McArdle Disease Treatment by Ketogenic Diet

Brief Title

McArdle Disease Treatment by Ketogenic Diet

Official Title

Ketogenic Diet in McArdle Disease: a Multicentric Single Blind Controlled Trial

Brief Summary

      McArdle's disease or Glycogen storage disease type 5 (GSD5), the most common muscle
      glycogenosis, is a rare disabling condition with no effective treatment. There are
      indications that a special dietary regimen could positively influence the disease
      manifestations. After contradictory indications for protein rich vs carbohydrate rich diets,
      several preliminary studies and more and more patients own experiences are now pointing to a
      low carbohydrate ketogenic diet (LCKD) as possibly effective in improving exercise tolerance
      and reducing muscle damage. The investigators propose a multicentre randomized single blind
      controlled trial testing efficacy of an individualized LCKD in GSD5. The investigators will
      test the ability of a 6 months dietary regimen with a 3:1 LCKD inducing a BOHB blood
      concentration of 1.5-4 mmol/l to improve the aerobic capacity as measured by peak VO2 at
      exercise testing in GSD5 patients. Thirty molecularly defined MCA adults will be enrolled: to
      half of them randomly selected the dietary regimen will be prescribed, while subjects in the
      control group will follow their usual balanced diet. The evaluators will be blinded to the
      diet followed by the examined patient

Detailed Description

      McArdle disease (myophosphorylase deficiency, glycogen storage disease type 5, GSD5, OMIM #
      232600) is an inherited metabolic disorder of skeletal muscle. Affected patients suffer from
      genetically determined lack of the enzyme muscle glycogen phosphorylase, which is essential
      for glycogen metabolism. The condition is caused by homozygous or compound heterozygous
      mutations in the muscle glycogen phosphorylase gene (PYGM) located at chromosome 11q13. Many
      pathogenic mutations have been identified in the gene, which spans 20 exons, and many are
      population specific. The most common mutation in Northern Europe and North America is a
      nonsense mutation at Arg50stop (R50X) in exon 1 (previously referred to as R49X). A second
      frequent mutation in this population, and in Spanish patients, is Gly205Ser (G205S). McArdle
      disease is a rare disorder with an estimated incidence of 1:100,000.

      Complete absence of muscle phosphorylase results in the inability to mobilize muscle glycogen
      stores, which are normally required as substrate for energy generation during anaerobic
      metabolism, which occurs during start of exercise and high-intensity efforts. In affected
      people, symptoms of fatigue and discomfort therefore occur within minutes of initiating any
      activity and during strenuous activity such as lifting heavy weights or walking uphill. If
      the activity is continued despite symptoms, a severe cramp (which is called a contracture in
      GSD5, because the muscle contraction is not caused by neural stimulation) occurs, which leads
      to muscle damage. If the damage is substantial, acute rhabdomyolysis may occur, which in turn
      can result in dark brown/black discoloration of urine (myoglobinuria). When rhabdomyolysis is
      severe, myoglobinuria can lead to acute renal failure, requiring treatment with dialysis.

      In patients with GSD5, aerobic metabolism is limited and varies as a function of the
      availability of alternative fuels as a function of exercise and diet. The second wind
      phenomenon is illustrative. The phenomenon is characterized by the ability to increase work
      output after about 7-8 minutes of exercise. The second wind occurs as a consequence of
      increased availability and metabolism of alternative fuel substrates, preferentially glucose
      supplied from the liver, but also free fatty acids metabolized through oxidative
      phosphorylation and ketones produced by the liver. Despite these compensatory fuels, which
      can substitute for the absent glycogen breakdown in muscle, the capacity for oxidative
      phosphorylation is impaired in GSD5, because of an almost complete absence of pyruvate, a
      by-product of glycolysis.

      Reduced oxidative phosphorylation in untrained patients with GSD5 in turn reduces oxygen
      consumption to approximately 35% of normal and there is a disproportionate increase in heart
      rate during exercise in patients with GSD5 compared with healthy controls. Thus,
      unconditioned people with GSD5 have very limited exercise capacity, which affects quality of

      Most patients present in the second or third decade, although symptoms are often reported
      retrospectively from childhood. With advancing age a 20-25% proportion of patients develop
      fixed muscle weakness predominantly affecting the shoulder girdle. No clear cut
      genotype-phenotype correlation has been found to explain the clinical variation in severity
      observed even within families, but the influence of polymorphisms in other genes has been

      Currently, there is no treatment for the condition. There have been a small number of
      randomized controlled treatment trials, however the largest number of participants in any
      previous study was 19.

      Taking glucose prior to exercise alleviates muscle symptoms by inducing a 'second wind' at
      the onset of exercise, but has detrimental effects on weight if used too frequently. A
      Cochrane systematic review of training in GSD5 identified a few non-randomized trials of
      aerobic training or dietary manipulation either with supplements such as creatine or with
      shift towards lipid sources, which showed no harmful effect and suggest benefit over a number
      of months however long-tern results and confirmation on larger cohorts are warranted.

      In spite of these indications, controlled training and dietary habits are seldom followed by
      patients, who experience significant limitations in activity of daily living and restriction
      in their participation.

      A key limitation to exercise in GSD5 is the bottleneck in fuel flow through the Tri
      Carboxylic Acid (TCA) cycle, which is imposed by the minimal supply of glucosyl units from
      muscle glycogen and thus glycolytic flux to feed the TCA cycle.

      Dietary manipulation has been identified since the eighties as a potential strategy to
      improve functioning in GSD5. In spite of initial indications for high protein regimens, later
      experimental comparison of high protein vs high carbohydrate diets indicated a superiority
      for the latter. Particular interest was also focussed on diets with predominant lipid energy
      source (ketogenic or low carbohydrate ketogenic LCKD) with the assumption that ketones are
      easily taken up by mitochondria and can substitute for the missing acyl-CoA moieties not
      provided by the staggering glycolysis blocked upstream for the inaccessibility of muscle
      glycogen. LCKD has a long history as a therapeutic strategy for several conditions (epilepsy,
      PDH defect, GLUT1 defect) with a good record of safety and efficacy and a poorer record of
      tolerability. Isolated experiences of LCKD have been carried out in GSD5 patients (maximum 4
      patients) with promising results.

Study Type


Primary Outcome

Change in maximal (peak) oxidative capacity (VO2max)

Secondary Outcome

 heart rate


Glycogen Storage Disease


Low carbohydrate ketogenic diet

Study Arms / Comparison Groups

 Ketogenic diet
Description:  patients will follow a low carbohydrate high lipid personalized diet causing blood BOHB level to be between 1.5-4 mmol/l for six months


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Dietary Supplement

Estimated Enrollment


Start Date

March 25, 2019

Completion Date

June 30, 2021

Primary Completion Date

December 31, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  molecularly defined Glycogen storage disease type 5, ability to perform a cycle
             ergometer exercise test

        Exclusion Criteria:

          -  pregnancy,

          -  medical condition preventing a LCKD regimen (CPT2 or acyl-CoA deficiency, liver heart
             or kidney failure, unstable diabetes).




18 Years - N/A

Accepts Healthy Volunteers



Andrea Martinuzzi, MD, PhD, , 

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

IRCCS Eugenio Medea


 University of Pisa

Study Sponsor

Andrea Martinuzzi, MD, PhD, Principal Investigator, IRCCS E Medea

Verification Date

August 2021