McArdle's Disease

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Welcome to PT 635 Pathophysiology of Complex Patient Problems This is a wiki created by and for the students in the School of Physical Therapy at Bellarmine University in Louisville KY. Please do not edit unless you are involved in this project, but please come back in the near future to check out new information!!

Original Editors - Ed Foring as part of Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Edward Foring, Kaylynn Schwamb, Michael Helton, Lucinda hampton, Elaine Lonnemann, Kim Jackson, Admin, 127.0.0.1, Simone Potts and WikiSysop   Read more.

 

Definition/Description

McArdle’s Disease, also referred to as Myophosphorylase Deficiency, or Type V Glycogen Storage Disease, was first described in 1951 by Dr. Brian McArdle while he was practicing in London, England. The condition is a recessive inherited disorder that presents as an inability to metabolize glycogen, the storage form of glucose. This results in a variety of symptoms affecting the musculoskeletal and urinary systems. Patients afflicted by McArdle’s Disease most commonly suffer from muscle fatigue.

Refer to the model below to see how muscle contraction differs in an unaffected muscle compared to one with McArdle’s Disease.

How Skeletal Muscle Normally Contract	A McArdle's Diease Model
	Image:Energy_2.gif

1. Acetylcholine is released from a motor nerve. This causes an entry of calcium into the muscle cell.	1. Acetylcholine is released from a motor nerve. This causes an entry of calcium into the muscle cell.
2. Calcium activates phosphorylase kinase – the first protein kinase discovered by Fischer and Krebs.	2. Calcium activates phosphorylase kinase – the first protein kinase discovered by Fischer and Krebs.
3. Phosphorylase kinase phosphorylates phosphorylase, which is activated	3. Phosphorylase kinase phosphorylates phosphorylase, which is missing or otherwise non-functional
4. Glycogen is broken to glucose. This is used to generate ATP	4. Glycogen is unable to be broken down, creating glucose (and ATP) shortage.
5. The muscle works and requires energy in the form of ATP	5. Motor proteins attach to muscle fibers require ATP for movement.
6. The muscle contains muscle cells	6. Muscles stop responding in absence of ATP .
7. Contractile proteins in the muscle are activated by calcium	7. Because ATP is required to both contract and relax muscles, injury can occur.

Prevalence

• McArdle's Disease is rare and affects approximately 1 in 100,000 people. However, it is one of the most common disorders affecting muscle metabolism.
• The disease presents more often in men than women.
• It is believed that many people remain undiagnosed.
• It presents in the second to third decade of life with symptoms reported at childhood.

Characteristics/Clinical Presentation

Symptoms typically present 10 seconds after strenous exercise has begun. After 10 seconds of exercise skeletal muscle relies on the conversion of glycogen to glucose to produce ATP which is the main energy source to power muscular contraction.

Premature Exhaustion: Skeletal muscles inability to metabolize glycogen into glucose with strenous activity leads to an abrupt feeling of exhaustion or fatigue, with an increase in heart rate. Individuals might complain of diffculty walking, jogging, ascending and descending steps, or any moderate levels of activity.

Muscle Failure: This particularly occurs under extreme stress where the muscle no longer can produce contraction regardless of the effort made. This is compaired to "wall" runners experience when doing a marathon.

Cramping: Muscle failure leads to electrically-silent contractures which are very painful and can lead to muscle damage.

Rhabdomyolysis: Damage to muscle tissue leads to the release of proteins,creatine kinase and myoglobin, into the blood which are than excreted with urination. These proteins are iron-rich and may cause urine to be a redish color. This

File:Myoglobinuria.jpg

symptom is refered to as myoglobinuria. Myoglobinuria has lead to renal dysfunction, therefore cramping and muscle failure episodes require medical attention.

Fixed Weakness: Muscle damage caused by rhabdomyolysis can lead to muscle weakness that seems to not get physically stronger or is extremely difficult to make strength gains.

Muscle Wasting: Muscle atrophy

Second Wind: The phenomenon has been observed in clincal trials in patients after following a "warm up" period. This second wind does not relieve failure symptoms for intense exercise but offers some relief for light to moderate exercise. Second wind can be monitored through the patients heart rate. Click the link above to learn more.

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Associated Co-morbidities

• Renal Failure: typically associated with rhadbomyolysis and myoglobinuria.
• Gout: Inhibited ATP production leads to the production or purine metabolites. Purine metabolites are than converted to uric acid leading to hyperuricemia. Most common place for gout to form is the first metatarsal however it can be found in the insteps, ankles, heels, knees, wrist, fingers, and elbows.

 

Medications

There are no medications right now that are used to treat McArdle's Disease.

Supplements

• B6 to help reduce fatigue. B6 attaches to myophosphorylase therefore absence of this enzyme might lead to B6 deficiency.
• B5 which is a precursor for pryruvate
• L-Caritine - promotes fat metabolism
• Creatine supplements - helps boost CP levels
• Whey Protein

Diet

Tarnopolsky’s diet recommendations

File:Q11-4 Tarnopolsys-Diet.jpg

• 40% Carbohydrates
• 30% Fats
• 30% Proteins
• A low carbohydrate is not recommended because it will deplete liver glycogen reducing glucose released into the blood stream. This will lead to hypoglycemia when the person becomes active
• With activity taking in a sugary substance or candy bar until "second wind" is achieved is recommended, especially if taking part in any kind of stenuous activity. Please refer to case reports for more information.

Diagnostic Tests/Lab Tests/Lab Values

Creatine Phosphokinase Test 

If lab work is conducted than the patient will have an elevated CPK test. This alone does not conclude the individual has McArdle's disease because CPK values will be elevated due to any muscle breakdown in the system. When the brain, heart or skeletal muscle has significant damage it releases an enzyme called creatine phosphokinase. In McArdle's disease the inability of glycogen to turn into glucose for energy; the muscle breaks down itself releasing this enzyme into the blood stream.

Ischemic Forearm Test

This test is a valuable diagnostic test for a number of metabolic diseases. Speaking generally, the test measures concentration of lactic acid in the blood before and after local exertion of a muscle group. The following protocol description is taken from the University of Florida School of Medicine website:

The test is performed by contracting the forearm to fatigue with a blood pressure cuff inflated to greater than systolic pressure. Antecubital blood samples for lactate and ammonia are collected before and following exercise at 0, 1, 2, 5, and 10 minutes. Ischemia blocks oxidative phosphorylation and ensures dependence on anaerobic glycogenolysis lactate normally rises at least fourfold within 1 to 2 minutes of exercise ammonia rises fivefold within 2 to 3 minutes.

Lactate concetration will rise several-fold under ischemic conditions in normal subjects (o-o-o). There will be no or minimal rise in patients with myophosphorylase deficiency (McArdle’s disease.)

The ischemic forearm test is only slightly uncomfortable to undergo, involving blood samples, a pressure cuff, and a device to squeeze with the hand for forearm muscle contraction, but takes a few hours in order to get blood samples at a resting metabolic rate.

This test has now been replaced by the non-ischemic forearm test.

Non-Ischemic Forearm Test

This test is done in the same manor as the ischemic forearm test but without the blood pressure cuff. Click here to learn more.

Muscle Biopsy
The biopsy looks for the presence of myophosphorylase activity, which is absent in and can confirm diagnosis of McArdle’s disease. Click here to view biopsy images of McArdle's Disease.

 

Etiology/Causes

The cause of this diseas<span id="fck_dom_range_temp_1300418515912_890" /><span id="fck_dom_range_temp_1300418515913_925" />e is due to a missing or non-functioning enzyme that breaks down glycogen into glucose during exercise called myophosphorylase. Genetic involvement shows an autosomal recessive inheritance pattern, requiring two defective copies of the gene for the condition to manifest. Carriers are not known to have symptoms of the disease.

Systemic Involvement

There has not been any long term studies that have found long term effects on the general health on individuals with McArdle's Diease. Typically individuals with this disease are in excellent health as long as the disease is managed properly. If the disease is unmanaged, resulting in constant cases of rhabdomyolysis, it can lead to kidney and liver dysfunctions. 

Precaution: Any patient with McArdle's disease that has cardiovascular complication could be on a statin medication. Statin's increase the potential risk for rhabdomyolysis. Therefore physical activity should be keep to an absolute minimum.

Medical Management (current best evidence)

Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD003458. DOI: 10.1002/14651858.CD003458.pub4

Physical Therapy Management (current best evidence)

One of the biggest roles a physical therapist can provide is keeping the person active because inactivity due to fatigue is very common in patients with McArdle's Disease.

Be Fit

• Optimal exercises programs for managing McArdles Disease are aerobic based; they provide light resistance along with a cardiovascular component.
• A disciplined regimen of aerobic physical activity of low to moderate intensity and duration can improve symptoms and reduce susceptiblity of injury to the muscle.
• Achieve "second wind" for each muscle group that is being worked. Please click here to learn more
• Light to moderate resistance training can be done but allow adequate time to rest inbetween sets,don't work the muscles to absolute fatigue, and work big muscle groups.
• If stenous activity must be done use a 6 second rule, only do that acitivity for 6 seconds prior to resting,  to ensure that only the phosphogen energy system is used in anareobic activity.

Be Flexible

• Stretching should be very light, maximal stretching will work the muscle anaerobically by inducing a protective contraction from the golgi tendon. This strong protective contraction can lead to muscle damage.
• Light stretching or easy passive ROM should be done.
• Stretching following walking offers immediate and dramatic pain relief to individuals.
• Stretching also promotes flexibility in areas that may be susceptible to contractures. 
• For active individuals stretching might have to take place very frequently to help reduce cramping.
• Due to the toxic build up in the muscle from activity, muscles will become tight and therefore stretching can become painful. 

Be Aware, Be Patient and WARM UP

• Individuals can easily over exhert themselves and become injuried without even realizing it.
• Indivduals need to be conscious of their energy levels, their blood sugar, their heart rate, and their general well being.
• Individuals should not avoid physical activity altogether, but if they are faced with a strenuous task they should be instructed to only work in 6 seconds boughts with ample rest to ensure only the phosphagen energy system is being used. 
• During any type of activity they should be instructed to warm up properly until they achieve the "second wind"

Alternative/Holistic Management (current best evidence)

Massage

• Individuals that live with this disease claim that a massage therapist with weekly sessions is necessary to remain active.
• If seeing a massage therapist, the massage should be light and fluid using effleurage techniques. Deep and hard massage for trigger point or myofascial release can be damaging to the muscle and should be avoided.
• Individuals claim the massage can be painful. If massage is painful it should be avoided incase the possibility of rhabdomyolysis is occuring.
• Due to the nature of this disease alot of toxic byproducts, commonly ammonia and urea, are released when the muscles experience activity. These two toxins lead to fatigue and therefore elimination of these toxins from the muscle should help reduce cramping, pain, and fatigue levels.
• Massage therapist help push the toxins out of the muscles and into the blood stream where they can be excreted from the body. It is recommended that you intake plenty of fluids following a massage to help flush the body of any toxins pushed out of the muscles.

Differential Diagnosis

• Rhabdomyolysis
• Fibromyalgia
• Muscular Dystrophy
• Myositis
• Tarui's Disease

Case Reports/ Case Studies

Haller Ronald G and John Vissig.The Effects of Oral Sucrose on Exercise Tolerance in Patients with McArdle's Disease. The New England Journal of Medicine. 2003 349;26 pg 2503-2509

• Please refer to PubMed and Association of Glycogen Storage UK for additional Case Reports and Case Studies

Recent Related Research (from Pubmed)

see tutorial on Adding PubMed Feed

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Resources

• Association for Glycogen Storage Disease UK 
• Association for Glycogen Storage Disease US
• Image:Facebook_icon.gif Join the Facebook Group: McArdle's Disease
• File:Nord.gif Support Community

• www.McArdlesDisease.org 

References

see adding references tutorial.

Special thank you to Andrew Wakelin, McArdle Disease (GSD Type V) Coordinator for AGSD UK for review and insight towards this page.