McArdle Disease

Updated April 6, 2020

This article was scientifically reviewed by YourDNA

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A list of references is also included at the bottom of this article.

McArdle disease is an inherited disorder that occurs when the body is not able to break down a complex sugar called glycogen, which is used as an energy source in muscle cells.

A lack of glycogen breakdown interferes with muscle cell functions. Glycogen is a critical energy source stored in all tissues, especially in the muscles and liver.

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What is McArdle Disease? 

Medically speaking, McArdle disease is caused by a deficiency of muscle isoform of a skeletal muscle enzyme that initiates glycogen breakdown. Specifically, this enzyme is known as glycogen phosphorylase myophosphorylase or PYGM.

Due to advancements in genetic research, more than 65 mutations of the PYGM gene have been found since the first clinical description of the disease in 1951.

McArdle disease is also known by several other names:

  • glycogen storage disease type 5
  • glycogenosis 5
  • GSD type V
  • GSD V
  • McArdle syndrome
  • McArdle type glycogen storage disease
  • McArdle's disease
  • muscle glycogen phosphorylase deficiency
  • muscle phosphorylase deficiency
  • myophosphorylase deficiency
  • PYGM deficiency

When McArdle disease is present, it is characterized by exercise intolerance, fatigue, a lack of endurance, and muscle cramps in children and adolescents.

As the condition advances into adulthood, progressive muscle weakness may lead to atrophy with fatty replacement. Overall, McArdle disease is a relatively benign condition.

However, exercise may cause a condition known as transient myoglobinuria. A severe form of this causes the destruction of muscle tissue and releases a protein called myoglobin, which is filtered through the kidneys, released in the urine, and can possibly lead to kidney failure over time.

In most cases, McArdle disease is progressive, getting worse over time. However, in about one-third of all cases, the disease stabilizes, resulting in a leveling out of muscle weakness. 

Signs and Symptoms of McArdle Disease 

About 10% of people with McArdle disease experience minor symptoms or no symptoms at all. The intensity of the symptoms can vary widely from person to person, and any skeletal muscle can be affected.

For those who do have symptoms, they usually appear during early childhood, but may also develop later in life, during the late teens, or even until a person is as old as 30.

In a few rare cases, progressive weakness may not manifest until a person is in their 50s or 60s.

Classic symptoms of McArdle disease are:

  • Exercise intolerance or poor stamina
  • Fatigue
  • Muscle cramps and stiffness
  • Muscle weakness
  • Muscle contractions

Discomfort caused by McArdle disease is usually alleviated through rest after attempting exercise. After resting and waiting for the pain to go away, an individual can usually resume exercising with little or no discomfort, which is known as getting a "second wind." However, prolonged or intense exercise can cause permanent muscle damage.

The ability to develop a second wind is enhanced for people who stay physically fit with regular aerobic exercise, such as walking.

There are also possible complications that can result from McArdle disease.

About half of people with McArdle disease experience muscle tissue breakdown, also known as rhabdomyolysis. When the destruction is severe, the muscle tissue will release a protein called myoglobin that is filtered through the kidney and released in urine. This is called myoglobinuria 1.

In severe cases, kidney failure can result. Kidney failure is almost always reversible, but it must be treated on an emergency basis 2.

Although uncommon, other complications can include difficulty chewing, dysphagia, and impaired oral motor functions.

Spontaneous compartment syndrome, mostly in those patients with diabetes, can also occur and will require immediate medical attention. It is caused by swelling or bleeding of a non-contracting muscle, meaning blood cannot circulate to muscle and nerves to supply them with nutrients and oxygen.

A few cases of severe obstructive hypertrophic cardiomyopathy have also been reported.

General anesthesia can sometimes cause complications, so be sure to ask your doctor if you need surgery for any reason.

Prevalence and Risk Factors for McArdle Disease

The incidence of McArdle disease is rare, and it is difficult to pinpoint how prevalent it is due to a lack of data. However, in the Dallas-Forth Worth area, where the disease has been studied, it is estimated to affect 1 in 100,000 people 3.

Since McArdle disease is inherited in an autosomal recessive pattern, the most significant risk factor is having at least one parent with a mutated PYGM gene.

Causes and Diagnosis of McArdle Disease

PYGM gene mutations cause McArdle disease. This gene provides instructions for making an enzyme called myophosphorylase, found only in muscle cells.

The enzyme breaks down glycogen into a simpler sugar called glucose-1-phosphate, which is then converted into glucose. This is a simple sugar that provides the main energy source for most cells.

Mutated genes prevent myophosphorylase from breaking down glycogen effectively. This means muscles can't produce enough energy, and they become easily fatigued. That fatigue causes the symptoms of McArdle disease to manifest.

There are several clinical indications that a person may have McArdle disease.

  • The onset of exercise-induced muscle pain and contractions, especially in the first 10 minutes of exercise, is a clear indicator.
  • This may be followed by the second-wind phenomenon, whereby cramps or pain lessens after a brief rest period or when exercise intensity is reduced.
  • The appearance of dark-colored urine.
  • Problems chewing, swallowing, or difficulties with oral motor functions.
  • Spontaneous compartment syndrome.
  • Contraction of neck muscles during dental procedures.
  • A wide range of high resting serum creatine kinase (CK) activity. 

Several tests may be used to help detect the presence of McArdle disease. These may include:

Because McArdle disease is inherited in an autosomal recessive pattern, several genetic tests can be used to diagnose the condition.

The goal is to look for PYGM pathogenic variants through targeted gene testing (with either a single gene or multigene panel) and a comprehensive genomic test using exome sequencing or genome sequencing.

Targeted testing requires a clinician to determine which gene is most likely to be involved. Genomic testing does not. Because the phenotype of McArdle disease is broad, people with possible clinical findings usually undergo targeted testing.



If McArdle disease has not been specifically considered, then a genome sequencing test is a more likely course of action.

In targeted gene testing, PYGM is analyzed to try and find variants, or mutations, in the gene. A metabolic myopathy multigene panel will include PYGM and other genes that may help provide a differential diagnosis if variants are found.

Genes included in the testing panel will vary by laboratory and could change as research advances.

Comprehensive exome and genome sequencing may be used to detect multiple exon deletions or duplications that can’t be detected by a targeted sequence analysis 4.

With an autosomal recessive inheritance pattern, two copies of an abnormal gene must be present for McArdle disease to develop.

If both parents carry the mutation, then a child has a 1 in 4 chance of inheriting the gene from both parents, which can lead to developing McArdle disease. That is because a person has a 50% chance of inheriting one abnormal gene, multiplied by two parents, results in a 25% chance.

A child born to a couple who both carry an abnormal gene means the outcome for each pregnancy is:

  • A 25 percent chance that the child is born with two normal genes (normal)
  • A 50 percent chance that the child is born with one normal and one abnormal gene (carrier, without disease)
  • A 25 percent chance that the child is born with two abnormal genes (at risk for the disease) 

Genetic counseling is an effective way to learn about the risks associated with McArdle disease. Ideally, if the abnormal gene is suspected or has been diagnosed, the best time to undergo genetic counseling is before pregnancy for family planning awareness and education.

Some counselors may recommend DNA banking to create stored DNA for possible future testing, as the understanding of genes and possible treatments improves over time.

Prenatal testing is also possible to determine if there is an elevated risk. Some medical professionals may not offer prenatal testing if it is being considered to determine if a pregnancy should be terminated or not.

Treatment and Care Options for McArdle Disease 

There are several general ways to treat symptoms of McArdle disease. There is no cure.

One of the most effective means is also one of the simpler regimens. Following a healthy lifestyle that includes a diet rich in vitamin B6, complex carbohydrates and proteins, and getting regular exercise is the best way to prevent and manage exercise intolerance related to McArdle disease.

For optimum results, the regimen should be professionally set up and supervised to ensure the right progression of intensity ramps up. For children who suffer from McArdle disease, parents, educators, and caregivers must also be well informed about how to best manage a person with McArdle disease.

It is possible for some people to become asymptomatic during normal activities in some cases.

Typically, patients are advised to avoid resistance training or lifting weights involving heavy loads for prolonged periods. Any exercise involving jumping, handgrip exercises, or competitive, high-intensity aerobic sports should also be avoided.

Swimming, cycling, or long-distance running is also not advised in most cases.

One strenuous activity that does not appear to be impacted is pregnancy and childbirth.

Nutritionally, diets that show some benefit include those that include oral sucrose, a high carbohydrate diet, ramipril, and low-dose creatine.

Drinking a high content sugary drink before exercise tends to improve performance. Taking a low-dose creatine supplement has also shown to increase the tolerance to exercise is some individuals.

Ramipril (Altace) is an angiotensin converting enzyme (ACE) inhibitor. It is often used to treat high blood pressure and congestive heart failure, as well as improving survival after a person has a heart attack. As an ACE inhibitor, it works by relaxing blood vessels so that blood can flow more freely 5.

Part of the problem with developing an effective nutritional and pharmacological protocol treatment is that McArdle disease is so rare, that it is difficult to develop standardized protocols that can be analyzed.

Prognosis of McArdle Disease 

People with McArdle disease can live a healthy life with a normal life expectancy if they manage their diet and physical activities.

What to do Next: Living with McArdle Disease 

Genetic counseling can be an effective way to educate yourself on the impacts of McArdle disease. You can better understand risk factors, genetic issues, and specific issues related to the condition.





There are also many organizations worldwide that can provide you with detailed information as well.

Muscular Dystrophy Association - USA (MDA)

222 South Riverside Plaza

Suite 1500

Chicago IL 60606

Phone: 800-572-1717

Email: [email protected]

www.mda.org

McArdle syndrome


National Organization for Rare Disorders (NORD)


Association for Glycogen Storage Disease

United Kingdom

Email: [email protected]

McArdle Disease (GSD5)


Association for Glycogen Storage Disease - US


Metabolic Support UK

5 Hilliards Court, Sandpiper Way

Chester Business Park

Chester CH4 9QP 

United Kingdom

Phone: 0845 241 2173

Email: [email protected]

www.metabolicsupportuk.org


EUROMAC

Spain

www.catalogue.rd-connect.eu/web/euromac

Referenced Sources

  1. Glycogen storage disease type V.
    Genetics Home Reference. Reviewed: June 2014, Published: March 31, 2020.
  2. Glycogen Storage Disease Type V.
    Miguel A Martín, PhD, Alejandro Lucia, MD, PhD, Joaquin Arenas, PhD, and Antonio L Andreu, MD, PhD.
    Initial Posting: April 19, 2006; Last Update: June 20, 2019.
  3. Glycogen storage disease type V.
    Genetics Home Reference. Reviewed: June 2014, Published: March 31, 2020.
  4. What are whole exome sequencing and whole genome sequencing?
    Genetics Home Reference. Published: March 31, 2020.
  5. Ramipril.
    WebMD. Retrieved online, March 2020.