A Phase II Pilot Study to Explore Treatment With Sodium Valproate in Adults With McArdle Disease (Glycogen Storage Disorder Type V, GSDV)
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.
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
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.
Change in VO2peak
Presence of phosphorylase positive fibres
Glycogen Storage Disease Type V
Study Arms / Comparison Groups
Description: Subjects will receive sodium valproate modified release 20mg/kg/day (maximum dose 2.0g/day) administered orally once daily for six months.
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
April 5, 2017
Primary Completion Date
April 5, 2017
- Male subjects and post-menopausal or infertile females
- Diagnosed with GSDV and over 18 years of age
- Normal serum carnitine level and acylcarnitine blood profile at screening visit
- Children under the age of 18 years
- People older than 64 years
- Females of child bearing potential
- Patients with Diabetes
- Inflammatory disorders especially systemic lupus erythematosis.
- A previous history of sensitivity/allergy to sodium valproate and its excipients
- Patients treated with sodium valproate for epilepsy or a psychiatric disorder within
the last 12 months prior to screening
- Patients with pre-existing liver disease or a family history of severe liver disease
affecting a first degree relative. Liver disease will be defined by abnormal liver
biopsy. Patients with GSDV may have raised serum transaminases that originate from
muscle but which may cause abnormal liver function tests measured in serum, this will
not be a reason for exclusion.
- Patients prescribed other anti-convulsant medication or any other medication known to
interact with sodium valproate (see section 9.3).
- Patients who are sensitive to local anaesthetics that would prevent muscle biopsy.
- Subjects with any co-morbid illness or disability which would prevent an exercise
assessment such as severe unstable/ untreated ischaemic heart disease, lower limb
disability such as severe muscle weakness with muscle strength assessed as worse than
MRC scale 3 in any pelvic girdle muscle.
- Inability to exercise due to a lower limb fracture would be an exclusion criterion
until there is complete recovery of the injury.
- Patients known to have porphyria or an affected first degree relative affected with
porphyria will be excluded from the study.
- Patients known to have mitochondrial disease or where there is a first degree relative
with mitochondrial disease.
- Patients with a history of abnormal acyl carnitine profile or low serum carnitine
- Male participants unwilling to use contraception
18 Years - 64 Years
Accepts Healthy Volunteers
Ros Quinlivan, FRCPCH, MD, ,
University College, London
Ros Quinlivan, FRCPCH, MD, Principal Investigator, University College, London