NORD gratefully acknowledges Megan Usovsky, NORD Editorial Intern from the University of Notre Dame, and Tomàs Pinós, PhD, Departament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron, Institut de Recerca, Universitat Autònoma de Barcelona and Centre for Biomedical Network Research on Rare Diseases , Instituto de Salud Carlos III, for assistance in the preparation of this report.
GSD-V is characterized by exercise intolerance. This typically consists in acute crises of early fatigue and muscle stiffness and contractures, especially at the start of the exercise, that usually disappear if exercise is stopped or the intensity is reduced. Symptoms usually present within the first ten years of life, but there is a wide range of clinical onset and severity. Some GSD-V patients have mild symptoms while another form progresses quickly and is apparent shortly after the person is born. Progressively weak muscles, in some individuals, do not manifest until the age of sixty to seventy years old.
Muscles of affected patients usually function normally while at rest or during moderate exercise. Only during strenuous exercise do severe muscle cramps occur. Exercising in the presence of severe pain results in muscle damage (rhabdomyolysis) and myoglobinuria in about 50% of those affected. The myoglobin protein can also damage the kidneys and lead to develop life-threatening kidney failure if not treated promptly.
A unique feature of the disease is the so-called “second wind” phenomenon, which most patients refers to as the ability to resume dynamic, large mass exercise, if they take a brief rest upon the appearance of premature fatigue early in exercise. This “second wind” phenomenon is present in approximately ~90% of people with GSD-V.
A severity scale has been developed to describe the variation in clinical features:
GSD-V is caused by mutations in the PYGM (glycogen phosphorylase, muscle form) gene that codes for the myophosphorylase enzyme. The PYGM gene is located on chromosome 11 at 11q13.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q13” refers to band 13 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait which are on the chromosomes received from an individual’s father and mother.
GSD-V is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to each carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
GSD-V is very rare with only a few hundred cases reported in the medical literature. Some researchers believe that it is probably under-diagnosed because of the mildness of the symptoms. The neonatal, early-onset and very late-onset forms are even rarer. The prevalence of GSD-V in the Dallas-Fort Worth, TX area has been estimated at 1:100,000 and the prevalence in Spain has been reported at 1:170,000.
Traditionally, diagnosis has been based on the inability of the patient to produce lactate during a forearm exercise test, lack of muscle glycogen phosphorylase on muscle biopsy (generally from vastus lateralis or biceps brachialis muscles), and more recently DNA studies to look for mutations in the PYGM gene. Additionally, the measure of plasma CK levels as well as the determination of the “second wind” phenomenon help to precisely provide a correct diagnosis. Currently, the diagnosis of GSD-V is mainly based on the molecular analysis of DNA obtained from blood samples. This is a minimally invasive method, and given the accumulated knowledge on the genetics of this disease in different populations, it can be highly targeted. Gene sequencing after PCR amplification is the most frequently utilized technique for screening the different PYGM mutations.
At present there is no curative therapy for GSD-V, but several different therapeutic approaches have been utilized.
No significant beneficial effects have been reported in GSD-V patients receiving branched chain aminoacids, depot glucagon, dantrolene sodium, verapamil, vitamin B6 or high-dose oral ribose. More controversial results have been obtained for creatine supplementation; low dose supplementation (60 mg/kg/day for 4 weeks) reduced muscle complaints in five of nine patients tested, but higher doses (150 mg/kg/day) actually increased exercise induced myalgia.
However, a beneficial intervention for alleviating exercise intolerance symptoms and protecting the muscle from rhabdomyolysis consists of ensuring that sufficient blood glucose is constantly made available to patients during daytime. This can be achieved by adopting a diet with high proportion (65%) of complex carbohydrates (as those found in vegetables, fruit, cereals, pasta and rice) and low fat (20%). A different strategy could be the ingestion of simple carbohydrates before engaging in a strenuous exercise (75 g of sucrose 30-40 min pre-exercise).
GSD-V patients adapt favorably to regular exercise, with a significant increase in VO2 peak after supervised aerobic exercise. In fact, it has been shown that physically active patients are much more likely to improve their clinical course over a four year period compared with their inactive peers.
The substitution of guanine for thymine at nucleotide 148 of the exon 1 of the PYGM gene is the most common mutation among Caucasians. This variation shows an allele frequency above 50% in the studied cohorts of Caucasian GSD-V patients. This mutation (p.R50X) generates a premature termination codon (PTC), which leads to a self-protective process known as non-sense mediated decay (NMD), which eliminates the majority of messenger RNA transcripts containing this type of mutation. The fact that several compounds might restore protein translation by inducing the ribosome to bypass a PTC (a process known as read-through), provides a promising perspective. However, a preliminary trial with short-term (10 days) gentamycin treatment in GSD-V patients with PTC failed to normalize P31-MRS indicators of myophosphorylase deficiency in the muscle. Further studies need to be performed to further ascertain the potential beneficial effects of read-through compounds treatment in GSD-V patients.
Induced expression of the brain and liver glycogen phosphorylase isoforms in the muscle
The brain and liver isoforms of glycogen phosphorylase are only expressed in muscle tissue in the uterus, in neonates, and in regenerating mature fibers, but not in adult non-regenerating mature fibers, where only the muscle isoform is expressed. Thus, any pharmacologic treatment able to upregulate the expression of the liver and brain isoforms of glycogen phosphorylase in mature muscles might be able to reduce the symptoms of the disease. In fact, treatment of the primary skeletal muscle cultures derived from the McArdle mouse model with sodium valproate induces expression of Pygb mRNA and protein, and consequently reduces the glycogen deposits observed in these cells. Additionally, myophosphorylase positive fibers were identified in five of seven sheep treated with this drug. Currently, a clinical trial sponsored by the University College of London and the University of Copenhagen is being developed:
Gene therapy using an adenovirus 5 vector and an adeno-associated virus serotype 2 containing myophosphorylase expression cassettes has been evaluated in the ovine model of GSD-V. Intramuscular application of both vectors produced local expression of functional myophosphorylase, limited to the surroundings of the injected site. Additionally, the number of fibers expressing myophosphorylase diminished with time, probably due to an immune response. Further gene-therapy studies in the McArdle animal models need to be performed to determine the potential benefits of this approach in GSD-V patients.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
For information about the European registry of GSD-V patients and other rare forms of neuromuscular glycogenosis, contact: http://euromacregistry.eu/portal1/default.asp
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