McArdle's Disease: Difference between revisions

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== Definition/Description ==
== Definition/Description ==
[[File:Chromosome-DNA-gene copy.jpg|right|frameless]]
McArdle disease is a [[Genetic Conditions and Inheritance|genetic disorder]] that mainly affects [[Muscle Cells (Myocyte)|skeletal muscles]]. It occurs due to the deficiency or absence of an [[Enzymes|enzyme]] called myophosphorylase, a key substance that the [[Muscle|muscles]] need to break down [[glycogen]] into sugar (glucose) for energy. Symptoms include painful [[Exercise-Associated Muscle Cramps|muscle cramps]], weakness, and fatigue manifested during periods of [[Physical Activity|physical activity]].<ref name=":0">Khattak ZE, Ashraf M. [https://www.statpearls.com/articlelibrary/viewarticle/24796/ McArdle Disease.] StatPearls [Internet]. 2020 Aug 15. Available:https://www.statpearls.com/articlelibrary/viewarticle/24796/ (accessed 23.10.2021)</ref> The disease can lead to dark [[urine]]. 


McArdle disease is a [[Genetic Disorders|genetic disorder]] that mainly affects [[Muscle Cells (Myocyte)|skeletal muscles]]. It occurs due to the deficiency or absence of an [[Enzymes|enzyme]] called myophosphorylase, a key substance that the muscles need to break down glycogen into sugar (glucose) for energy. Symptoms include painful muscle cramps, weakness, and fatigue manifested during periods of [[Physical Activity|physical activity]].<ref name=":0">Khattak ZE, Ashraf M. [https://www.statpearls.com/articlelibrary/viewarticle/24796/ McArdle Disease.] StatPearls [Internet]. 2020 Aug 15. Available:https://www.statpearls.com/articlelibrary/viewarticle/24796/ (accessed 23.10.2021)</ref> The disease can lead to dark urine. 
* Severe, uncontrolled McArdle disease can cause life-threatening [[kidney]] problems.<ref name=":1">Cedars Sinai [https://www.cedars-sinai.org/health-library/diseases-and-conditions/m/mcardle-disease.html McArdle Disease] Available: https://www.cedars-sinai.org/health-library/diseases-and-conditions/m/mcardle-disease.html (accessed 23.10.2021)</ref>
 
* Severe, uncontrolled McArdle disease can cause life-threatening kidney problems.<ref name=":1">Cedars Sinai [https://www.cedars-sinai.org/health-library/diseases-and-conditions/m/mcardle-disease.html McArdle Disease] Available: https://www.cedars-sinai.org/health-library/diseases-and-conditions/m/mcardle-disease.html (accessed 23.10.2021)</ref>
* To avoid the unpleasant symptoms associated with this condition and improve the [[Quality of Life|quality of life]], the disease requires prompt diagnosis and treatment.<ref name=":0" />  
* To avoid the unpleasant symptoms associated with this condition and improve the [[Quality of Life|quality of life]], the disease requires prompt diagnosis and treatment.<ref name=":0" />  


== Etiology ==
== Etiology ==
McArdle disease typically results from mutations involving the muscle-specific isoform of the glycogen phosphorylase enzyme (abbreviated as PGYM). This enzyme plays a key role in the first step of glycogenolysis that release glucose-1-phosphate monomers in muscle fibers. As a result, carbohydrate metabolism of the skeletal-muscle is affected, and energy cannot be generated from the glycogen stores of muscles.
McArdle disease typically results from mutations involving the muscle-specific isoform of the glycogen phosphorylase enzyme. This enzyme plays a key role in the first step of [[Glycolysis|glycogenolysis]] that release glucose-1-phosphate monomers in muscle fibers. As a result, [[Carbohydrates|carbohydrate]] metabolism of the skeletal-muscle is affected, and energy cannot be generated from the glycogen stores of muscles.


Refer to the model below to see how muscle contraction differs in an unaffected muscle compared to one with McArdle’s Disease.<br>  
Image 2:How muscle contraction differs in an unaffected muscle compared to one with McArdle’s Disease.<br>  


[[Image:Screen Shot 2017-04-04 at 10.14.25 PM.png|center|771x771px|alt=]]<ref name="p1">MedPoster 1992. nobelprize.org. [cited 3 April 2011]. Available from: http://nobelprize.org/nobel_prizes/medicine/laureates/1992/illpres/glycogen.html</ref><ref name="p2">McArdlesDisease.org. [cited 17 March 2011]. Available from: www.mcardledisease.org</ref>  
[[Image:Screen Shot 2017-04-04 at 10.14.25 PM.png|center|771x771px|alt=]]<ref name="p1">MedPoster 1992. nobelprize.org. [cited 3 April 2011]. Available from: http://nobelprize.org/nobel_prizes/medicine/laureates/1992/illpres/glycogen.html</ref><ref name="p2">McArdlesDisease.org. [cited 17 March 2011]. Available from: www.mcardledisease.org</ref>  
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== Characteristics/Clinical Presentation ==
== Characteristics/Clinical Presentation ==
McArdle disease causes muscle symptoms. Generally, it can make it hard to exercise without becoming tired, this may not happen with gentle walking. With strenuous exercise for more than a few minutes person may notice that after a brief rest you feel a “second wind” that lets you exercise again. These symptoms can vary in intensity. Some common symptoms of McArdle disease are:
McArdle Disease patients can have critical episodes of early fatigue when exercising, muscle pain (myalgia), myoglobinuria (when muscles break down and release myoglobin in urine, making it brown/red in colour), and then subsequent kidney failure<ref name=":2">Brain Foundation McArdle Disease Award - 2012 Available: https://brainfoundation.org.au/research-grants/2012/mcardle-disease-award/ (accessed 23.10.2021)</ref>. Some common symptoms of McArdle disease are:


* Better able to do aerobic exercise after 8 to 10 minutes (second-wind phenomenon)
* Better able to do aerobic exercise after 8 to 10 minutes (second-wind phenomenon)
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Most of the time, people notice these symptoms before age 15. Often, people assume the symptoms are “growing pains” or due to some other cause. Different people may have symptoms of different severity eg person noticing that the symptoms seem worse or better at different times.<ref name=":1" />
Most of the time, people notice these symptoms before age 15. Often, people assume the symptoms are “growing pains” or due to some other cause. Different people may have symptoms of different severity eg person noticing that the symptoms seem worse or better at different times.<ref name=":1" />


== Associated Co-morbidities ==
== Diagnosis ==
Some diagnostic tests include:


[[Image:Untitled2.png|right|300x200px]]  
* [[Blood Tests|Blood tests]] to check for muscle enzymes, such as creatine kinase
* DNA blood tests for known McArdle disease mutations
* Electromyography to measure the electrical activity of the muscles
* Forearm exercise test
* [[MRI Scans|MRI]] studies of your muscles
* Muscle biopsy to examine the muscle cells for glycogen buildup
* Urine tests to check for myoglobin, which darkens the urine<ref name=":1" />


*'''Renal''' '''Failure''': Kidney dysfunction and failure are associated with rhadbomyolysis and myoglobinuria.
== Associated Co-morbidities ==
 
*[[Chronic Kidney Disease|'''Renal''' '''Failure''']]: Kidney dysfunction and failure are associated with rhadbomyolysis and myoglobinuria.
*'''Gout''': Inhibited ATP production leads to the production or purine metabolites. These metabolites are converted to uric acid, which can lead to hyperuricemia. The 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 as well.<br>
 
<br>
 
<ref name="p1" /><ref name="p2" /><ref>Driver MDCB. Gout Causes, Diet, Symptoms, Treatment &amp; Medication [Internet]. MedicineNet. [cited 2017Apr5]. Available from: http://www.medicinenet.com/gout_gouty_arthritis/article.htm</ref>
 
== Medications ==
 
There are currently no medications used to treat McArdle's Disease.<br>
 
=== Supplements  ===
 
[[Image:Untitled3.png|right|300x200px]]
 
*'''Vitamin''' '''B6''' (mixed evidence): Izume et al. found decreased fatigue and increased glycogenolysis as seen on the ischemic forearm test with B6 supplementation. Beynon et al. found no significant improvements compared to a placebo treatment. However, approximately 80% of vitamin B6 binds to myophyphoralyse, so patients with McArdle’s Disease may need to supplement B6 to avoid deficiency.<br>
 
*'''Ramipril''': 2.5 mg orally daily showed some subjective improvement in participants with the D/D ACE polymorphism
*'''Creatine''' '''supplements''': Vorgerd et al. found an increase in exercise tolerance of workload and depletion in phosphocreatine with low levels of creatine supplementation, but an increase in symptoms with high levels of creatine supplementation.
*'''Oral''' '''Sucrose''': Vissing et al. concluded that oral ingestion of sucrose can significantly improve exercise tolerance in McArdle’s Disease. However, overtime this supplementation may cause weight gain and is contraindicated for any individual with diabetes.
*There is a lack of evidence to show benefit from supplementation with branched chain amino acids, depot glucagon, dantrolene sodium, verapamil or, high-dose oral ribose.<br>
 
<ref name="p9">Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). 2017.</ref><ref>B. Vitamin B6 (pyridoxine) │ Nutrients │ Health Benefits [Internet]. Bujint. 2016 [cited 2017Apr5]. Available from: https://bujint.com/vitamin-b6/</ref>
 
=== Diet  ===
 
*Carbohydrate-rich diet: (20% fat, 15% protein and 65% carbohydrate)
*Anderson et al. found that this diet, compared to a protein rich diet (55% protein, 30% carbohydrate and 15% fat), resulted in a significant drop in heart rate and work effort with a 25% increase in maximal oxygen uptake.
*A low carbohydrate diet is not recommended because it will deplete liver glycogen and reduce the amount of glucose released into the blood stream. This will lead to hypoglycemia (low blood sugar) when the person becomes active.
*It is recommended to consume a sugary drink or snack before participating in strenuous activity to provide the body with immediate energy before the second wind is achieved.<br>
 
<ref name="p6">Izumi R, Suzuki N, Kato K, Warita H, Tateyama M, Nakashima I et al. A Case of McArdle Disease: Efficacy of Vitamin B6 on Fatigability and Impaired Glycogenolysis. Internal Medicine. 2010;49(15):1623-1625.</ref><ref name="p8">Association of Glycogen Storage Disease. Second Wind. [cited 20 April 2011] Available from: http://www.agsd.org.uk/Home/GSDTypes/TypeVMcArdledisease/ExerciseandMcArdledisease/Secondwind/tabid/1386/Default.aspx</ref><ref name="p8" />
 
== Diagnostic Tests/Lab Tests/Lab Values ==
 
=== Creatine Phosphokinase Test  ===
 
When lab work is conducted on a patient with McArdle’s Disease, creatine phosphokinase (CPK) will be elevated; however, this value alone does not indicate that the individual has McArdle's Disease. CPK values will be elevated due to muscle breakdown in the system because the enzyme is released into the blood stream any time the brain, heart, or skeletal muscle undergoes significant damage.<br>
 
=== Ischemic Forearm Test  ===
 
The Ischemic Forearm Test is a valuable diagnostic tool for many metabolic diseases as it measures concentration of lactic acid in the blood before and after local exertion of a muscle group.&nbsp;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 levels normally rises at least fourfold within 1 to 2 minutes of exercise and ammonia rises fivefold within 2 to 3 minutes.
*Lactate concentration will rise several-fold under ischemic conditions in normal subjects. There will be no or minimal rise in patients with McArdle’s Disease.
*The ischemic forearm test is uncomfortable to undergo, and may take hours to get blood samples at a resting metabolic rate.
*This test may produce false negative or false positive results, and has now been replaced by the non-ischemic forearm test.<br>
 
===  Non-Ischemic Forearm Test'' ''  ===
 
This test is done in the same manner as the ischemic forearm test but without the blood pressure cuff.&nbsp;Kazemi-Esfarjani et al. described one method of this test below.
 
'''Aerobic 100% Maximal Voluntary Handgrip (MVC) Test'''
 
*Kazemi-Esfarjani et al. recommend that the aerobic forearm test at 100% MVC should be used as the routine diagnostic test for patients with suspected disorders of muscle carbohydrate metabolism.
*The test is similar to the Ischemic Forearm Test, except that cuff inflation is not used.
*This test uses maximal handgrip exercise averages so that work intensity does not have to be monitored as closely.
*The study showed that the aerobic 100% MVC test provides the highest sensitivity and specificity for glycolytic disorders of muscle metabolism and is best tolerated.
 
=== Muscle Biopsy  ===
 
The biopsy looks for the presence of myophosphorylase activity, which is absent in an[[Image:Phosphorylasehelp.jpg|right|300x200px]]d can confirm diagnosis of McArdle’s Disease.<br>
 
<br>
 
<ref name="p1" /><ref name="p2" /><ref name="p0">Olafsen A. Quest - Article - McArdle’s Disease: The Right Diagnosis Can Lighten the Load - A Quest Article | Muscular Dystrophy Association. Muscular Dystrophy Association. 2017 [cited 18 March 2017]. Available from: https://www.mda.org/quest/article/mcardles-disease-diagnosis</ref><ref name="p1" /><ref name="p2" /><ref name="p3">Baechle Thomas R and Roger W Earle. Essentials of Strength Training and Conditioning. Human Kinetics. Champaign,IL 2008.</ref><ref>Phosphorylase deficiency [Internet]. Phosphorylase deficiency. [cited 2017Apr5]. Available from: http://neuromuscular.wustl.edu/pathol/phosphorylase.htm</ref>
 
== Etiology/Causes ==
 
McArdle’s Disease has been shown to have an autosomal recessive inheritance pattern, requiring two defective copies of the gene for the condition to manifest. The defect exists as mutation of the gene for myophosphorylase (PYGM), which occurs on chromosome 11. Myophosphorylase is an enzyme that helps break down glycogen into glucose during exercise. Carriers of the gene are not known to have symptoms of the disease.<br>
 
<ref name="p2" /><ref name="p4">McArdle’s Disease (Glycogen Storage Disease Type V). Patient.info. 2017 [cited 18 March 2017]. Available from: http://patient.info/doctor/mcardles-disease-glycogen-storage-disease-type-v</ref>
 
== Bioenergetics ==


There are three basic energy systems.  
*'''[[Gout]]''': Inhibited ATP production leads to the production or purine metabolites. These metabolites are converted to uric acid, which can lead to hyperuricemia. <ref name="p1" /><ref name="p2" /><ref>Driver MDCB. Gout Causes, Diet, Symptoms, Treatment &amp; Medication [Internet]. MedicineNet. [cited 2017Apr5]. Available from: http://www.medicinenet.com/gout_gouty_arthritis/article.htm</ref>
== Treatment ==
[[File:Fish.jpeg|right|frameless]]
Patients with McArdle Disease cannot utilise their glycogen energy stores in their skeletal muscles. Despite a great deal of intensive investigation, no effective treatment for McArdle Disease has been found.<ref name=":2" />


===  1. Phosphagen System  ===
Image 3: Creatine rich food, most people get creatine through seafood and red meat (though at levels far below those found in synthetically made creatine supplements)


*This system is an anaerobic mechanism that occurs in the sarcoplasm of a muscle cell which provides ATP for short term, high intensity activities.  
Persons may be able to use certain diet and exercise strategies to help control the problem. A well-designed low or moderate exercise routine may help the body get the most out of its' ability to use glucose. Overdoing exercise can harm the muscles and kidneys in people with McArdle disease. A healthcare team is vital in creating the best care plan for the situation. Some therapies used to help manage McArdle disease are:
*The Phosphagen System is active at the start of all exercise, regardless of intensity.
*It relies on hydrolysis of ATP and breakdown of creatine phosphate (CP) which supplies a phosphate group to ADP to replenish ATP.
*CP is only stored in small amounts, so it cannot sustain continuous, long duration activity.  
*'''This system is intact in patients with McArdle’s Disease.'''


===  2. Glycolysis  ===
* Careful attention to a diet rich in carbohydrates
* [[Creatine and Exercise|Creatine]] supplements
* Eating or drinking prescribed amounts of sucrose before exercise
* Prescribed, moderate aerobic exercise plan
* Other medicines, such as ACE inhibitors


----
People with McArdle disease need to work with their care team and physio to establish a safe exercise plan.


[[Image:Untitled7.png|right|200x300px]]
There are currently no medications used to treat McArdle's Disease.<ref name=":1" />


Breakdown of carbohydrates:  
== Diet ==
Certain dietary interventions which confer favorable effects include taking a sugary meal before planning exercise - for example, having a drink containing 75g sucrose 40 minutes before exercise alleviates typical symptoms of exercise intolerance. A diet rich in carbohydrates results in much better outcomes in comparison to a protein-rich diet. Other nutritional agents that were helpful for some patients but could not yield convincing outcomes during actual experimental studies include branched-chain amino acids, depot glucagon preparations, verapamil, dantrolene sodium, vitamin B6, high dose D-ribose, and high-dose creatine ingestion.<ref name=":0" />


*Glycolysis utilizes either glycogen stored in the muscle or glucose delivered in the blood to resynthesize ATP production during glycolysis. This system is not as fast as the phosphagen system, but the output is much higher due to the stores of glycogen and glucose.  
== Physical Therapy Management ==
*'''This system is not intact in patients with McArdle’s Disease because glycogen is not readily available to break down.'''  
The physical therapist has an important role in keeping the patient active and avoiding inactivity due to fatigue.'''<br>'''Optimal exercise programs for managing McArdle’s Disease are aerobic based; they provide light resistance along with a [[Aerobic Exercise|cardiovascular]] component.  
*The end product of glycolysis is pyruvate. Pyruvate can then be converted to lactate, or be shuttled into the mitochondria.


Anaerobic glycolysis or fast glycolysis:
*A plan of care incorporating low to moderate intensity [[Aerobic Exercise|aerobic physical activity]] can improve symptoms and reduce susceptibility to injury of the muscle.
 
*Pyruvate is converted into lactate.
*ATP production is rapid, but short in duration.
*This energy system is typically trained in sprinters or resistance trainers.
 
Aerobic glycolysis or slow glycolysis:
 
*Pyruvate is shuttled into the mitochondria, converted to Acetyl CoA, and entered into the Krebs Cycle.
*ATP re-synthesis is slow, but can occur for a long duration if the exercise intensity is low.
*This energy system is typically trained in long distance runners or other athletes engaging in aerobic activity.
 
Phosphorylation:
 
*This is the process of adding an inorganic phosphate to another molecule.
 
Oxidative Phosphorylation:
 
*The re-synthesis of ATP in the electron transport chain (ETC). NADH and FADH2 are byproducts of fatty acids and amino acids converting to pyruvate, acetyl CoA, oxaloaceate, succinyl- CoA, and ketoglutarate in order to enter the Krebs Cycle.
*NADH and FADH2 are used to re-phosphorylate ADP to ATP by providing a hydrogen ion. The Hydrogen ion is necessary to phosphoraylize the ADP.
*'''This is where the "second wind" that McArdle's patients experience is derived from.'''
 
===  3. The Oxidative System  ===
 
*The aerobic system is the primary source of ATP at rest and during low-intensity activities.
*This system uses primarily carbohydrates and fats as substrates, but proteins will be metabolized during long-term starvation and long bouts of exercise.
*'''Since carbohydrate metabolism cannot occur in McArdle's patients, they primarily function with blood glucose metabolism, fat metabolism, and ultimately protein metabolism which can result in rhabdomyolysis.'''
*At rest, 70% of ATP production comes from fats and 30% from carbohydrates, while high intensity aerobic activity utilizes almost 100% carbohydrates.
*In prolonged sub-maximal, steady state work, there is a gradual shift from the use of carbohydrates to fats and proteins for energy.
*Oxidative metabolism of blood glucose and muscle glycogen begins with glycolysis. Pyruvate, the end product of glycolysis, is then converted to Acetyl-CoA and enters the Krebs cycle. Oxidation of the substrate-level phosphorylation yields ATP. Byproducts NADH and FADH2 enter the electron transport train. The total yield of this process is 38 ATP.
*Triglycerides stored in fats can be broken down by hormone sensitive lipase. This releases fatty acids from the fat cells into the blood, where they can circulate and enter the muscles. Fatty acids enter the mitochondria where they undergo beta oxidation, breaking down the fatty acids into acetyl-CoA and hydrogen protons. Acetyl-CoA enters the Krebs Cycle and hydrogen atoms attach to NADH and FADH2 and enter the electron transport chain. The total yield is 463 ATP.
*Proteins can be broken down into amino acids by various metabolic processes. These amino acids can be converted to glucose, pyruvate, and various Krebs Cycle intermediates. The major amino acids believed to be oxidized in skeletal muscle are Branches Chained Amino Acids, which are leucine, isoleucine, and valine. The waste products of amino acid degradation are urea and small amounts of ammonia.
*'''This can lead to hyperuricemia in McArdle's patients resulting in gout. Urea and ammonia are also toxic to skeletal muscle, and can contribute to fatigue.'''
 
<br> <ref name="p1" /><ref name="p4" /><ref name="p4" />
 
== Systemic Involvement ==
 
There have not been any studies that have found long-term effects on the general health on individuals with McArdle's Disease. Typically, individuals with this disease are in excellent health as long as the disease is managed properly. If the disease is unmanaged, it can lead to cases of rhabdomyolysis, kidney failure, and liver dysfunction.
 
<br>'''Precaution''': Any patient with McArdle's Disease who has cardiovascular complications could be on a statin medication. Statins increase the potential risk for rhabdomyolysis. In this case, physical activity should be keep to an absolute minimum.<br>
 
<ref name="p1" /><ref name="p2" />
 
== Medical Management (current best evidence) ==
 
In general, no specific treatment exists for McArdle's Disease.
 
*In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development.
*Some findings suggest that corrective gene therapy or enzyme replacement for McArdle's Disease may be possible in humans in the future.
*Interest in glucagon treatment for McArdle's disease has developed, but studies have shown no benefit over a placebo treatment.<br>
 
<ref name="p7">MedScape. [cited 19 April 2011]. Available from: http://www.medscape.org/viewarticle/581307_4</ref><br>
 
== Physical Therapy Management (current best evidence) ==
 
'''[[Image:Untitled5.png|right|300x200px]]'''
 
'''The physical therapist has an important role in keeping the patient active and avoiding inactivity due to fatigue.<br>'''
 
*Optimal exercise programs for managing McArdle’s Disease are aerobic based; they provide light resistance along with a cardiovascular component.
*A plan of care incorporating low to moderate intensity aerobic physical activity can improve symptoms and reduce susceptibility to injury of the muscle.  
*The goal is to achieve the "second wind" for each muscle group that is being worked.  
*The goal is to achieve the "second wind" for each muscle group that is being worked.  
*Light to moderate resistance training can also help, but allow adequate time to rest in between sets.  
*Light to moderate resistance training can also help, but allow adequate time to rest in between sets.  
*As a rule, do not work the muscles to absolute fatigue, and be sure to target larger muscle groups.  
*As a rule, do not work the muscles to absolute fatigue, and be sure to target larger muscle groups.  
*If strenuous activity must be done, use a 6 second rule. Only do that activity for 6 seconds prior to resting to ensure that only the phosphagen energy system is used in anaerobic activity.<br>
*If strenuous activity must be done, use a 6 second rule. Only do that activity for 6 seconds prior to resting to ensure that only the phosphagen energy system is used in [[Anaerobic Exercise|anaerobic activity]].<br>


'''Physical therapists can promote flexibility in order to prevent muscle contractures and reduce pain.'''  
'''Physical therapists can promote flexibility in order to prevent muscle contractures and reduce pain.'''  


*Stretching should be very light because 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.  
*[[Stretching]] should be very light because maximal stretching will work the muscle anaerobically by inducing a protective contraction from the [[Golgi Tendon Organ|Golgi tendon]]. This strong protective contraction can lead to muscle damage.
*Stretching following walking may offer immediate and dramatic pain relief to individuals with McArdle’s Disease.  
*Stretching following walking may offer immediate and dramatic pain relief to individuals with McArdle’s Disease.  
*For active individuals, stretching should take place very frequently to help reduce cramping. If not, muscles may become tight due to the toxic build up throughout activity and stretching can become painful.  
*For active individuals, stretching should take place very frequently to help reduce cramping. If not, muscles may become tight due to the toxic build up throughout activity and stretching can become painful.  
Line 213: Line 88:


*Individuals with McArdle’s Disease can easily overexert themselves and become injured without even realizing it.  
*Individuals with McArdle’s Disease can easily overexert themselves and become injured without even realizing it.  
*It is important that they be conscious of their energy levels, blood sugar, heart rate, and general well-being.  
*It is important that they be conscious of their energy levels, blood sugar, [[Pulse rate|heart rate]], and general well-being.
*These individuals have a place in physical therapy to improve aerobic capacity, strength, and flexibility.
*During any low to moderate intensity activities, patients with McArdle’s Disease should warm up properly until they achieve the "second wind." Strenuous activities should be limited to six seconds to ensure the use of the phosphagen system.
 
For a brief discussion of treating a patient with McArdle's Disease, refer to the video below. {{#ev:youtube|qsnDu-fLdRs}}<br><br>
 
<ref name="p5">Reference G. glycogen storage disease type V. Genetics Home Reference. 2017 [cited 18 March 2017]. Available from: https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-v</ref><ref name="p0" /><ref name="p5" /><ref name="p7" /><ref>Exercise for Homeschoolers [Internet]. Texas Rock Gym. [cited 2017Apr5]. Available from: http://www.texasrockgym.com/exercise-for-homeschoolers/</ref>
 
== Alternative/Holistic Management (current best evidence) ==


'''Massage''' [[Image:Untitled6.png|right|300x200px]]


*&nbsp;Individuals with McArdle’s Disease claim that massage therapy can be beneficial in maintaining an active lifestyle.
For a brief discussion of treating a patient with McArdle's Disease, refer to the video below. {{#ev:youtube|qsnDu-fLdRs}}
*&nbsp;Any 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.
*&nbsp;Massages help push fatigue causing toxins out of the muscles and into the blood stream where they can be excreted from the body. It is recommended that individuals with McArdle’s Disease take in plenty of fluids following a massage to help flush the body of toxins.
*&nbsp;Pain with massage is a sign that rhabdomyolysis may be occurring. Do not continue massage therapy with pain.<br>


<br>


<ref name="p1" /><ref name="p2" /><ref>Home [Internet]. Natural Tranquility Massage and Bodywork LLC. [cited 2017Apr5]. Available from: http://naturaltranquilitymassage.com/</ref>  
<ref name="p5">Reference G. glycogen storage disease type V. Genetics Home Reference. 2017 [cited 18 March 2017]. Available from: https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-v</ref><ref name="p0">Olafsen A. Quest - Article - McArdle’s Disease: The Right Diagnosis Can Lighten the Load - A Quest Article | Muscular Dystrophy Association. Muscular Dystrophy Association. 2017 [cited 18 March 2017]. Available from: https://www.mda.org/quest/article/mcardles-disease-diagnosis</ref><ref name="p5" /><ref name="p7">MedScape. [cited 19 April 2011]. Available from: http://www.medscape.org/viewarticle/581307_4</ref><ref>Exercise for Homeschoolers [Internet]. Texas Rock Gym. [cited 2017Apr5]. Available from: http://www.texasrockgym.com/exercise-for-homeschoolers/</ref>  


== Alternative/Holistic Management ==
[[Massage]]''':''' Individuals with McArdle’s Disease claim that massage therapy can be beneficial in maintaining an active lifestyle. Any 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. Massages help push fatigue causing toxins out of the muscles and into the blood stream where they can be excreted from the body. It is recommended that individuals with McArdle’s Disease take in plenty of fluids following a massage to help flush the body of toxins. Pain with massage is a sign that rhabdomyolysis may be occurring. Do not continue massage therapy with pain.<ref name="p1" /><ref name="p2" /><ref>Home [Internet]. Natural Tranquility Massage and Bodywork LLC. [cited 2017Apr5]. Available from: http://naturaltranquilitymassage.com/</ref>
== Differential Diagnosis ==
== Differential Diagnosis ==


'''Rhabdomyolysis''': a clinical and biochemical syndrome resulting from skeletal muscle injury that alters the integrity of the muscle cell membrane sufficiently to allow the release of the muscle cell content into the plasma. Due to the quick breakdown of the skeletal muscle there is a big accumulation of the breakdown products which can cause renal failure. Although rhabdomyolysis is a symptom of McArdle’s disease, it can be a symptom of other conditions, or it can exist independently.
* [[Rhabdomyolysis]]
 
* [[Fibromyalgia]]
'''Fibromyalgia''': a syndrome characterized by widespread chronic unabated pain in addition to a host of several additional co-morbidities that can severely impact and disrupt a person’s daily life. The symptoms associated with fibromyalgia may originate from abnormal central nervous system output. Fibromyalgia isn't just one condition; it's a complex syndrome involving many different factors. McArdle’s Disease and Fibromyalgia share many symptoms, but they have different causes, so their treatments differ.
* [[Muscular Dystrophy]]
 
* [[Myositis Ossificans of the Quadriceps|Myositis]]
'''Muscular Dystrophy''': a group of more than 30 inherited diseases. They all cause muscle weakness and muscle loss. Some forms of MD appear in infancy or childhood. Others may not appear until middle age or later. The different types can vary in whom they affect, which muscles they affect, and what the symptoms are. All forms of MD grow worse as the person's muscles get weaker. Most people with MD eventually lose the ability to walk. McArdle’s Disease and Muscular Dystrophy share many symptoms, such as weakness and muscles loss.
* Tarui's Disease: A condition in which there exists a deficiency of the phosphofructokinase enzyme, which is needed to facilitate the breakdown of glucose into energy in muscle during exercise. Tarui’s Disease is also a glycogen storage deficiency, so it has many similarities to McArdle’s Disease. Consequently, they are treated in a similar manner. <ref name="p0" /><ref name="p1" /><ref name="p2" /><ref name="p3">Baechle Thomas R and Roger W Earle. Essentials of Strength Training and Conditioning. Human Kinetics. Champaign,IL 2008.</ref><ref name="p4">McArdle’s Disease (Glycogen Storage Disease Type V). Patient.info. 2017 [cited 18 March 2017]. Available from: http://patient.info/doctor/mcardles-disease-glycogen-storage-disease-type-v</ref>  
 
'''Myositis''': Myositis means inflammation of the muscles that you use to move your body. An injury, infection, or autoimmune disease can cause it. Two specific kinds are polymyositis and dermatomyositis. Polymyositis causes muscle weakness, usually in the muscles closest to the trunk of your body. Dermatomyositis causes muscle weakness, plus a skin rash. Because Myositis also causes muscle weakness, it can present similarly to McArdle’s Disease.
 
'''Tarui's Disease''': A condition in which there exists a deficiency of the phosphofructokinase enzyme, which is needed to facilitate the breakdown of glucose into energy in muscle during exercise. Tarui’s Disease is also a glycogen storage deficiency, so it has many similarities to McArdle’s Disease. Consequently, they are treated in a similar manner. <br>
 
<ref name="p0" /><ref name="p1" /><ref name="p2" /><ref name="p3" /><ref name="p4" />  
 
==[[Case Study McArdle Disease]]==
 
<ref name="p9" />  


== Resources ==
==Case Study McArdle Disease==
This [[Case Study McArdle Disease|case]] demonstrates some of the day-to-day struggles of living with McArdle's Disease along with associated signs and symptoms of the disease. It also discusses abnormal lab values and possible physical therapy interventions and outcomes


*[http://www.agsd.org.uk/ Association for Glycogen Storage Disease UK]&nbsp;
<ref name="p9">Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). 2017.</ref>
*[http://www.agsdus.org/ Association for Glycogen Storage Disease US]
*[[Image:Facebook icon.gif|Image:Facebook_icon.gif]]&nbsp;[http://www.facebook.com/home.php#!/group.php?gid=2646925066 Join the Facebook Group: McArdle's Disease]
*[[Image:Nord.gif]]&nbsp;[http://www.inspire.com/groups/rare-disease/discussion/glycogen-storage-disease-v-mcardles-disease/ Support Community]


*[http://www.McArdlesDisease.org www.McArdlesDisease.org]&nbsp;
<div class="researchbox"></div>
== References ==
== References ==


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


<references /><br>
<references />
[[Category:Conditions]]
[[Category:Conditions]]
[[Category:Paediatrics - Conditions]]
[[Category:Genetic Disorders]]

Latest revision as of 15:28, 23 July 2023

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  

Definition/Description[edit | edit source]

Chromosome-DNA-gene copy.jpg

McArdle disease is a genetic disorder that mainly affects skeletal muscles. It occurs due to the deficiency or absence of an enzyme called myophosphorylase, a key substance that the muscles need to break down glycogen into sugar (glucose) for energy. Symptoms include painful muscle cramps, weakness, and fatigue manifested during periods of physical activity.[1] The disease can lead to dark urine.

  • Severe, uncontrolled McArdle disease can cause life-threatening kidney problems.[2]
  • To avoid the unpleasant symptoms associated with this condition and improve the quality of life, the disease requires prompt diagnosis and treatment.[1]

Etiology[edit | edit source]

McArdle disease typically results from mutations involving the muscle-specific isoform of the glycogen phosphorylase enzyme. This enzyme plays a key role in the first step of glycogenolysis that release glucose-1-phosphate monomers in muscle fibers. As a result, carbohydrate metabolism of the skeletal-muscle is affected, and energy cannot be generated from the glycogen stores of muscles.

Image 2:How muscle contraction differs in an unaffected muscle compared to one with McArdle’s Disease.

[3][4]

Epidemiology[edit | edit source]

The exact prevalence of McArdle disease is not precisely known and appears to range from 1 in 50,000 to 1 in 200,000 in the United States. [1]

Characteristics/Clinical Presentation[edit | edit source]

McArdle Disease patients can have critical episodes of early fatigue when exercising, muscle pain (myalgia), myoglobinuria (when muscles break down and release myoglobin in urine, making it brown/red in colour), and then subsequent kidney failure[5]. Some common symptoms of McArdle disease are:

  • Better able to do aerobic exercise after 8 to 10 minutes (second-wind phenomenon)
  • Brownish red urine, especially after periods of activity
  • Easily tiring during activity, with stiffness or weakness soon after starting exercise
  • Muscle cramping
  • Muscle pain
  • Lasting (permanent) weakness in the thigh or other muscles. This happens in a small portion of people with the condition.

Most of the time, people notice these symptoms before age 15. Often, people assume the symptoms are “growing pains” or due to some other cause. Different people may have symptoms of different severity eg person noticing that the symptoms seem worse or better at different times.[2]

Diagnosis[edit | edit source]

Some diagnostic tests include:

  • Blood tests to check for muscle enzymes, such as creatine kinase
  • DNA blood tests for known McArdle disease mutations
  • Electromyography to measure the electrical activity of the muscles
  • Forearm exercise test
  • MRI studies of your muscles
  • Muscle biopsy to examine the muscle cells for glycogen buildup
  • Urine tests to check for myoglobin, which darkens the urine[2]

Associated Co-morbidities[edit | edit source]

  • Renal Failure: Kidney dysfunction and failure are associated with rhadbomyolysis and myoglobinuria.
  • Gout: Inhibited ATP production leads to the production or purine metabolites. These metabolites are converted to uric acid, which can lead to hyperuricemia. [3][4][6]

Treatment[edit | edit source]

Fish.jpeg

Patients with McArdle Disease cannot utilise their glycogen energy stores in their skeletal muscles. Despite a great deal of intensive investigation, no effective treatment for McArdle Disease has been found.[5]

Image 3: Creatine rich food, most people get creatine through seafood and red meat (though at levels far below those found in synthetically made creatine supplements)

Persons may be able to use certain diet and exercise strategies to help control the problem. A well-designed low or moderate exercise routine may help the body get the most out of its' ability to use glucose. Overdoing exercise can harm the muscles and kidneys in people with McArdle disease. A healthcare team is vital in creating the best care plan for the situation. Some therapies used to help manage McArdle disease are:

  • Careful attention to a diet rich in carbohydrates
  • Creatine supplements
  • Eating or drinking prescribed amounts of sucrose before exercise
  • Prescribed, moderate aerobic exercise plan
  • Other medicines, such as ACE inhibitors

People with McArdle disease need to work with their care team and physio to establish a safe exercise plan.

There are currently no medications used to treat McArdle's Disease.[2]

Diet[edit | edit source]

Certain dietary interventions which confer favorable effects include taking a sugary meal before planning exercise - for example, having a drink containing 75g sucrose 40 minutes before exercise alleviates typical symptoms of exercise intolerance. A diet rich in carbohydrates results in much better outcomes in comparison to a protein-rich diet. Other nutritional agents that were helpful for some patients but could not yield convincing outcomes during actual experimental studies include branched-chain amino acids, depot glucagon preparations, verapamil, dantrolene sodium, vitamin B6, high dose D-ribose, and high-dose creatine ingestion.[1]

Physical Therapy Management[edit | edit source]

The physical therapist has an important role in keeping the patient active and avoiding inactivity due to fatigue.
Optimal exercise programs for managing McArdle’s Disease are aerobic based; they provide light resistance along with a cardiovascular component.

  • A plan of care incorporating low to moderate intensity aerobic physical activity can improve symptoms and reduce susceptibility to injury of the muscle.
  • The goal is to achieve the "second wind" for each muscle group that is being worked.
  • Light to moderate resistance training can also help, but allow adequate time to rest in between sets.
  • As a rule, do not work the muscles to absolute fatigue, and be sure to target larger muscle groups.
  • If strenuous activity must be done, use a 6 second rule. Only do that activity for 6 seconds prior to resting to ensure that only the phosphagen energy system is used in anaerobic activity.

Physical therapists can promote flexibility in order to prevent muscle contractures and reduce pain.

  • Stretching should be very light because 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.
  • Stretching following walking may offer immediate and dramatic pain relief to individuals with McArdle’s Disease.
  • For active individuals, stretching should take place very frequently to help reduce cramping. If not, muscles may become tight due to the toxic build up throughout activity and stretching can become painful.
  • Physical therapists should encourage a stretch that feels sufficient without causing pain.

Physical therapists should promote active participation by patients in managing their disease.

  • Individuals with McArdle’s Disease can easily overexert themselves and become injured without even realizing it.
  • It is important that they be conscious of their energy levels, blood sugar, heart rate, and general well-being.


For a brief discussion of treating a patient with McArdle's Disease, refer to the video below.


[7][8][7][9][10]

Alternative/Holistic Management[edit | edit source]

Massage: Individuals with McArdle’s Disease claim that massage therapy can be beneficial in maintaining an active lifestyle. Any 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. Massages help push fatigue causing toxins out of the muscles and into the blood stream where they can be excreted from the body. It is recommended that individuals with McArdle’s Disease take in plenty of fluids following a massage to help flush the body of toxins. Pain with massage is a sign that rhabdomyolysis may be occurring. Do not continue massage therapy with pain.[3][4][11]

Differential Diagnosis[edit | edit source]

  • Rhabdomyolysis
  • Fibromyalgia
  • Muscular Dystrophy
  • Myositis
  • Tarui's Disease: A condition in which there exists a deficiency of the phosphofructokinase enzyme, which is needed to facilitate the breakdown of glucose into energy in muscle during exercise. Tarui’s Disease is also a glycogen storage deficiency, so it has many similarities to McArdle’s Disease. Consequently, they are treated in a similar manner. [8][3][4][12][13]

Case Study McArdle Disease[edit | edit source]

This case demonstrates some of the day-to-day struggles of living with McArdle's Disease along with associated signs and symptoms of the disease. It also discusses abnormal lab values and possible physical therapy interventions and outcomes

[14]

References[edit | edit source]

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

  1. ↑ 1.0 1.1 1.2 1.3 Khattak ZE, Ashraf M. McArdle Disease. StatPearls [Internet]. 2020 Aug 15. Available:https://www.statpearls.com/articlelibrary/viewarticle/24796/ (accessed 23.10.2021)
  2. ↑ 2.0 2.1 2.2 2.3 Cedars Sinai McArdle Disease Available: https://www.cedars-sinai.org/health-library/diseases-and-conditions/m/mcardle-disease.html (accessed 23.10.2021)
  3. ↑ 3.0 3.1 3.2 3.3 MedPoster 1992. nobelprize.org. [cited 3 April 2011]. Available from: http://nobelprize.org/nobel_prizes/medicine/laureates/1992/illpres/glycogen.html
  4. ↑ 4.0 4.1 4.2 4.3 McArdlesDisease.org. [cited 17 March 2011]. Available from: www.mcardledisease.org
  5. ↑ 5.0 5.1 Brain Foundation McArdle Disease Award - 2012 Available: https://brainfoundation.org.au/research-grants/2012/mcardle-disease-award/ (accessed 23.10.2021)
  6. ↑ Driver MDCB. Gout Causes, Diet, Symptoms, Treatment & Medication [Internet]. MedicineNet. [cited 2017Apr5]. Available from: http://www.medicinenet.com/gout_gouty_arthritis/article.htm
  7. ↑ 7.0 7.1 Reference G. glycogen storage disease type V. Genetics Home Reference. 2017 [cited 18 March 2017]. Available from: https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-v
  8. ↑ 8.0 8.1 Olafsen A. Quest - Article - McArdle’s Disease: The Right Diagnosis Can Lighten the Load - A Quest Article | Muscular Dystrophy Association. Muscular Dystrophy Association. 2017 [cited 18 March 2017]. Available from: https://www.mda.org/quest/article/mcardles-disease-diagnosis
  9. ↑ MedScape. [cited 19 April 2011]. Available from: http://www.medscape.org/viewarticle/581307_4
  10. ↑ Exercise for Homeschoolers [Internet]. Texas Rock Gym. [cited 2017Apr5]. Available from: http://www.texasrockgym.com/exercise-for-homeschoolers/
  11. ↑ Home [Internet]. Natural Tranquility Massage and Bodywork LLC. [cited 2017Apr5]. Available from: http://naturaltranquilitymassage.com/
  12. ↑ Baechle Thomas R and Roger W Earle. Essentials of Strength Training and Conditioning. Human Kinetics. Champaign,IL 2008.
  13. ↑ McArdle’s Disease (Glycogen Storage Disease Type V). Patient.info. 2017 [cited 18 March 2017]. Available from: http://patient.info/doctor/mcardles-disease-glycogen-storage-disease-type-v
  14. ↑ Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). 2017.
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