Myophosphorylase

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 7. Myophosphorylase deficiency (McArdle s disease) enzyme is absent from muscle fibers but present in smooth muscle cells of blood vessel (arrow).

Glycogenosis type VI (liver myophosphorylase deficiency) gives rise to hepatomegaly and hypoglycemia in childhood. The enzyme involved is under separate genetic control from the muscle isoform and has been assigned to chromosome 14. 

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. 

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. 

G. M. Myophosphorylase deficiency (glycogenosis type V McArdle disease) Curr. Mol. Med. 2 189-196,2002. 

Myotoxicity linked to ezetimibe has been described in a 45-year-old overweight man with McArdle disease, which is the most common disorder of muscle carbohydrate metabolism, caused by mutations in the gene that encodes myophosphorylase (5). 

Malignant hyperthermia is probably due to the inability of certain individuals to control calcium concentrations in the muscle fiber and may involve a generalized alteration in cellular or subcellular membrane permeability, as suggested from research on pigs. This anomaly is genetically determined, but pre-anesthetic evaluation of susceptibility to malignant hyperthermia is a matter of controversy measurement of blood creatine kinase, ATP muscle depletion, or myophosphorylase A, histological... 

GSD type V, McArdle s disease Myophosphorylase deficiency, inability to utilize glycogen. See text. 

Myophosphorylase deficiency is the classic example of a carbohydrate-related dynamic syndrome. Affected persons are unable to mobilize glycogen therefore they cannot perform high-intensity work and must rely extensively on lipid metabolism. Several other defects of glycolysis produce similar symptoms. All are characterized by inability to do anaerobic work and to produce lactate during ischemic exercise, which is the basis for the customary screening test for these disorders. Patients are asked to perform maximal hand grip contractions at the rate of one per second for 60 seconds with the forearm circulation... 

Tsujino, S., Shankse, S., Martinuzzi, A., Heiman Patterson, T., and Di Mauro, S. (1995). Two novel missense mutations (E6S4K, L396P) in Caucasian patients with myophosphorylase defidency. Hum. Mutat 3,276-277. 

Rgure 26.5 GSD V, McArdle s disease. GSD V (autosomal recessive) is caused by a deficiency of the muscle form of phosphorylase (myophosphorylase). Consequently, GSD V patients are unable to mobilise glycogen for energy metabolism, which results in fatigue, muscle peiin and myoglobinuria following exercise. 

In most cases of type-2 fiber atrophy we have observed histochemically that the atrophic type-2 fibers seem to have somewhat reduced oxidative enzyme activity, while maintaining the usual abundant myophosphorylase activity typical of type-2 fibers. Possible caveat there could be impairment of an unstudied glycolytic or other non-mitochondrial enzyme involved in ATP production (or other important mitochondrial-supporting function). 

Engel WK, Beydoun SR. (1985) Myophosphorylase deficiency (MPD) probably also involves lower motor neurons (LMNs) in some cases. Neurology 35, 304. 

Salmon et al., 1970), pseudocholinesterase deficiency (Hodgkin et al., 1965), myophosphorylase deficiency (Robbins, 1960), acatalasia (Nishi-mura et al., 1961 Takahara et al., 1962), a variant of factor VIII deficiency (hemophilia) (Feinstein et al., 1969), and several others (Boyer et al., 1973). Because of the absence of any identifiable protein in these conditions, it has been cautioned that enzyme or nonenzyme replacement be carefully weighed, since the patient may treat such replacement as foreign protein (Boyer et al., 1973). 

---