Glycogen deficiency

J. F. Cannon, J. R. Pringle, A. Fiechter, M. Khalil, Characterization of glycogen-deficient glc mutants of Saccharomyces cerevisiae Genetics 136 1994, 485-503. 

Eleven defects in the metabolism of glycogen have been reported nine of them affect skeletal muscle directly (see Figure 5), but only glycogenosis type II (acid maltase deficiency) and glycogenesis type V (myophosphorylase deficiency) are reasonably common the rest are rare and some have been recorded in isolated case studies only. 

Figure 6. Glycogen storage in acid maltase (AM) deficiency in this late-onset case not all muscle fibers are affected.

Glycogenosis type IV (branching enzyme deficiency) results in the formation of a variant of glycogen, characterized by abnormally long inner and outer glucosyl chains and fewer branch points than normal. The abnormal variant is stored in sufficient amounts to cause some vacuolation. The clinical manifestations of this... 

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. 

Glycogen storage disease is a generic term to describe a group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in the tissues. The principal glycogenoses are summarized in Table 18—2. Deficiencies of adenylyl kinase and cAMP-dependent protein kinase have also been re-... 

Type 1 Von Gierke s disease Deficiency of glucose-6-phosphatase Liver cells and renal tubule cells loaded with glycogen. Hypoglycemia, lactic-acidemia, ketosis, hyperlipemia. 

Type II Pompe s disease Deficiency of lysosomal a-1 4- and 1 ->6-glucosldase (acid maltase) Fatal, accumulation of glycogen in lyso-somes, heart failure. 

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. 

Type VI Hers disease Deficiency of liver phosphorylase High glycogen content in liver, tendency toward hypoglycemia. 

Inherited deficiencies in specific enzymes of glycogen metabolism in both liver and muscle are the causes of glycogen storage diseases. 

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. 

There are important methodologic considerations which apply to the use of cultured amniotic fluid cells for the detection of biochemical disorders. The first is that the enzymes which can be sampled are those which are usually present in fibroblasts or fibroblast-like cells. Therefore, conditions such as phenylketonuria and glycogen storage disease type I, which are associated with deficiencies of enzymes present only in liver and kidney, are not amenable to this approach. The same also pertains to enzyme deficiencies affecting other specific tissues. 

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. 

The clinical picture includes cramps and recurrent myoglobinuria following intense exercise. Aside from episodes of myoglobinuria, none of the patients was weak. Forearm ischemic exercise caused a 1.5-2.0-fold increase in venous lactate concentration, an abnormally low but not absent response. Muscle biopsy showed normal or only moderately increased glycogen concentration. Because other accessible tissues, such as erythrocytes, leukocytes and cultured fibroblasts, express a different isoenzyme, the diagnosis of PGM-M subunit deficiency must be established by biochemical studies of muscle. Four different... 

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