Glycogen phosphorylase deficiency

Hepatic Glycogen Phosphorylase Deficiency (Hers Disease)... 

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). 

Hepatomegaly increased hepatic glycogen stores probably X-linked, but there may be more than one type, with some autosomally inherited must be distinguished from glycogen phosphorylase deficiency. 

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

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. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

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. 

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. 

Lederer B, Van Hoof F, Van den Berghe G, Hers HG (1975) Glycogen phosphorylase and its converter enzymes in haemolysates of normal human subjects and of patients with type VI glycogen storage disease. A study of phosphorylase kinase deficiency. Biochem J 147 23-35... 

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. 

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. 

The normed muscle concentration of pyridoxal phosphate is of the order of 10 nmol per g in patients with McArdle s disease (glycogen storage disease from congenital lack of glycogen phosphorylase), the muscle content of pyridoxal phosphate is reduced to one-fifth of this. There is some evidence that patients with McArdle s disease show signs of vitamin Be deficiency, su esting that the muscle pool of the vitamin is important in maintenance of vitamin Be homeostasis (Beynon et ed., 1995). 

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. 

D-l) Liver phosphorylase deficiency (Type VI GSD Hers Disease), There is glycogen accumulation in the liver and liver enlargement. There is growth retardation, as amino acids are shunted toward gluconeogenesis rather than growth. 

Hepatic glycogenosis (type VI) (G.H. Hers, 1959) is due to hepatic phosphorylase deficiency. Subtype Via is caused by a lack of phos-phorylase-B kinase, and it is transmitted by the x-chromosomal recessive route. Subtype Vib shows a deficiency in glycogen phosphorylase, and its transmission is autosomal recessive. In the musculature, the analogous enzyme is, however, intact. Nevertheless, there is pronounced genetic and phenotypical heterogeneity. 

It acts as a cofactor for glycogen phosphorylase in glycogenolysis. Decreased glucose tolerance may be associated with vitamin B-6 deficiency. 

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-... 

The molecular basis of HFI involves the deficiency of normal D-fructose 1-phosphate aldolase activity, and low activity of D-fructose 1,6-bisphosphate aldolase in liver, intestine, and renal cortex. Accumulated D-fructose 1-phosphate leads to a diminution of liver-glycogen phosphorylase activity, causing severe hypoglycemia. An accumulation of D-fructose 1-phosphate produces renal acidification and subcellular pathology of the jejunum and liver. 

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