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Valproate Sodium (McArdle Disease)

A Pilot Study of Valproate Sodium for McArdle Disease

Sponsor University College London (UCL)
Funder Muscular Dystrophy campaign
PI Dr Ros Quinlivan
Contact r.quinlivan@ucl.ac.uk
More information on the trial  

Background

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)
  • myoglobinuria
  • 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.

Trial information

This is an open label uncontrolled pilot study.

Primary objective

To assess safety and efficacy of Sodium valproate (slow release) 20mg /kg once daily for six months.

Recruitment

15 subjects, adult male and post-menopausal female

Patients attending specialist centres for McArdle disease across three sites:

  1. London
  2. Copenhagen
  3. Dallas