SOJ Neurology

McArdle’s disease is an Autosomal recessive disorder of glycogen metabolism caused by deficiency of myophosphorylase. It typically presents in infancy or adolescence. Adult onset cases have been reported primarily in the second decade but some late-onset cases have been rare. The cause of fixed weakness in a metabolic myopathy like McArdle’s is unclear, but repeated episodes of myoglobinuria may lead to failure of the regenerative processes resulting in atrophy and weakness. Early diagnosis could potentially prevent development of significant atrophy or fixed weakness by making the patient aware of risks of exertion and promote life style changes. We report a case of 55 year old male presenting with progressive asymmetric weakness and atrophy. Muscle biopsy showed absent phosphorylase staining and genetic testing showed a homozygous mutation for R49X (p.Arg49Ter; c.148 C>T).

McArdle’s disease is an autosomal recessive disorder of glycogen metabolism, which occurs due to deficiency of myophosphorylase, an enzyme required for conversion of glycogen to glucose-1-phosphate in the muscle [1]. It is also known as Glycogen storage disease type V or glycogenosis type V.

This syndrome typically presents in the first two decades of life with exercise intolerance, muscle pain, cramps, rhabdomyolysis and myoglobinuria. The patients notice stiffness after exercise and a second-wind phenomenon during exercise [2]. It can present in infancy with progressive weakness, hypotonia, respiratory distress and early death. In the adult onset form, the findings are atypical with symmetric progressive limb-girdle weakness and delayed onset wasting [3]. Heart and liver have a different isomer of the phosphorylase, and are thus not affected. An ischemic exercise test can be used to screen for this condition. In a diseased person, there is absence of increase in serum lactate with an increase in ammonia production.

Histopathology of the muscle shows nonspecific type 1 fiber atrophy Felice[4], with absence of phosphorylase staining in the muscle membrane. Glycogen accumulation is seen in the subsarcolemmal region. The gene encoding for myophosphorylase has been localized to chromosome 11q13. The R49X nonsense mutation in exon 1 is the most common mutation in Northern Europe and North America, but 55 other distinct mutations have been identified all over the world. There has been no genotype-phenotype correlation that has been identified [5].

We report an adult onset McArdle’s disease in a 55-year-old male with atypical clinical features of asymmetric onset and early atrophy. One other similar case has been reported in an 83-year old male [6].

A 55-year-old right-handed male presented to our neuromuscular clinic for evaluation of progressive weakness and exercise intolerance. He reported mild difficulties since childhood with early fatigue during physical exercise classes and inability to keep up with his peers. He noted myalgias with activity and second wind phenomenon. Few episodes of myoglobinuria could be elicited on further history especially after strenuous activity. He denied any exercise induced cramps or contractures. He reported no previous evaluations for this problem. A neurological evaluation was sought due to development of persistent weakness and atrophy in the last 5 years.

His past medical history was significant for coronary artery disease with stent placement, elevated liver enzymes of unclear etiology, hypertension, hyperlipidemia and gout.

Family history was positive for a brother diagnosed of Poliomyelitis at the age of two. There was no history of neuromuscular disorders but he reports many family members with “big calves”.

Pertinent findings in his exam include asymmetric atrophy of his deltoids, infraspinatus, supraspinatus and quadriceps, which was worse on the right. He had winging of the scapula on the right (Figure 1) and calf hypertrophy (Figure 2). His strength examination was as follows (Table 1). His reflexes were symmetric and 1+ except for absent right knee jerk. His cranial nerve, sensory and cerebellar examinations were normal.

There was a history of elevated CK in the range of 2000’s during cardiac evaluations in the past. In our lab his CK was elevated at 843 U/l (Normal 70- 185). He had electrodiagnostic studies performed which showed myopathic changes proximally and distally with membrane irritability and myotonia. A limb girdle dystrophy panel showed sequence alterations in Fukutin, Calpain 3 and Lamin A/C of unknown clinical significance. As the diagnosis was unclear muscle biopsy was performed.

Left Biceps muscle biopsy was performed which showed vacuolar myopathy with subsarcolemmal accumulation of glycogen on PAS staining (Figures 3-5). There was variation is fiber size with type 1 greater than type 2 atrophy. Also seen was endomysial fibrosis with rare regenerating and necrotic fibers. Phosphorylase staining in the muscle was absent. Electron microscopy showed increased subsarcolemmal glycogen along with focal increase in glycogen between the myofibrils.

Due to the absence of phosphorylase staining a sample of the muscle tissue was sent toBuffalo, NY for biochemical analysis. This showed a profound and reproducible deficiency on myophosphorylase activity. Genetic testing performed at Duke university medical center showed a homozygous mutation for R49X (p.Arg49Ter; c.148 C>T).

McArdle’s disease typically presents in infancy or adolescence. Adult onset cases have been reported mostly in the second decade of life but some late onset cases have been reported [7-9]. 9 cases with onset after 4th decade have been reported in literature. One case reported asymmetric wasting at late stages of disease [10]. 5 of the 9 cases had symmetric fixed weakness with one case presenting with asymmetric weakness [11]. The cause of fixed weakness in a metabolic myopathy like McArdle’s is unclear, but repeated episodes of myoglobinuria may lead to failure of the regenerative processes resulting in atrophy and weakness. Regeneration of muscle fibers has been reported to occur only in muscle diseases with necrosis [12]. These include dystrophies, inflammatory myopathies, metabolic myopathies like McArdle’s, malignant hyperthermia, and congenital myopathies like CPT deficiency. Skeletal muscle fibers usually have good capacity to regenerate due to the presence of satellite cells or myogenic precursor cells. But these cells have a limited capacity to regenerate. It is predicted that these cells have a limited capability of 60 mitotic cycles, after which they become senescent and lose their regenerative capability. This may be the reason for muscle atrophy and fixed weakness in later stages of McArdle’s disease with necrosis from repeated exertional injury to the muscle. This does not however explain asymmetric weakness and atrophy as seen in our case. The other case reported with similar features had compound heterozygous mutation in R49X allele. Our case had a homozygous mutation in the same gene. This strengthens the genotype phenotype variability in this disease. It has been proposed that in patients diagnosed later in life, there is more chance of atrophy and fixed weakness as they are less likely to refrain from strenuous exercise or activity due to lack of awareness of the disease. So early diagnosis could potentially prevent development of significant atrophy or fixed weakness by making the patient aware of risks of exertion and promote life style changes.

Cases of late onset McArdle’s disease have been reported but asymmetric fixed weakness is rare. The occurrence of persistent weakness in McArdle’s disease may be prevented by early diagnosis and life style changes to avoid recurrent rhabdomyolysis, but further prospective natural history studies are needed to support this hypothesis.

1. Lucia A, Nogales-Gadea G, Perez M, et al. (2008) McArdle disease: what do neurologists need to know? Nature Clinical Practice Neurology 4(10): 568- 577.
2. Pourmand R, Sanders DB, Corwin HM (1983) Late-onset McArdle’s disease with unusual electromyographic findings. Archives of Neurology 40(6): 374-377.
3. McKineel IW, Rudnicki MA (2004) Molecular mechanisms of Muscle atrophy. Cell 119(7): 907-910.
4. Felice KJ, Grunnet ML, Sima AA (1996) Selective atrophy of type 1 muscle fibers in McArdle’s disease. Neurology 47(2): 581-583.
5. Martin MA, Rubio CJ, Buschbinder J, et al. (2001) Molecular heterogeneity of Myophosphorylase deficiency (McArdle’s disease): A genotype-phenotype correlation study. Annals of Neurology:50(5): 574-581.
6. Quinlivan R, Buckley J, James M, et al. (2010) McArdle’s disease: A clinical review. Journal of Neurology Neurosurgery and Psychiatry 81:1182-1188.
7. Engel WK, Eyerman EL, Williams HE (1963) Late-onset type of skeletal-muscle phosphorylase  deficiency. New England Journal of Medicine 268:135-137.
8. Felice KJ, Schneebaum AB, Jones Jr HR (1992) McArdle’s disease and late-onset symptoms: case report and review of the literature. Journal of Neurology Neurosurgery Psychiatry 55(5): 407-408.
9. Nadaj-Pakleza AA, Vincitorio CM, Laforet A, et al. (2009) Permanent Weakness in McArdle Disease. Muscle Nerve: 40(3): 350-357.
10. Hewlett RH, Gardner-Thorpe C (1978). McArdle’s disease- What limit to the age of onset? South African Medicine 53(2):60-3.
11. Wolfe GI, Baker NS, Haller RG, Burns DK and Barohn RJ (2000). McArdle’s disease presenting with asymmetric, late-onset arm weakness. Muscle & Nerve 23(4):641-645.
12. Karpati G, Molnar MJ (2008) Muscle fibre regeneration in human skeletal muscle diseases. In: S Schiaffino and T Partridge (Eds.), Skeletal muscle repair and regeneration. Springer science+Business Media B.V. Dordrecht Netherlands, pp. 199-215.