|Synonym||Glycogen Storage Disease Type V|
|Genetics||Biallelic pathogenic variants in PYGM gene|
|Clinical Features||Exercise intolerance and muscle cramps, rhabdomyolysis. Progressive muscle weakness later in life.|
|Tests||CK, Ischaemic forearm exercise test (low values of post-exercise plasma lactate-to-ammonia ratio), molecular genetics.|
McArdle disease (also known as glycogen storage disease type V, type V glycogenosis, or myophosophorylase deficiency) is an autosomal recessive disorder of carbohydrate metabolism. It is characterized by the absence of muscle glycogen phosphorylase resulting in impaired muscle metabolism. Glycogen phosphorylase is a key enzyme that takes part in the first step of glycogenolysis. Misdiagnoses are common even through adult years.
Glycogen phosphorylase catalyzes glycogen into glucose-1-phosphate through removing alpha-1,4-glucoside residues from the outer branches of the glycogen molecule. This degradation continues until the peripheral branches of glycogen are shortened to around 4 glucosyl units.
The muscle symptoms relate to the inability to generate energy from muscle glycogen because of deficiency of the muscle isoform of glycogen phosphorylase (PYGM). Of note, There are also liver (PYGL)and brain (PYGB) isoforms of glycogen phosphorylase, however PYGM is also expressed in non-muscular tissues.
Patients cardinally experience exercise intolerance in childhood or in young adulthood with exertional muscle pain and cramps induced by brief but intense activities such as weight lifting or sprinting. However symptoms can also occur with prolonged low-intensity exercise. Exertional fatigue without pain is a feature in some patients.
In infants, symptoms may include difficulty crawling more than a few yards, while toddlers may want to be carried or put in a push-chair all the time and complain of pain when walking. In children, the disease can lead to an inability to run more than 100 meters, an inability to keep up with peers, and collapse or vomiting during sporting activities.
One hallmark of McArdle disease is the "second wind" phenomenon. During aerobic activity, patients experience a period where symptoms improve after 8-10 minutes of exercise. This is thought to be due to the mobilisation and use of blood-borne glucose.
Rhabdomyolysis/myoglobinuria can occur but usually not until the second or third decade, with approximately 50% being related to exertion. Acute renal failure can be a complication of this.
Examination is usually normal between attacks. However around one third have fixed proximal weakness due to recurrent episodes of rhabdomyolysis. Rarely it presents in late-adulthood with progressive proximal muscle atrophy rather than exercise intolerance.
Diagnosis of McArdle disease involves a combination of clinical presentation, laboratory tests, and genetic testing.
- Baseline serum CK is usually raised (10-15 times the normal range), while serum urate is frequently elevated.
- A non-ischemic forearm exercise test shows no significant rise in lactate.
- DNA analysis can identify common mutations of PYGM in Northern Europeans, such as p.Arg50X and p.Gly205Ser. Next-tier testing involves full PYGM sequencing.
- Muscle biopsy is rarely required but can be done if there is no access to molecular genetics. Findings are vacuolar myopathy, sub-sarcolemmal glycogen deposition, and absent muscle glycogen phosphorylase activity.
Treatment for McArdle disease is mainly supportive, with an emphasis on avoiding strenuous exercise and preventing muscle damage. Patients are encouraged to engage in regular low-intensity exercise, which can improve muscle function and reduce symptoms. Intense isometric exercises and maximum aerobic exercises should be avoided. Any bout of moderate exercise should be preceeded by 5-15 minutes gentle warm-up to active the second-wind effect.
Oral sucrose (75g) can result in improvement of exercise tolerance.
Neuromuscular Disorders - Amato 2008
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