Over 100 mutations in the
myophosphorylase gene, which cause
McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype-phenotype correlation has been identified in this condition. We evaluated physiologic and genetic features of two patients with a variant form of
McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical
McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess
lactate and
ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical
McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma
lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients with atypical
McArdle disease compared to typical McArdle patients.
Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical
McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype relationship in
McArdle disease, and indicate that minimal
myophosphorylase activity ameliorates the typical
McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of
McArdle disease provides important clues to the level of functional
myophosphorylase needed to support muscle oxidative metabolism.