Sodium Valproate for GSDV
Condition: Glycogen Storage Disease Type V; McArdle Disease
MeSH terms: Glycogen Storage Disease; Glycogen Storage Disease Type V; Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      McArdle disease is a metabolic myopathy characterised by the absence of glycogen
      phosphorylase in skeletal muscle. Sodium Valproate is part of a group of drugs known as
      histone deacetylase inhibitors, which have a direct effect on chromatin. Recently a drug
      trial in an animal model of McArdle disease showed that sodium valproate stimulated the
      expression of a different isoform of the missing enzyme in skeletal muscle.

      A safety and feasibility study of sodium valproate in people with McArdle disease has been
      carried out in London (UK) and Copenhagen (DK) since January 2015. Participants will receive
      20mg/Kg/day of sodium valproate for 6 months. The primary outcome measure is exercise
      performance assessed by cycle ergometry. Pre and post-treatment skeletal muscle biopsies will
      be performed to assess for glycogen phosphorylase. Together with blood analyses for safety.
      Additional functional exercise tests will be performed.
    

Detailed description: 
      McArdle disease (Glycogen storage disease type V, GSDV) is an inherited metabolic disorder of
      skeletal muscle. Affected patients are unable to perform strenuous exercise due to a
      congenital absence of the enzyme muscle glycogen phosphorylase, essential for glycogen
      metabolism. This enzyme deficiency results in the inability to mobilise muscle glycogen
      stores from muscle, required for energy during strenuous exercise. In affected people
      symptoms of fatigue and cramps occur within minutes of initiating any activity and during
      strenuous activity such as lifting heavy weights or walking uphill, if activity is continued
      despite severe cramping, a contracture occurs which leads to muscle damage (rhabdomyolysis),
      myoglobinuria (dark brown/black discolouration of urine) and, when severe, acute renal
      failure.

      Currently no satisfactory treatment can be recommended other than aerobic exercise. Although
      most people with McArdle disease have complete absence of skeletal muscle phosphorylase,
      there are a small minority of patients who possess splice site mutations that enable
      production of very small amounts (1-2%) of functional enzyme. These people have a milder
      phenotype with less severe symptoms, and functional exercise assessments have shown better
      exercise capacity than typical patients with the condition. Findings from these atypical
      individuals suggest potential therapeutic agents might only need to produce very small
      amounts of enzyme for significant functional improvement. Furthermore, finding a therapeutic
      agent to 'switch on' expression of the foetal isoenzyme may be a potential therapeutic
      strategy. There is some evidence from animal studies to suggest that sodium valproate can
      'switch on' the foetal phosphorylase isoenzyme. The current proposes to undertake a
      feasibility study of 8 participants recruited in the UK and 7 in Denmark.
    

Intervention name(s): Sodium Valproate
Intervention type(s): Drug
Intervention description(s): Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months.
Intervention MeSH terms: Valproic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: McArdle Disease; McArdle's Disease; Glycogen Storage Disease Type V; GSDV; Sodium Valproate; Valproic Acid; Myophosphorylase Deficiency; Muscle Phosphorylase Deficiency; Glycogenosis; Glycogen Storage Disorder