives rise to muscle weakness, frequent cramp and ease of fatigue (McArdle s syndrome). It also gives rise to hypoglycae-mia if the liver enzyme is deficient (Chapter 6). 

Some 80% of the body s total vitamin Be is as pyridoxal phosphate in muscle, and some 80% of this is associated with glycogen phosphorylase. This does not seem to function as a reserve of the vitamin and is not released from the muscle in deficiency. 

An adolescent patient with a deficiency of muscle phosphorylase was examined while exercising her forearm by squeezing a rubber ball. Compared to a normal person performing the same exercise, this patient... 

A. Glycogen accumulates because muscle phosphorylase is deficient in McArdle s disease (a glycogen storage disease). 

Bartram, C., Edwards, R. H. T., and Beynon, R. J. (199S). McArdle s disease Muscle glycogen phosphorylase deficiency. Biochim. Biophys. Acta 1272, 1-13. 

Kost GJ, Verity MA. A new variant of late-onset myo-phosphorylase deficiency. Muscle Nerve. 1980 3(3) 195-201. 

Muscle phosphorylase (EC 2.4.1.1) deficient. Glycogen structure normal. Glycogen accumulates only in muscle. Exercise causes muscle cramps myoglobin from damaged muscle may appear in urine. Patients symptomless if they refrain from strenuous exercise. Prognosis favorable. 

Glycogenosis type VIII (phosphorylase b kinase deficiency) gives rise to myopathy and liver disease, either singly or in combination. Phosphorylase b kinase (PBK) converts the inactive b form of both muscle and liver phosphorylases to the active a forms of the enzymes. The ischemic lactate test sometimes shows a flat result as in McArdle s disease, but is more likely to be normal. Histochemical demonstration of myophosphorylase activity in tissue sections shows a near-normal reaction due to the presence of phosphorylase a. Accumulation of glycogen is modest and found mainly in type 2 (fast-twitch glycolytic) muscle fibers. 

Six compounds have vitamin Bg activity (Figure 45-12) pyridoxine, pyridoxal, pyridoxamine, and their b -phosphates. The active coenzyme is pyridoxal 5 -phos-phate. Approximately 80% of the body s total vitamin Bg is present as pyridoxal phosphate in muscle, mostly associated with glycogen phosphorylase. This is not available in Bg deficiency but is released in starvation, when glycogen reserves become depleted, and is then available, especially in liver and kidney, to meet increased requirement for gluconeogenesis from amino acids. 

Patients with this deficiency present with myopathy, recurrent aching muscles and myoglobinuria after prolonged exercise or starvation. It is interesting to note that there are more cases of a deficiency of this enzyme in muscle than there are cases of a deficiency of any of the glycolytic enzymes (including phosphorylase, see Chapter 6). 

Pyridoxine is present in food in the free form and as a glucoside, which may undergo partial hydrolysis in the gut lumen, or may be absorbed intact. Although pyridoxine is associated with the enzyme glycogen phosphorylase in muscles, it is not released in response to a dietary deficiency therefore it cannot be regarded as a storage form of the vitamin. 

After purine nucleotides have been converted to the corresponding nucleosides by 5 -nucleotidases and by phosphatases, inosine and guanosine are readily cleaved to the nucleobase and ribose-1-phosphate by the widely distributed purine nucleoside phosphorylase. The corresponding deoxynucleosides yield deoxyribose- 1-phosphate and base with the phosphorylase from most sources. Adenosine and deoxyadenosine are not attacked by the phosphorylase of mammalian tissue, but much AMP is converted to IMP by an aminohydrolase (deaminase), which is very active in muscle and other tissues (fig. 23.20). An inherited deficiency of purine nucleoside phosphorylase is associated with a deficiency in the cellular type of immunity. 

Oka T, Komori N, Kuwahata M, Suzuki I, Okada M, and Natori Y (1994) Effect of vitamin Be deficiency on the expression of glycogen phosphorylase mRNA in rat liver and skeletal muscle. Experientia 50, 127-9. 

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