Neuromuscular Case Vignettes

Diagnosis: McArdle disease (glycogen storage disease type V)

The next diagnostic step would have been genetic testing for McArdle disease, or a muscle biopsy. The latter was done, which demonstrated sub-sarcolemmal glycogent contaning vacuoles (A,B on the right). There was also negative histochemical staining for myophosphorylase (C, on the right), confirming the diagnosis of McArdle disease.

McArdle disease (glycogen storage disease type V) is caused by deficiency of the muscle isoform of glycogen phosphorylase (myophosphorylase) by pathogenic mutations in both copies of PYGM, the gene that encodes myophosphorylase.  Myophosphorylase catalyzes the breakdown of muscle glycogen into glucose-1- phosphate by removing α-1,4 glucosyl units from the outer glycogen branches. As a result, the patients develop exercise intolerance (a uniform feature of the disease) due to inability to use glycogen which is the most important source of energy during early stages of heavy exercise. Other symptoms include fatigue, cramping and stiffness, which are more intense at the onset of exercise. A particular danger is exertion induced rhabdomyolysis which happens in about 50% of the cases with potentially serious complications such as hyperkalemia and acute kidney failure. Around one third of patients also develop  fixed muscle weakness later in the course of disease, which could be proximal or asymmetrical and mimicking fascioscapulohumeral dystrophy ^1,2. Another pathognomonic feature is the second wind phenomenon, a marked improvement in the fatigue, shortness of breath, and tachycardia, after about 10 minutes into the exercise or being able to resume the same level of exertion after taking a brief period of rest. Second wind phenomenon is explained by exercise induced vasodilatation which provides blood supply of glucose to the exerting muscle, and can be abolished by glucose infusion or sucrose ingestion prior to the exercise ^1,3. Second wind phenomenon and response to carbohydrate intake do not occur in phosphofructokinase deficiency (glycogen storage disease type VII) and carnitine palmitoyl transferase type 2, two diseases that often resemble McArdle’s. Baseline CK level is always high (always >200 IU/L, and >1000 IU/L in 50%). Diagnosis can be made by genetic testing (mutations in both alleles of PYGM) in patients with typical features. On the other hand,muscle biopsy is often done which will often show glycogen accumulation. There is lack of histochemical staining and of enzymatic activity of myophosphorylase in the muscle tissue.

Patients with McArdle disease should avoid exercises that cause severe myalgia and cramping, specially isometric and high intensity dynamic exercises.(as that may cause rhabdomyolysis). On the other hand, dynamic, it is recommended that they engage in low to moderate intensity exercise program. Ingestion of  carbohydrates before the onset of exercise (≥30–40 g of glucose, fructose or sucrose in adults) results in improved exercise tolerance and the occurrence of symptoms.

References

1.         Lucia A, Nogales-Gadea G, Perez M, Martin MA, Andreu AL, Arenas J. McArdle disease: what do neurologists need to know? Nature clinical practice. Neurology. Oct 2008;4(10):568-577.

2.         Nadaj-Pakleza AA, Vincitorio CM, Laforet P, et al. Permanent muscle weakness in McArdle disease. Muscle & nerve. Sep 2009;40(3):350-357.

3.         Haller RG, Vissing J. Spontaneous “second wind” and glucose-induced second “second wind” in McArdle disease: oxidative mechanisms. Archives of neurology. Sep 2002;59(9):1395-1402.