In childhood, the onset of symptoms may be noticed, but most often the diagnosis is made in the third or the fourth decade of life. Most people suffering from this disease appear physically fit and healthy though they may undergo premature fatigue, weakness, and pain during exercise. Hence, it is assumed that the person is out of shape or unwilling to exercise. When an individual suffering from GSD5 exercises, they experience fatigue, muscle pain, cramps, etc. within the first few minutes of exercise. Weight lifting or jogging usually trigger these symptoms in such an individual. Taking rest ameliorates the symptoms. This can be followed by a ‘second-wind phenomenon’ . After exercising the affected person feel fatigued, but if he slows down or stops and allows the pain to reduce then he can resume exercises again without previous discomfort or pain. According to Braakhekke and colleagues, this may be resultant due to increased recruitment of motor units, improved cardiac output, and the use of free fatty acids for muscle metabolism . When patients with GSD5 continue exercises for a long duration without rest or perform intense exercises, rhabdomyolysis and consequent myoglobinuria may occur causing renal dysfunction and eventually leading to acute renal failure. Voduc and colleagues have reported unexplained dyspnoea as a symptom of GSD5 . In rare cases, early-onset with generalized muscle weakness, hypotonia, and progressive respiratory failure has been reported.
Entire Body System
- Difficulty Climbing Stairs
No sport activities were possible and the boy had even difficulties climbing stairs due to muscle weakness. Moreover, he complained of chest pain after physical exercise and recurrent nausea. [ojrd.biomedcentral.com]
- Intravenous Administration
However, the oral ingestion of sucrose and the intravenous administration of glucose induce different neurohormonal responses and levels of glucose availability. 19 In a recent study of patients with impaired fatty-acid oxidation due to carnitine palmitoyltransferase [doi.org]
Haller, Metabolic and Mitochondrial Myopathies, Neurologic Clinics, 32, 3, (777), (2014). [doi.org]
McArdle: Myopathy due to a defect in muscle glycogen breakdown. Clinical Science, London, 1951, 10: 13-33. R. Schmid, R. Mahler: Chronic progressive myopathy with myoglobinuria: demonstration of a glycogenolytic defect in the muscle. [whonamedit.com]
Creatine kinase levels were elevated, serum lactate did not rise on ischemic exercise testing, and muscle biopsy showed a vacuolar myopathy with absent myophosphorylase activity. [ncbi.nlm.nih.gov]
- Muscle Weakness
Proximal muscle weakness may progress with time, and no specific treatment exists. [emedicine.medscape.com]
In middle or old age some people with McArdle disease experience fixed muscle weakness, possibly from cumulative muscle damage. With diagnosis, correct advice on management can be followed and further problems can be avoided. [agsd.org.uk]
- Muscle Cramp
This causes many symptoms such as muscle pain, muscle cramping, muscle fatigue, and muscle tenderness. [web.archive.org]
Ischemic forearm exercise invariably causes muscle cramps and pain in patients with glycolytic defects. We investigated an alternative diagnostic exercise test that may be better tolerated. [ncbi.nlm.nih.gov]
cramps Exercise-induced muscle cramping Muscle cramps following exercise Muscle cramps on exercise Muscle cramps on exertion Muscle cramps with exertion [ more ] 0003710 Exercise-induced myalgia Exercise-induced muscle pain Muscle pain on exercise Muscle [rarediseases.info.nih.gov]
Electrical activity may be absent during exercise-induced muscle cramps. [patient.info]
Burgundy-colored urine (myoglobinuria) Fatigue Exercise intolerance, poor stamina Muscle cramps Muscle pain Muscle stiffness Muscle weakness There is no specific treatment. [nlm.nih.gov]
He had no history of exercise-induced cramps, myalgias, or myoglobinuria. [ncbi.nlm.nih.gov]
He had no history of exercise‐induced cramps, myalgias, or myoglobinuria. [doi.org]
The disease is characterized by muscle fatigue, stiffness, myalgia, and weakness often caused by activity and improved by rest. [genedx.com]
- Proximal Muscle Weakness
Proximal muscle weakness may progress with time, and no specific treatment exists. [emedicine.medscape.com]
Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly. The diagram below illustrates metabolic pathways of carbohydrates. [emedicine.medscape.com]
Any seizure can cause severe brain damage or, even worse, death. Having chronic low blood sugar can cause you to develop tumors in your liver called adenomas, typically becoming cancerous if not dealt with fast enough. [themighty.com]
For the clinical rating scores of muscle complaints, we performed the sign test on the intraindividual period differences (neglecting group membership and hence having to assume no period effects). [archneur.ama-assn.org]
Creatine kinase levels are high in about 90% of cases suffering from GSD5. It may be the only sign of the disease. Urine testing is advised since myoglobinuria is present in about 50% of GSD5 patients. The ischemic forearm test reveals a lack of lactate elevation in blood. The muscle biopsy confirms the absence of myophosphorylase activity. Molecular genetic testing may be done to determine the presence of gene mutations on the PYGM gene.
Phenotype and clinics Patients have poor tolerance to fasting (with hypoglycemia and hyperlactacidemia after 3 to 4 hours of fasting), marked hepatomegaly, full-cheeked round face, growth retardation (small stature and delayed puberty), generally improved [atlasgeneticsoncology.org]
- Free Fatty Acids Decreased
The exercise-induced increase in plasma ammonia was attenuated, and the availability of free fatty acids, as inferred from the plasma levels of free fatty acids, decreased with sucrose. [doi.org]
A patient suffering from GSD5 must not perform any strenuous workouts like lifting weights, pushing heavy objects or intense gym exercises, etc. However, it is important to perform controlled physical training like walking regularly to keep fit and healthy. A healthy diet and weight control are also recommendable.
GSD5 by itself is not a life-threatening disease. Patients with the condition are generally in good health. If rhabdomyolysis is avoided, then the prognosis is good. If myoglobinuria is experienced then it can lead to acute renal failure and death. Death can also occur due to respiratory failure in cases of severe muscle weakness. Genetic counseling is a must for patients as it is a genetic disorder.
Glycogen storage disease Type 5 involves mutations of the PYGM gene located on 11q13 chromosome leading to muscle phosphorylase deficiency. GSD 5 has two autosomal recessive forms, a childhood-onset form, and an adult-onset form.
GSD5 is a rare autosomal recessive disease. The heterozygote forms are usually asymptomatic. The prevalence is estimated at around 1 per 100,000 population. The mildness of the symptoms in patients has caused it to be an under-diagnosed disorder. The majority of cases are diagnosed in the second to third decade of life.
Wolfe and colleagues have documented a unique case presenting in a person at an age of 73 years . Felice and colleagues and Pourmand and colleagues also have documented late presentations of GSD5 cases. This suggests that doctors should have clinical suspicion irrespective of the age of presentation  .
The PYGM gene is involved in the production of an enzyme called myophosphorylase which breaks down glycogen into glucose-1-phosphate, a simple form of sugar, then converted to glucose.
Being an inherited genetic defect, there is no way to prevent or reverse the condition.
Glycogen storage disease Type 5 (McArdle disease or GSD5) is one among the many in a group of inherited glycogen storage diseases. Specific enzymes catalyze reactions that help convert glycogen to glucose. Many different mutations have been reported for each type of GSD . The deficiency of these enzymes causes glycogen accumulation in tissues leading to systemic outcomes or specific tissue-related outcomes . GSD 5 is an inherited autosomal recessive disease and the deficient enzyme is myophosphorylase . The disease was first reported in 1951 by Dr. Brian McArdle of Guy's Hospital, London. GSD 5 has two autosomal recessive forms, a childhood-onset form, and an adult-onset form.
Glycogen storage disease type 5 (GSD5) is a genetic disorder. It is caused due to the deficiency of enzyme myophosphorylase. Most people with GSD5 may suffer from it since childhood but it goes undiagnosed till adulthood. People with GSD5 usually appear physically healthy but suffer from fatigue post exercises. This can be confused with being not fit or disinclined to exercise. Hence, symptoms of GSD5 are usually detected in the second or third decade of life. Fatigue, pain, and weakness with strenuous activities like jogging, swimming, or even walking are the characteristic symptoms of the disease. However, if they stop their activity and rest, then they can resume the physical exertion probably because the body uses other sources of energy production. This is known as the second-wind phenomenon. In cases when strenuous exercise is continued it leads to rapid muscle breakdown called rhabdomyolysis. This causes the release of proteins like creatine kinase and myoglobin in the urine causing it to turn dark red or brown called myoglobinuria. This can lead to acute kidney failure.
Diagnosis can be made from the history of the patient. Physical examination may not reveal many abnormal findings. Tests advised include creatine kinase testing, urine analysis, ischemic forearm test, and muscle biopsy. The biochemical assay is a confirmatory test for the enzyme activity.
Affected persons must remember to mention the disease whenever you visit any medical setup. A balanced diet rich in protein and vitamins aids to improve muscle tolerance. GSD5 patients must avoid strenuous exercises. Though they must continue light exercises and stretches to improve muscle strength and flexibility.
- Duno M, Quinlivan R, Vissing J, et al. High-resolution melting facilitates mutation screening of PYGM in patients with McArdle disease. Ann Hum Genet. May 2009;73:292-7.
- Rubio JC, Garcia-Consuegra I, Nogales-Gadea G, et al. "A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients". Hum. Mutat. 28 (2): 203–4.
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- Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan;105(1):e10.
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- Orngreen MC, Jeppesen TD, Andersen ST, et al. Fat metabolism during exercise in patients with McArdle disease. Neurology. Feb 24 2009;72(8):718-24.
- Braakhekke JP, de Bruin MI, Stegeman DF. The second wind phenomenon in McArdle's disease. Brain. 109 (Pt 6):1087-101.
- Voduc N, Webb KA, D'Arsigny C, et al. McArdle's disease presenting as unexplained dyspnea in a young woman. Can Respir J. Mar 2004;11(2):163-7.