Pilot clinical trial with valproate shows no significant benefits in McArdle disease patients.
McArdle disease is a rare condition caused by the lack of a particular enzyme - called muscle glycogen phosphorylase - that helps to provide muscles with energy.
McArdle disease is a rare condition caused by the lack of a particular enzyme - called muscle glycogen phosphorylase - that helps to provide muscles with energy. This enzyme converts energy stored in the form of starch to sugar that the muscle can use as fuel during exercise. This lack of energy causes people with McArdle disease to experience severe muscle pain and fatigue. If they rest for a few minutes once the pain occurs, they can usually then continue to exercise without pain - this is called the "second wind". Exercising through the pain however, can cause severe muscle spasms and then damage. This damage causes muscle breakdown which can in some cases lead to kidney failure.
In the brain there is an enzyme similar to muscle glycogen phosphorylase called brain glycogen phosphorylase. The brain form of the enzyme has been seen in muscle fibres after they have been damaged, suggesting that it might be possible to "switch on" the brain enzyme in muscle to compensate for the missing muscle glycogen phosphorylase. Some drugs are known to have the ability to make the body "switch on" certain genes and when one of these was tested in an animal model of McArdle disease it was shown that the drug could switch on the foetal/brain enzyme in the muscle. A recent clinical trial in McArdle sheep that were given sodium valproate showed the presence of phosphorylase positive muscle fibres. The result is probably due to the effect of sodium valproate on gene expression. Sodium valproate is a drug usually prescribed to treat epilepsy. This drug is also part of a group of drugs known to affect gene expression by having a direct effect on chromatin (histone deacetylase inhibitors – HDACIs).
In a phase II open label, feasibility pilot study to assess efficacy of six months treatment with Valproate (20 mg/kg/day) in 16 patients with McArdle disease, no clinically meaningful changes were observed in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. This study was performed by the University College London, United Kingdom (PI Ros Quinlivan) and the University of Copenhagen (PI John Vissing). The complete results of this study can be read in the following article:
