Glycogen Storage Disease V

A number sign (#) is used with this entry because McArdle disease, or glycogen storage disease type V (GSD5), is caused by homozygous or compound heterozygous mutation in the PYGM gene (608455), which encodes muscle glycogen phosphorylase, on chromosome 11q13.

Description

McArdle disease is an autosomal recessive metabolic disorder characterized by onset of exercise intolerance and muscle cramps in childhood or adolescence. Transient myoglobinuria may occur after exercise, due to rhabdomyolysis. Severe myoglobinuria may lead to acute renal failure. Patients may report muscle weakness, myalgia, and lack of endurance since childhood or adolescence. Later in adult life, there is persistent and progressive muscle weakness and atrophy with fatty replacement. McArdle disease is a relatively benign disorder, except for possible renal failure as a complication of myoglobinuria (summary by Chen, 2001).

Clinical Features

The original patient of McArdle (1951) was a 30-year-old man who experienced first muscle pain and then weakness and stiffness with exercise of any muscle, including the masseters. Symptoms disappeared promptly with rest. Blood lactate did not increase after exercise, suggesting that the patient was unable to convert muscle glycogen into lactate. Schmid and Mahler (1959) and Mommaerts et al. (1959) identified the cause of the disorder as a glycogenolytic defect in the muscle with the absence of muscle phosphorylase.

Engel et al. (1963) observed onset of first manifestations at age 49 in a sister and brother. The sister had progressive generalized muscular weakness without cramps and had complete absence of enzyme. The brother had muscle cramps after exercise and about 35% normal activity of phosphorylase. Neither had myoglobinuria. Grunfeld et al. (1972) found evidence for the existence of 2 forms of McArdle disease, i.e., CRM-positive and CRM-negative forms. They also observed renal failure from acute rhabdomyolysis in 2 patients. They noted that the muscle cramps are 'electrically silent,' showing no activity on electromyography, which may lead to interpretation of psychoneurosis.

Braakhekke et al. (1986) studied the 'second wind' phenomenon which was first described in this disorder by Pearson et al. (1961). During the first 15 minutes the 3 patients they studied experienced progressive fatigue and weakness of exercised muscles, with rapid and complete recovery (adaptation phase). Following this, all 3 patients were able to continue exercise without difficulty ('second wind' phase). The processes occurring during the 'second wind' phase included an increase in cardiac output, changes in the metabolic pathways, and an increase in EMG activity, which probably represented recruitment of more motor units to compensate for a failure of force generation in the muscle fibers.

Chui and Munsat (1976) described a 40-year-old woman with myophosphorylase deficiency and the clinical features of McArdle syndrome, including exercise intolerance, muscle cramping, and myoglobinuria. The family history was unusual in that 4 other family members were also affected: an older sister, a younger brother, a 10-year-old son, her 75-year-old mother, and possibly her maternal grandmother. The authors postulated dominant inheritance. Schmidt et al. (1987) described the disorder in 2 generations, but in their family, as in the family of Chui and Munsat (1976), the enzyme defect was not proven biochemically in all persons. In the family reported by Schmidt et al. (1987), a 17-year-old boy and his 38-year-old mother were both clinically affected. Muscle phosphorylase activity in the son was 0.6% of normal. The mother had 20% activity level and the father 45%; the mother may have been a manifesting heterozygote.

Papadimitriou et al. (1990) reported 2 patients with McArdle disease from the same pedigree. The first patient had progressive muscle weakness and atrophy with a residual phosphorylase enzyme activity of 28%. The second patient had typical McArdle disease, clinically and biochemically. The authors concluded that the first patient was a heterozygote and the second was a homozygote, the genetic transmission being autosomal recessive.

Wu et al. (2011) reported 6 unrelated patients with McArdle disease. All had typical features of the disorder, including exercise intolerance, decreased or absent PYGM activity and immunostaining in muscle samples, and increased serum creatine kinase. All had the 'second wind' phenomenon. Three had rhabdomyolysis and myoglobinuria. Muscle biopsy of 5 patients showed glycogen accumulation. Three patients who underwent the nonischemic forearm exercise test showed flat cubital venous plasma lactate levels after exercise. Although the median age at diagnosis was 29.5 years, most recalled having onset of symptoms in childhood or adolescence.

Clinical Variability

DiMauro and Hartlage (1978) described an infant with severe McArdle disease. She developed generalized, rapidly progressive weakness at age 4 weeks and died at age 13 weeks of respiratory failure. Muscle showed complete lack of phosphorylase activity, and absence of the enzyme protein was suggested by immunodiffusion studies. Milstein et al. (1989) reported a premature infant with McArdle disease who showed joint contractures and signs and symptoms of perinatal asphyxia. The parents were consanguineous. The authors noted the wide clinical spectrum of the disorder.

Kost and Verity (1980) reported an affected patient in whom immobilizing cramps, stiffness, and muscle swelling began abruptly at age 60, after a life of physical vigor. Abarbanel et al. (1987) described a 59-year-old man with myophosphorylase deficiency who presented with long-standing painless and relatively static weakness starting in early childhood. EMG was myopathic, serum CK was elevated, and muscle biopsy showed accumulations of glycogen. Biochemical studies showed absence of myophosphorylase activity. Abarbanel et al. (1987) noted the unusual course and emphasized the clinical heterogeneity of the disorder.

Inheritance

McArdle disease is inherited in an autosomal recessive pattern. Wu et al. (2011) reported a family with pseudodominant inheritance of McArdle disease. A father and son were similarly affected, but the mother was unaffected. Genetic analysis showed that the son was compound heterozygous for the common R50X (608455.0001) mutation in the PYGM gene, inherited from his father, and a novel mutation (D51G; 608455.0020), inherited from his mother. His father was compound heterozygous for R50X and another truncating mutation in the PYGM gene.

Diagnosis

Dawson et al. (1968) suggested a test for detection of asymptomatic heterozygotes based on the development of brief painful cramps during exercise.

Ross et al. (1981) used (31)P nuclear magnetic resonance to study McArdle disease. The inorganic phosphate resonance gives a direct measurement of intracellular cytoplasmic pH in muscle. During exercise, the pH fell relatively little, while phosphocreatine was shown to fall during aerobic exercise and was rapidly exhausted during minimal ischemic exercise.

The ischemic forearm exercise test for McArdle disease invariably causes muscle cramps and pain in patients with this glycolytic defect. Kazemi-Esfarjani et al. (2002) investigated an alternative diagnostic exercise test in 9 patients with McArdle disease, 1 patient with the partial glycolytic defect phosphoglycerate mutase deficiency (261670), and 9 matched, healthy subjects. The classic ischemic forearm protocol was compared with the identical protocol without ischemia. All patients developed pain and cramps during the ischemic test (4 had to abort the test prematurely), whereas none experienced cramps in the nonischemic test, which all completed. Blood was sampled in the median cubital vein of the exercised arm. Plasma lactate levels increased similarly in healthy subjects during ischemic and nonischemic tests and decreased similarly in McArdle patients. Post-exercise peak lactate-to-ammonia ratios clearly separated patients and healthy controls. Similar differences in lactate-to-ammonia ratios between patients and healthy subjects were observed in 2 other work protocols using intermittent handgrip contraction at 50%, and static handgrip exercise at 30%, of maximal voluntary contraction force.

Clinical Management

Vissing and Haller (2003) hypothesized that ingesting sucrose before exercise would increase the availability of glucose and would therefore improve exercise tolerance in patients with McArdle disease. In a single-blind, randomized, placebo-controlled crossover study, 12 patients were studied. Ingestion of sucrose before exercise markedly improved exercise tolerance. The treatment took effect during the time when muscle injury would commonly develop in these patients. In addition to increasing the patients' exercise capacity and sense of well-being, the treatment may protect against exercise-induced rhabdomyolysis.

Biochemical Features

By immunodiffusion and gel electrophoresis, Cerri and Willner (1981) demonstrated presence of the myophosphorylase protein in 4 patients who had no myophosphorylase activity. Phosphorylase activity was restored by incubation of muscle homogenate supernatants with cyclic AMP-dependent protein kinase and ATP. The authors concluded that McArdle disease is not due to lack of normal phosphorylation. Using high resolution SDS-polyacrylamide gel electrophoresis, Mantle et al. (1987) found absence of the myophosphorylase protein in 4 of 6 unrelated patients; the other 2 had severe reduction of the protein.

Haller et al. (1983) found very low pyridoxine in muscle in McArdle syndrome without evidence of pyridoxine deficiency. They pointed out that pyridoxal phosphate is a covalently bound cofactor of glycogen phosphorylase; one molecule of the vitamin is linked to a lysine residue of each subunit of the enzyme. Since phosphorylase is a major muscle protein (about 5% of soluble protein), the enzyme-bound vitamin is a significant pool of pyridoxal phosphate.

In 8 unrelated patients with McArdle disease, Gautron et al. (1987) found that 5 had no muscle phosphorylase mRNA and 3 had normal length muscle phosphorylase mRNA in reduced amounts. Southern blot analysis of DNA isolated from white blood cells of 4 patients showed no major deletion or rearrangement of the phosphorylase gene compared to controls. In 41 of 48 patients with McArdle disease, Servidei et al. (1988) found no detectable muscle phosphorylase enzyme. Six patients had markedly decreased protein and 1 patient had a normal amount of protein. Northern blot analysis in 4 patients showed normal muscle phosphorylase mRNA in 2, abnormally short mRNA in 1, and no mRNA in the fourth.

Martinuzzi et al. (1993) studied the glycogen phosphorylase isoenzymatic pattern in cultured muscle of 5 patients with McArdle disease that lacked glycogen phosphorylase activity, PYGM protein, and PYGM mRNA. GP activity, PYGM isozyme, and anti-PYGM antiserum reactivity were present in patients' aneural cultures, increased after innervation, and were indistinguishable from controls. PYGM mRNA was demonstrated in both aneural and innervated cultures of patients and controls by primer extension and PCR amplification of total RNA. The results indicated that the PYGM gene is normally transcribed and translated in cultured muscle of these patients.

Among 7 individuals who were heterozygous carriers of a PYGM mutation, Andersen et al. (2006) found no evidence of symptoms of McArdle disease during exercise tests of oxidative capacity and lactate levels. Although the carriers had an approximately 50% decrease in myophosphorylase activity, the residual activity was sufficient to sustain maximal glycolytic flux in muscle that was similar to controls.

In a study of fatty acid oxidation during bicycle ergometer exercise, Orngreen et al. (2009) found that 11 patients with McArdle disease had higher palmitate oxidation and disposal, higher total fat oxidation, and higher levels of free fatty acids compared to controls. There was also augmented fat oxidation during the second-wind phenomenon, which occurred in all patients. However, more prolonged exercise did not increase fatty acid oxidation, perhaps due to limitation of glycogenolysis.

Molecular Genetics

Among 40 patients with McArdle disease, Tsujino et al. (1993) identified 3 point mutations in the PYGM gene (608455.0001-608455.0003). Thirty-three patients were adults with typical clinical manifestations of the disease, 6 were children, including 3 sibs, and 1 was an infant reported by DiMauro and Hartlage (1978) who died of the disease at 13 weeks. Eighteen patients, including the infant, were homozygous for the same nonsense mutation, arg50-to-ter (R50X; 608455.0001), originally reported as R49X. Twelve other patients had an R50X allele in compound heterozygosity with another mutation in the PYGM gene; the R50X mutation was thus present in 75% of patients. In 1 family with apparent autosomal dominant inheritance, the mother was a compound heterozygote and the asymptomatic father carried 1 different mutation.

Martin et al. (2001) performed mutation analysis on DNA from 54 Spanish patients (40 families) with glycogen storage disease V and found that 78% of the mutant alleles could be identified with RFLP analysis for R50X, G205S (608455.0002) originally reported as G204S, and W797R (608455.0015). They also identified 6 novel mutations in the PYGM gene. Martin et al. (2001) found no clear genotype-phenotype correlations.

Garcia-Consuegra et al. (2009) used skeletal muscle mRNA and cDNA analysis to identify a second defect in the PYGM gene in 4 patients with McArdle disease in whom heterozygous PYGM mutations were initially detected by genomic DNA analysis. They identified a large deletion and splice site mutation in 1 patient each and a synonymous (K215K) substitution in exon 5 in 2 patients. Real-time PCR of muscle from 1 patient with the K215K substitution showed a drastic decrease in mRNA, implicating nonsense-mediated mRNA decay as a mechanism.

In 5 unrelated patients with McArdle disease, Wu et al. (2011) identified compound heterozygosity for the common R50X mutation and another pathogenic mutation in the PYGM gene (see, e.g., D51G, 608455.0020). A sixth patient was homozygous for a small deletion (608455.0021).

Genetic Modifiers

In 47 patients with myophosphorylase deficiency, Martinuzzi et al. (2003) found an association between increased clinical severity and the D allele of the ACE insertion/deletion (I/D) polymorphism (106180.0001). The authors noted that the ACE I/D polymorphism is associated with muscle function and thus may modulate some clinical aspects of myophosphorylase deficiency, which may account for some of the phenotypic variability of the disorder.

Genotype/Phenotype Correlations

Vissing et al. (2009) reported 2 unrelated patients, ages 30 and 39 years, respectively, with a mild form of McArdle disease caused by compound heterozygosity for PYGM mutation. Each patient carried 1 typical mutation (R50X; 608455.0001 and G205S; 608455.0002) and 1 splice site mutation (608455.0018 and 608455.0019). The splice site mutations were found to cause aberrant splicing and production of abnormally spliced proteins that were expressed in small amounts. Biochemical studies showed 1.0 to 2.5% residual PYGM activity, suggesting that the mutations were 'leaky' and allowed some normally spliced products to be generated. Both patients reported muscle cramps, pain, and episodes of rhabdomyolysis and myoglobinuria after exercise. One had 2 to 3 episodes, whereas the other had more than 10 with 1 episode of renal failure. Both also had increased serum creatine kinase, similar to patients with typical disease. However, both patients also had a high capacity for sustained exercise. Exercise testing showed an intermediate phenotype between controls and individuals with typical McArdle disease. The patients could complete 60 minutes of ischemic exercise before muscle cramping occurred, and peak oxidative capacity was about 2-fold higher compared to patients with typical McArdle disease. The findings indicated that very low levels of PYGM are sufficient to sustain glycogenolysis and muscle oxidative metabolism, and provided the first genotype/phenotype correlation at the molecular level.