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Chronic therapy for McArdle disease: the randomized trial with ACE inhibitor.

McArdle disease (MCA) is the muscle glycogenosis due to defect of myophosphorylase. The pathological hallmark of the disease is the accumulation in the skeletal muscle of normal glycogen, and the absence of histochemical staining for glycogen phosphorylase in muscle. The pathology reflects the biochemical functional block in access to muscle glycogen, which while causing the local storage, is the physiopathological basis of the clinical signs associated with the disease. Patients with MCA show exercise intolerance which is maximal for the efforts which depend upon the rapid mobilization of muscle glycogen. Acute anaerobic efforts, when sustained after the first minute, depend heavily upon glycolytic metabolism, which in skeletal muscle utilises blood born glucose and glucose-1-P obtained from glycogen breakdown, which is blocked in MCA patients (1). Indeed, one of the most typical sign of MCA is the second-wind phenomenon, by which the patient, who experienced exhaustion after few minutes of acute effort slightly above the anaerobic threshold, is able to resume the effort with a much improved capacity and resistance (2). There are two rational approaches to circumvent this metabolic limitation, either the provision of a sufficient and continuous blood glucose flux, or a more efficient utilization of the available fuels. 
 
The first approach is efficiently achieved by timely oral administration of sugar (2), which was shown to significantly improve perceived exhaustion and sustainable workload. This approach however cannot cover for all the unforecasted efforts, and has obvious limitation in terms of sustainable amount of sugar ingested. The second approach aims to a more chronic improvement of fuel use by muscle cells during various degrees of efforts in any circumstance. 
 
The efficiency of muscle adaptation to training has been shown to be associated with polymorphic variants of the gene for angiotensin converting enzyme (ACE). In particular the insertion/deletion (I/D) polymorphism is associated with muscle performance in exercise and training (3, 4). Persons with I alleles, which is associated with lower ACE activity (5), show better results after aerobic training and higher muscle performance especially in tasks entailing resistance. The I/D ACE polymorphism was also associated with severity in a large group of MCA patients (6), and ACE activity modulation is easily achieved by drugs with excellent record of efficacy and tolerability. ACE activity modulation thus appears as a suitable target for chronic therapeutic intervention. The use of the ACE inhibitor Ramipril may mimic the condition associated with I alleles, and may improve functioning in MCA patients.