A Pilot Study of Valproate Sodium for McArdle Disease
|Sponsor||University College London (UCL)|
|Funder||Muscular Dystrophy campaign|
|PI||Dr Ros Quinlivan|
|More information on the trial|
McArdle disease is an inherited metabolic disorder of skeletal muscle. Affected patients cannot produce lactate during ischaemic exercise.
This is because they have a congenital absence of the enzyme muscle glycogen phosphorylase. The enzyme is essential for glycogen metabolism. The condition is caused by mutations in the muscle glycogen phosphorylase gene (PYGM). In affected people, fatigue and cramp occur:
- within minutes of initiating any activity
- during strenuous activity such as lifting heavy weights or walking uphill
If the activity is continued despite severe cramping, a contracture occurs which leads to
- muscle damage (rhabdomyolysis)
- and when severe acute renal failure
Currently, there is no satisfactory treatment for the
condition. Taking glucose before exercise may reduce muscle symptoms but
this is not a good daily strategy as it may result in significant weight gain.
One randomised controlled trial showed some subjective benefit from creatine supplements in five out of nine patients. But this has not been confirmed in the clinic setting.
Most McArdle sufferers have complete absence of skeletal
muscle phosphorylase. But a small minority of patients have splice site
mutations, so they can produce small amounts (1-2%) of the functional enzyme.
These people have less severe symptoms. Functional exercise assessments
have shown better exercise capacity than typical patients with the condition.
This suggests that potential therapeutic agents might only need to produce
small amounts of enzyme for significant functional improvement.
Also, finding a therapeutic agent to 'switch on' expression of the foetal enzyme may be a potential treatment.
Sodium Valproate (Valproic acid) is one drug that can affect gene expression. Some animal studies have shown that it can 'switch on' the foetal phosphorylase isoenzyme.
Sodium valproate was recently given in a sheep model of the McArdle disease for three months. It showed the presence of phosphorylase positive muscle fibres, in the absence of muscle necrosis and/or regeneration.
This is an open label uncontrolled pilot study.
To assess safety and efficacy of Sodium valproate (slow release) 20mg /kg once daily for six months.
15 subjects, adult male and post-menopausal female
Patients attending specialist centres for McArdle disease
across three sites: