Additional Investigation After the Muscle Biopsy Diagnosis

A part of the patient’s muscle biopsy tissue was sent for myoglobinuria panel (biochemical analysis of enzyme activities involved in muscle energy metabolism, the deficiencies in which could cause recurrent rhabdomyolysis). It showed a reproducible and profound deficiency in myophosphorylase activity.

Final Diagnosis

Glycogen Storage Disease Type V (McArdle Disease)

Patient Follow-up

The test results were discussed with the patient . Due to the long distance, she preferred to be managed by her local physicians. She was recommended to obtain the PYGM gene test and genetic counseling. She was instructed to receive physical therapy, modify her exercise and diet, and take nutritional supplements.

Discussion

McArdle disease, also known as glycogen storage disease type V , is an autosomal recessive metabolic myopathy caused by mutations in the PYGM gene which encodes the muscle isoenzyme of glycogen phosphorylase (myophosphorylase) [1]. Myophosphorylase is one of the key enzymes involved in converting glycogen to glucose 1-phosphate (glycogenolysis) which enters the glycolytic pathways to produce the energy molecule ATP to support muscle activity. Deficiency in myophosphorylase causes abnormal glycogen accumulation and impaired energy metabolism in skeletal muscle.

Among the metabolic myopathies that are caused by the defects in carbohydrate metabolism, McArdle disease is the most common with an estimated prevalence of 1:100,000 in Dallas-Fort Worth of Texas [2] and 1:167,000 in Spain [3]. The usual symptom onset is in the first or second decade of life but it can vary. The clinical presentation of McArdle disease is heterogeneous. The majority of patients present with exercise intolerance, and they start to notice muscle symptoms when they become athletic at school ages. The common symptoms include myalgia, cramps, and fatigue in exercising muscles, which are usually developed a few minutes after isometric (e.g., carrying weights) or sustained aerobic exercise (e.g., jogging). The symptoms may improve after a brief rest or reducing the exercise intensity (second wind phenomenon). Recurrent rhabdomyolysis occurs in approximately 50% of the patients. These episodes may cause acute renal failure. Fixed proximal limb weakness can be detected in 11% of the patients, mostly in those above 40 years of age [3, 4].

The diagnosis of McArdle disease is often delayed due to the rarity and underrecognition of the disease. It can be misdiagnosed with inflammatory myopathy as seen in our case because of the persistent CK elevation and fixed proximal limb weakness. Misdiagnosis causes diagnostic delay in McArdle disease [5]. Making a correct diagnosis of McArdle disease at an early stage of the disease is important because patients can be managed appropriately to avoid unnecessary exposure to the side effects of immunosuppressive therapies.

Diagnostic evaluation of McArdle disease mainly includes serum CK, NCS/EMG, muscle biopsy, and gene test. Forearm non-ischemic test and cycle and walking test to detect the heart rate response to the second wind phenomenon may also be used to screen for McArdle disease [6, 7]. As exercise intolerance with an early age at onset is a common feature of metabolic myopathies which also include mitochondrial myopathies and lipid storage myopathies, one may also check serum lactate, pyruvate, carnitines, acylcarnitine profile, and urine organic acids during the initial evaluation. Resting serum CK is usually persistently elevated in McArdle disease. The CK elevation is mild or moderate at baseline and severe during the episodes of rhabdomyolysis. EMG may show myopathic changes but can be normal. Muscle biopsy is useful in evaluating a patient with a suspected metabolic myopathy. It can differentiate a glycogen storage myopathy from a lipid storage myopathy or a mitochondrial myopathy, as these individual metabolic myopathies have distinct pathological features. It can also rule out other chronic myopathies which can cause exercise intolerance and muscle weakness such as muscular dystrophy. The phosphorylase stain allows histochemical analysis of the myophosphorylase activity in muscle fibers to detect myophosphorylase deficiency. Myophosphorylase activity can also be measured by biochemical analysis using biopsied muscle tissue, and the diagnosis of McArdle disease can be established when the myophosphorylase enzyme activity is deficient. The PYGM gene test identifies specific mutations causing myophosphorylase deficiency. So far, 147 pathological mutations of the PYGM gene have been identified [8]. There is no genotype-phenotype correlation [9–14]. Some neurologists prefer genetic testing first; if negative, proceed with a muscle biopsy.

Muscle pathology of McArdle disease features the presence of subsarcolemmal vacuoles or blebs . These vacuoles are filled with glycogen granules, which may be striking on PAS stain (Fig. 13.2). Unlike lysosomal glycogen storage disease (e.g., Pompe disease), these vacuoles are not autophagic with no reactivity to acid phosphatase (see Fig. 13.2). EM allows ultrastructural visualization of glycogen granules accumulated in the subsarcolemmal areas corresponding to the blebs seen under light microscopy (see Fig. 13.1) [15]. Phosphorylase reactivity is completely absent in muscle fibers but often retain in the wall of blood vessels (see Fig. 13.2) as blood vessel smooth muscle contains a different phosphorylase isoenzyme. The finding is specific to McArdle disease as long as the biopsied muscle tissue contains endogenous glycogen. A positive control should be used to avoid false-negative results of the phosphorylase stain. Muscle fiber type proportion or size is not altered [16].

Management of patients with McArdle disease consists of aerobic training, exercise and dietary modifications, and nutritional supplementation. The goal is to reduce exercise intolerance and to avoid rhabdomyolysis. Aerobic training is beneficial as it can improve fitness by improving cardiorespiratory capacity and increasing delivery of blood-born fuels without adverse events in patients with McArdle disease [17–20]. Intense isometric exercise (e.g., weight lifting) or maximal aerobic exercise (e.g., running, strenuous swimming, or cycling) should be avoided. As McArdle disease is caused by the defect in the breakdown of glycogen to generate glucose for glycolysis, rich carbohydrate diet (65% carbohydrates) and taking carbohydrates (glucose, fructose, or sucrose) right before exercise have been shown beneficial to reduce exercise intolerance [21–23]. Combining aerobic exercise training and carbohydrates ingestion before exercise has been advocated [24, 25]. Low-dose creatine monohydrate also appears beneficial [26–28]. Large-scale, double-blinded, and placebo-controlled studies are needed to confirm the efficacy of nutritional and pharmacological treatments. Such studies may be difficult to do because the disease is rare. Genetic counseling should be provided to every patient. These patients should also be instructed to recognize myoglobinuria (pigmenturia). They should go to a local emergency department when pigmenturia occurs to obtain acute treatment (intravenous hydration, etc.) to avoid acute renal failure.

Pearls