Glycogen storage disease type V
Encyclopedia
Glycogen storage disease type V (GSD-V) is a metabolic disorder, more specifically a glycogen storage disease
, caused by a deficiency of myophosphorylase
. Its incidence is reported as 1 in 100,000, approximately the same as glycogen storage disease type I
.
GSD type V is also known as McArdle's disease or muscle phosphorylase (myophosphorylase) deficiency. The disease was first reported in 1951 by Dr. Brian McArdle
of Guy's Hospital
, London.
to be recognized, when Dr. McArdle described the first case in a 30-year-old man who always experienced pain and weakness after exercise. Dr. McArdle noticed this patient’s cramps were electrically silent and his venous lactate
levels failed to increase upon ischemic exercise. (The ischemic exercise consists of the patient squeezing a hand dynamometer at maximal strength for a specific period of time, usually a minute, with a blood pressure cuff, which is placed on the upper arm and set at 250 mmHg, blocking blood flow to the exercising arm.) Notably, this is the same phenomenon that occurs when muscle is poisoned by iodoacetate
, a substance that blocks breakdown of glycogen into glucose and prevents the formation of lactic acid. Dr. McArdle accurately concluded that the patient had a disorder of glycogen breakdown that specifically affected skeletal muscle. The associated enzyme deficiency was discovered in 1959 by W. F. H. M. Mommaerts et al.
. Myoglobinuria, the condition where myoglobin is present in urine, may result from serious damage to the muscles, or rhabdomyolysis
, where muscle cells breakdown, sending their contents into the bloodstream.
Patients may exhibit a “second wind” phenomenon. This is characterized by the patient’s better tolerance for aerobic exercise such as walking and cycling after approximately 10 minutes. This is attributed to the combination of increased blood flow and the ability of the body to find alternative sources of energy, like fatty acids and proteins. In the long term, patients may exhibit renal failure due to the myoglobinuria, and with age, patients may exhibit progressively increasing weakness and substantial muscle loss.
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. Left untreated this can be life threatening. In a small number of cases compartment syndrome has developed, requiring prompt surgical referral.
PYGM genetic sequencing may be done to determine the presence of gene mutations, determining if McArdle's is present. This type of testing is considerably less invasive than a muscle biopsy. The test involves bidirectional sequencing of the coding regions of all 20 PYGM exons plus about 50 Bp of non-coding flanking DNA on each side. Because the disease consists of two gene mutations and because the test can be performed to identify carries of the disease, the test has two tiers. Tier 1 involves sequencing of exons 1 and 5. If two likely causative mutations are detected in patients in Tier 1 or one mutation carriers in Tier 1, then the testing stops. Otherwise, testing continues with Tier 2 involving sequencing the remaining 18 exons. These tests require a simple blood draw.
The physician can perform an ischemic forearm exercise test as described above. Some findings suggest a nonischemic test could be performed with similar results. The nonischemic version of this test would involve not cutting off the blood flow to the exercising arm. Findings consistent with McArdle’s disease would include a failure of lactate rise in venous blood and exaggerated rise of ammonia levels. These findings would indicate a severe muscle glycolytic block. Ammonia arises from the impaired buffering of ADP, which leads to an increase in AMP concentration resulting in an increase in AMP deamination.
Physicians may check creatine kinase resting levels (which are moderately increased in 90% of patients). This piece of data helps distinguish McArdle's from carnitine palmitoyltransferase deficiency. Also, serum electrolytes, endocrine studies (such as thyroid function, parathyroid function and growth hormone levels) will be completed. Urine studies are required only if rhabdomyolysis is suspected. Urine volume, urine sediment and myoglobin levels would be ascertained. If rhabdomyolysis is suspected, serum myoglobin, creatine kinase, lactate dehydrogenase
, electrolytes and renal function will be checked.
Supervised exercise programs have been recommended to lessen the risks of extended inactivity.
Sucrose treatment is now being recommended prior to exercise.
The exact method of protein disruption has been elucidated in certain mutations. For example, R138W is known to disrupt to pyridoxal phosphate binding site.
. Cells form glucose-1-phosphate instead of glucose during glycogen breakdown because the polar, phosphorylated glucose cannot leave the cell membrane and so is marked for intracellular catabolism.
Myophosphorylase exists in the active form when phosphorylated. The enzyme phosphorylase kinase
plays a role in phosphorylating glycogen phosphorylase to activate it and another enzyme, protein phosphatase-1, inactivates glycogen phosphorylase through dephosphorylation.
, a cofactor required by myophosphorylase. By similarity other sites have been estimated: Tyr-76 binds AMP, Cys-109 and Cys-143 are involved in subunit association, and Tyr-156 may be involved in allosteric control.
equilibrium and exaggerates the rise of ADP.
Glycogen storage disease
Glycogen storage disease is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by any inborn error of metabolism involved in these processes...
, caused by a deficiency of myophosphorylase
Myophosphorylase
Myophosphorylase is the muscle isoform of the enzyme glycogen phosphorylase.This enzyme helps break down glycogen into glucose-1-phosphate, so that it can be utilized within the muscle cell....
. Its incidence is reported as 1 in 100,000, approximately the same as glycogen storage disease type I
Glycogen storage disease type I
Glycogen storage disease type I or von Gierke's disease, is the most common of the glycogen storage diseases. This genetic disease results from deficiency of the enzyme glucose-6-phosphatase. This deficiency impairs the ability of the liver to produce free glucose from glycogen and from...
.
GSD type V is also known as McArdle's disease or muscle phosphorylase (myophosphorylase) deficiency. The disease was first reported in 1951 by Dr. Brian McArdle
Brian McArdle
Brian McArdle was a British doctor. Glycogen storage disease type V was named for him as McArdle's disease.-References:...
of Guy's Hospital
Guy's Hospital
Guy's Hospital is a large NHS hospital in the borough of Southwark in south east London, England. It is administratively a part of Guy's and St Thomas' NHS Foundation Trust. It is a large teaching hospital and is home to the King's College London School of Medicine...
, London.
History
The deficiency was the first metabolic myopathyMyopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
to be recognized, when Dr. McArdle described the first case in a 30-year-old man who always experienced pain and weakness after exercise. Dr. McArdle noticed this patient’s cramps were electrically silent and his venous lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
levels failed to increase upon ischemic exercise. (The ischemic exercise consists of the patient squeezing a hand dynamometer at maximal strength for a specific period of time, usually a minute, with a blood pressure cuff, which is placed on the upper arm and set at 250 mmHg, blocking blood flow to the exercising arm.) Notably, this is the same phenomenon that occurs when muscle is poisoned by iodoacetate
Iodoacetate
Iodoacetic acid is a derivative of acetic acid. It is a toxic compound, because, like many alkyl halides, it is an alkylating agent. It reacts with cysteine residues in proteins...
, a substance that blocks breakdown of glycogen into glucose and prevents the formation of lactic acid. Dr. McArdle accurately concluded that the patient had a disorder of glycogen breakdown that specifically affected skeletal muscle. The associated enzyme deficiency was discovered in 1959 by W. F. H. M. Mommaerts et al.
Symptoms and Presentation
The onset of this disease is usually noticed in childhood, but often not diagnosed until the third or fourth decade of life. Symptoms include exercise intolerance with myalgia, early fatigue, painful cramps, weakness of exercising muscles and myoglobinuriaMyoglobinuria
Myoglobinuria is the presence of myoglobin in the urine, usually associated with rhabdomyolysis or muscle destruction. Myoglobin is present in muscle cells as a reserve of oxygen.-Causes:...
. Myoglobinuria, the condition where myoglobin is present in urine, may result from serious damage to the muscles, or rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
, where muscle cells breakdown, sending their contents into the bloodstream.
Patients may exhibit a “second wind” phenomenon. This is characterized by the patient’s better tolerance for aerobic exercise such as walking and cycling after approximately 10 minutes. This is attributed to the combination of increased blood flow and the ability of the body to find alternative sources of energy, like fatty acids and proteins. In the long term, patients may exhibit renal failure due to the myoglobinuria, and with age, patients may exhibit progressively increasing weakness and substantial muscle loss.
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. Left untreated this can be life threatening. In a small number of cases compartment syndrome has developed, requiring prompt surgical referral.
Laboratory Tests
There are some laboratory tests that may aid in diagnosis of GSD-V. A muscle biopsy will note the absence of myophosphorylase in muscle fibers. In some cases, acid-Schiff stained glycogen can be seen with microscopy.PYGM genetic sequencing may be done to determine the presence of gene mutations, determining if McArdle's is present. This type of testing is considerably less invasive than a muscle biopsy. The test involves bidirectional sequencing of the coding regions of all 20 PYGM exons plus about 50 Bp of non-coding flanking DNA on each side. Because the disease consists of two gene mutations and because the test can be performed to identify carries of the disease, the test has two tiers. Tier 1 involves sequencing of exons 1 and 5. If two likely causative mutations are detected in patients in Tier 1 or one mutation carriers in Tier 1, then the testing stops. Otherwise, testing continues with Tier 2 involving sequencing the remaining 18 exons. These tests require a simple blood draw.
The physician can perform an ischemic forearm exercise test as described above. Some findings suggest a nonischemic test could be performed with similar results. The nonischemic version of this test would involve not cutting off the blood flow to the exercising arm. Findings consistent with McArdle’s disease would include a failure of lactate rise in venous blood and exaggerated rise of ammonia levels. These findings would indicate a severe muscle glycolytic block. Ammonia arises from the impaired buffering of ADP, which leads to an increase in AMP concentration resulting in an increase in AMP deamination.
Physicians may check creatine kinase resting levels (which are moderately increased in 90% of patients). This piece of data helps distinguish McArdle's from carnitine palmitoyltransferase deficiency. Also, serum electrolytes, endocrine studies (such as thyroid function, parathyroid function and growth hormone levels) will be completed. Urine studies are required only if rhabdomyolysis is suspected. Urine volume, urine sediment and myoglobin levels would be ascertained. If rhabdomyolysis is suspected, serum myoglobin, creatine kinase, lactate dehydrogenase
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
, electrolytes and renal function will be checked.
Treatment/Therapy
Oral vitamin B6 appears to impart greater resistance to fatigue. No specific therapy exists, but combined aerobic exercise programs and high-protein diets may help. Some patients learn the limits of their exercise and work within their restrictions, going on to live fairly normal lives.Supervised exercise programs have been recommended to lessen the risks of extended inactivity.
Sucrose treatment is now being recommended prior to exercise.
Genetic Basis
There are two autosomal recessive forms of this disease, childhood-onset and adult-onset. The gene for myophosphorylase, PYGM (muscle-type glycogen phosphorylase gene), is located on chromosome 11q13. According to the most recent publications, 95 different mutations have been reported. The forms of the mutations may vary between ethnic groups. For example, the Arg49Stop mutation is most common in North America and Europe, the R49X mutation is most common in Dutch patients, and the Y84X mutation is most common among central Europeans.The exact method of protein disruption has been elucidated in certain mutations. For example, R138W is known to disrupt to pyridoxal phosphate binding site.
The Reaction
Myophosphorylase is involved in the breakdown of glycogen to glucose for use in muscle. The enzyme removes 1,4 glycosyl residues from outer branches of glycogen and adds inorganic phosphate to form glucose-1-phosphateGlucose-1-phosphate
Glucose 1-phosphate is a glucose molecule with a phosphate group on the 1'-carbon.-Catabolic:In glycogenolysis, it is the direct product of the reaction in which glycogen phosphorylase cleaves off a molecule of glucose from a greater glycogen structure.To be utilized in cellular catabolism it must...
. Cells form glucose-1-phosphate instead of glucose during glycogen breakdown because the polar, phosphorylated glucose cannot leave the cell membrane and so is marked for intracellular catabolism.
Myophosphorylase exists in the active form when phosphorylated. The enzyme phosphorylase kinase
Phosphorylase kinase
Phosphorylase kinase is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen...
plays a role in phosphorylating glycogen phosphorylase to activate it and another enzyme, protein phosphatase-1, inactivates glycogen phosphorylase through dephosphorylation.
Structure
The myophosphorylase structure consists of 842 amino acids. Its molecular weight of the unprocessed precursor is 97 kDa. The 3D structure has been determined of this protein. The interactions of several amino acids in myophosphorylase’s structure are known. Ser-14 is modified by phosphorylase kinase during activation of the enzyme. Lys-680 is involved in binding the pyridoxal phosphate, which is the active form of vitamin B6Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...
, a cofactor required by myophosphorylase. By similarity other sites have been estimated: Tyr-76 binds AMP, Cys-109 and Cys-143 are involved in subunit association, and Tyr-156 may be involved in allosteric control.
Function
Myophosphorylase is the form of the glycogen phosphorylase found in muscle. (see The Reaction above). Failure of this enzyme ultimately impairs the operation of ATPases. This is due to the lack of normal pH fall during exercise, which impairs the creatine kinaseCreatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
equilibrium and exaggerates the rise of ADP.
External links
- The Association for Glycogen Storage Disease
- The Association for Glycogen Storage Disease (UK) McArdle information
- McArdle Disease Emergencies - AGSD (UK)
- Information About McArdle's Disease
- GeneReview/NIH/UW entry on Glycogen Storage Disease Type V