Summary: McArdle’s disease is resulted from the deficiency of the muscle isoform of glycogen phosphorylase (myophosphorylase). This is the first myopathy in which a single enzyme defect was demonstrated. It is also entirely restricted to muscle. Other than the fatal infantile form, McArdle’s disease is compatible with long-term survival. It is classically associated with life long exercise intolerance. The initial symptoms are mild and patient may be carrying a label of “lazyness”. Later symptoms include muscle cramps after exercise, myoglobinuria, and, in later course of the disease, muscle wasting. Severe sternous exercise may cause myoglobinuria that is severe enough to cause acute renal failure. In the past, many cases are not diagnosed until adulthood. Histologically, there is an increased storage of glycogen and absence of phosphorylase activity. The presence of abundance of necrotic and regenerating fibers could qualify this disease as a muscular dystrophy. The biochemical structure of the stored glycogen is normal.

Clinical: Other than the fatal infantile form, McArdle’s disease is compatible with long-term survival. The involvement is completely restricted to skeletal muscle. Symptoms are highly variable. Patients may be completely normal in between attacks. Although presentation usually begins at childhood, case that presents at elderly age has also been described [Wolfe GI et al., 2000]. Severe sternous exercise may cause myoglobinuria that is severe enough to cause acute renal failure. Generally, three clinical stages can be recognized.

· Early stage: In children and adolescence the only symptoms may be easy fatiguability.

· Early adulthood: Severe cramps and weakness on exertion and transient myoglobinuria.

· Advanced stage: Wasting of proximal muscle and weakness.

· Ischemic changes have been described in McArdle’s disease [Wheeler SD, Brooke MH., Neurology 1983 Feb;33(2):249-50; Brumback RA. Neurology 1984 Apr;34(4):559]

Fatal infantile form: This rare form has been reported and remains to be seen if the biochemistry and genetics are the same as the more common form. [DiMauro S, Hartlage PL. Neurology 1978 Nov;28(11):1124-9; Miranda AF et al., Neurology 1979 Nov;29(11):1538-41; Milstein JM et al., J Child Neurol 1989 Jul;4(3):186-8]

CK level is consistently elevated.

Biochemistry: Deficiency of the muscle isoform of glycogen phosphorylase that convert glycogen into glucose-1-phosphate. The enzyme remove a-1,4-glusyl residues form the outer chains of glycogen to generate glucose-1-phosphate with vitamin B₆ as the co-enzyme. The muscle isoform is expressed in adult muscle fibers. Embryonic and regenerating muscle fibers express the brain isoform. There is no raise in lactate level after ischemic exercise.

Genetics: The gene is on chromosome 11q13. The pattern of inheritance is not clear. There are evidence to suggest autosomal recessive [Schmidt B et al., Neurology 1987 Sep;37(9):1558-61] and, less likely, autosomal dominant transmission.

Molecular pathology: The molecular pathology is heterogeneous [McConchie SM et al., Biochim Biophys Acta 1990 Nov 14;1096(1):26-32]. Mutation at codon 49 is particularly common in Caucasian patients and account for three fourths of the cases. Molecular diagnosis is possible [el-Schahawi M et al., Neurology 1996 Aug;47(2):579-80].

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

MUSCLE PATHOLOGY

Histology: The fibers may be of normal sized or even hypertrophic but advanced cases may have small fibers. There is minimal to light glycogen accumulation in form of subsarcolemmal pockets that is PAS(+) and PASD(-). Necrotic and regenerating fibers are present in most biopsy specimens. There is no phosphorylase activity or immunoreactivity for phosphorylase in normal appearing fiber. The amount of necrotic fibers may be most abundant if the biopsy is performed several hours after sternous exercise. Most necrotic fibers are likely to be type 2B fibers. Weak phosphorylase activity may be seen in the regenerating fibers. Comment: The abundance of necrotic and regenerating fibers should qualify this also as a muscular dystrophy.

EM: Abnormal mitochondria have been described in some cases. Otherwise, the ultrastructural findings are that of nonspecific necrotic and regenerating fibers.

OTHER PATHOLOGY

Vascular smooth muscle and peripheral nerve: Increased amounts of free and membrane-bound glycogen may be found within axons, Schwann cells, fibroblasts and occasional vascular smooth muscle and endothelial cells that had been included within the skeletal muscle biopsy. [Byard RW et al., Pathology 1991 Jan;23(1):62-5; Wheeler SD, Brooke MH., Neurology 1983 Feb;33(2):249-50; Brumback RA. Neurology 1984 Apr;34(4):559]

DIFFERENTIAL DIAGNOSIS: Head

Muscular dystrophy: McArdle’s disease may be confused with muscular dystrophy. Clinical history and a high index of suspicion is helpful.