Glycogen storage disease type 5 (GSD5), also known as myophosphorylase deficiency or McArdle's disease, is a rare inherited metabolic disorder, characterized by exercise intolerance.
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
One hallmark of McArdle disease is weakness with exertion. Proximal muscle weakness may progress with time, and no specific treatment exists. [emedicine.com]
We describe an elderly man who developed asymmetric proximal arm weakness at age 73. He had no history of exercise-induced cramps, myalgias, or myoglobinuria. [ncbi.nlm.nih.gov]
We describe an elderly man who developed asymmetric proximal arm weakness at age 73. He had no history of exercise‐induced cramps, myalgias, or myoglobinuria. [doi.org]
- Short Stature
Short stature & growth delay Abdomen protrusion Build up of glycogen and fat in the liver Enlarged liver and malignant/benign growths in the liver Yellow plaques on skin (xanthomas) Spider-like arteries, gout in the ear or kidney Bleeding disorders Hypoglycemia [en.wikibooks.org]
Some individuals have short stature and noncancerous (benign) tumors called adenomas in the liver. GSDIII is cause by mutations in the AGL gene and is inherited in an autosomal recessive manner. [diseaseinfosearch.org]
In addition, type I may produce the following symptoms: ❑ infants — acidosis, hyperlipidemia, GI bleeding, coma ❑ children — low resistance to infection and, without proper treatment, short stature ❑ adolescents — gouty arthritis and nephropathy; chronic [checkorphan.org]
Methodology Polymerase chain reaction (PCR) and primer extension Additional Information Some infants who are untreated develop severe hypoglycemia (low blood sugar). 1,2 Long-term complications of untreated GSD1a include short stature, osteoporosis, delayed [labcorp.com]
"A syndrome of mental retardation, short stature, hemolytic anemia, delayed puberty, and abnormal facial appearance: similarities to a report of aldolase A deficiency". Am J Med Genet. 28 (4): 965–70. doi : 10.1002/ajmg.1320280423. [wikidoc.org]
Most of the individuals who submit Social Security Disability claims will have to wait more than a year before actually receiving the disability benefits they are entitled to. [disabilitybenefitscenter.org]
[…] related to disease duration 14 Disability not predictable based on age of disease onset Eventual respiratory involvement common Many need wheelchair or walking devices Some patients remain independent & employed Death: Due to respiratory failure Serum [neuromuscular.wustl.edu]
In GSD V, this form of glycogenolysis is disabled and glucose is not available. [medical-dictionary.thefreedictionary.com]
There is at the moment too much emphasis on impairment (biochemical and physiological measurements) and not enough on disability (activities) and handicap (participation). [cochranelibrary.com]
Sixteen patients (16 %) were unemployed, with eight of these patients being unemployed due to mental and/or physical disability. Thirty patients (21 females) had 64 healthy children. [link.springer.com]
- Severe Pain
If activity is continued after symptoms appear, severe, painful muscle cramping and contracture may occur; this may be accompanied by myoglobinuria and can lead to rhabdomyolysis with possible renal failure if not treated properly. [genedx.com]
Patients may present at emergency rooms with severe fixed contractures of the muscles and often severe pain. These require urgent assessment for rhabdomyolysis as in about 30% of cases this leads to acute renal failure. [en.wikipedia.org]
Prolonged activity in the presence of severe pain can lead to muscle damage ( rhabdomyolysis ) and rust-colored urine (myoglobinuria) with the risk of acute kidney (renal) failure.  The symptoms of glycogen storage disease type 5 usually start during [rarediseases.info.nih.gov]
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. [physio-pedia.com]
- 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]
Because Patient 6 had diarrhea during therapy with cornstarch, nocturnal nasogastric infusions of glucose were begun. The improvement in his proximal renal tubular function was still evident 12 months after the institution of therapy. [nejm.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.com]
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. [symptoma.com]
- Muscle Cramp
Under these circumstances, the body breaks down muscle when trying to attain energy. This causes many symptoms such as muscle pain, muscle cramping, muscle fatigue, and muscle tenderness. [web.archive.org]
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 pain with exercise Muscle pain, exercise-induced [rarediseases.info.nih.gov]
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]
Up to 85% of patients can be confirmed without muscle biopsy. [ 4 ] Electromyography: may show nonspecific myopathic changes or increased muscle irritability. Electrical activity may be absent during exercise-induced muscle cramps. [patient.info]
Patients experience early onset of fatigue and muscle pain with exercise. The body breaks down muscle when trying to attain energy, which causes many symptoms such as muscle pain, muscle cramping, muscle fatigue, and muscle tenderness. [mda.org.au]
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]
Patients present with a syndrome of muscular exercise intolerance with myalgia, cramps, fatigue, and muscle weakness. [orpha.net]
The disease is characterized by muscle fatigue, stiffness, myalgia, and weakness often caused by activity and improved by rest. [genedx.com]
- Muscle Contracture
Physical therapists can promote flexibility in order to prevent muscle contractures and reduce pain. [physio-pedia.com]
Under control conditions the person with McArdle disease fatigued with an impending muscle contracture at two minutes and 10 seconds. [cochranelibrary.com]
The low levels of glucose in the blood of these individuals often result in chronic hunger, fatigue, and irritability. These symptoms are especially noticeable in infants. [liverfoundation.org]
Symptoms These are symptoms of Von Gierke disease: Constant hunger and need to eat often Easy bruising and nosebleeds Fatigue Irritability Puffy cheeks, thin chest and limbs, and swollen belly Exams and Tests Your health care provider will perform a physical [mountsinai.org]
All five participants completed the trial, although some developed symptoms of hypoglycaemia which included light‐headedness and hunger. One participant developed increased bowel frequency after ribose. [cochranelibrary.com]
- Kidney Failure
Large amounts of myoglobin may precipitate in the kidneys and cause temporary kidney failure. Some patients have developed significant muscle problems (myopathies) later in life. Links for Type V GSD This page created in June 2001. [web.archive.org]
If activity is continued whilst in pain, muscle damage ensues with the risk of muscle breakdown (rhabdomyolysis), which can lead to acute kidney failure or compartment syndrome. [agsd.org.uk]
This condition is associated with burgundy-colored urine and a risk for kidney failure, if it is severe. [nlm.nih.gov]
Early treatment also decreases the rate of severe problems such as: Gout Kidney failure Life-threatening low blood sugar Liver tumors Possible Complications These complications can occur: Frequent infection Gout Kidney failure Liver tumors Osteoporosis [mountsinai.org]
- Renal Insufficiency
Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. [atlasgeneticsoncology.org]
insufficiency Renal failure Renal failure in adulthood [ more ] 0000083 1%-4% of people have these symptoms Muscle weakness Muscular weakness 0001324 Myoglobinuria 0002913 Percent of people who have these symptoms is not available through HPO Autosomal [rarediseases.info.nih.gov]
[…] disease with focal segmental glomerulosclerosis and interstitial fibrosis. 4 This renal disease is manifested by hyperfiltration, proteinuria, and progressive renal insufficiency. 4, 5 In the kidney, most metabolic activity is associated with the proximal [nejm.org]
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.com]
Common symptoms include: Protruding abdomen from an enlarged liver and seizures from low blood sugar are common in infants Signs of low blood sugar including Paleness Irritability Fatigue Seizures Growth delay Copyright © Nucleus Medical Media, Inc. [cancercarewny.com]
This disease principally affects the liver. It causes swelling of the liver, slowing of growth, low blood sugar levels and, sometimes, seizures. [slideshare.net]
Pompe’s Disease Infantile onset < 12 months Late onset > 12 months Head lag Enlarged tongue Respiratory insufficiency Delayed motor development Muscle weakness Organomegaly Cardiomegaly/ cardiomyopathy Morning headache Daytime somnolence Shortness of [slideshare.net]
Young adults Weakness: Older adults; Legs & Trunk; Running & Sports Muscle discomfort: Cramps May present with high CK but normal strength Weakness Symmetric Respiratory failure Presenting feature in 5% to 30%: Often with other signs Symptoms: Headache; Somnolence [neuromuscular.wustl.edu]
Dose‐dependent side‐effects were noted which included tiredness, somnolence, dizziness and muscle weakness that resulted in dose reduction in four of the five participants. [cochranelibrary.com]
After she was informed in detail of the possible discomfort associated with the exercise protocol (leg pain, feeling of tachycardia, breathlessness, and dizziness), she gave her written consent to performing the test. [doi.org]
Except for slight headache and dizziness during the first 4 days of the creatine phase in patient 3, no relevant adverse effects were noted. The FSS scores at the end of the creatine and placebo phases did not differ significantly ( P = .54). [archneur.ama-assn.org]
Dose‐dependent side‐effects were noted which included tiredness, somnolence, dizziness and muscle weakness that resulted in dose reduction in four of the five participants. [cochranelibrary.com]
[…] the rate of severe problems such as: Gout Kidney failure Life-threatening low blood sugar Liver tumors Possible Complications These complications can occur: Frequent infection Gout Kidney failure Liver tumors Osteoporosis (thinning bones) Seizures, lethargy [mountsinai.org]
• Seizures, lethargy, confusion due to low blood sugar. • Short height. • Underdeveloped secondary sexual characteristics (breasts, pubic hair). • Ulcers of the mouth or bowel. Symptoms 9. [slideshare.net]
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]
- Creatine Phosphokinase Increased
[…] serum creatine kinase Increased CPK Increased creatine kinase Increased creatine phosphokinase Increased serum CK Increased serum creatine kinase Increased serum creatine phosphokinase [ more ] 0003236 30%-79% of people have these symptoms Myopathy Muscle [rarediseases.info.nih.gov]
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.
- Dimaur S, Andreu AL, Bruno C, et al. Myophosphorylase deficiency (glycogenosis type V; McArdle disease). Curr Mol Med. 2002 Mar;2(2):189-96.
- Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan;105(1):e10.
- Wolfe GI, Baker NS, Haller RG. McArdle's disease presenting with asymmetric, late-onset arm weakness. Muscle Nerve. Apr 2000;23(4):641-5.
- Felice KJ, Schneebaum AB, Jones HR Jr. McArdle's disease with late-onset symptoms: case report and review of the literature. J Neurol Neurosurg Psychiatry. May 1992;55(5):407-8.
- Pourmand R, Sanders DB, Corwin HM. Late-onset Mcardle's disease with unusual electromyographic findings. Arch Neurol. Jun 1983;40(6):374-7.
- 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.