Glycogen storage disease type V

Glycogen storage disease type V
Classification and external resources
ICD-10	E74.0
ICD-9	271.0
OMIM	232600
DiseasesDB	5307
eMedicine	med/911
MeSH	D006012

Glycogen storage disease type V (GSD-V) is a metabolic disorder, more specifically a glycogen storage disease, caused by a deficiency of myophosphorylase.^[1] Its incidence is reported as 1 in 100,000,^[2] 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.^[3]

History

The deficiency was the first metabolic myopathy 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.

Symptoms and Presentation

The onset of this disease is usually noticed in childhood,^[4] 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 myoglobinuria. 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. ^[5] 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.^[6]

The physician can perform an ischemic forearm exercise test as described above. Some findings suggest a nonischemic test could be performed with similar results.^[7] 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.

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.^[8]

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.^[9]

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-phosphate. 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.

The Enzyme

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 B₆, 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 kinase equilibrium and exaggerates the rise of ADP.

References

1. ^ Rubio JC, Garcia-Consuegra I, Nogales-Gadea G, et al. (2007). "A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients". Hum. Mutat. 28 (2): 203–4. doi:10.1002/humu.9474. PMID 17221871. 
2. ^ http://mcardlesdisease.org/
3. ^ doctor/2191 at Who Named It?
4. ^ Wolfe GI, Baker NS, Haller RG, Burns DK, Barohn RJ (2000). "McArdle's disease presenting with asymmetric, late-onset arm weakness". Muscle Nerve 23 (4): 641–5. doi:10.1002/(SICI)1097-4598(200004)23:4<641::AID-MUS25>3.0.CO;2-M. PMID 10716777. 
5. ^ Pearson, C et al. A metabolic myopathy due to absence of muscle phosphorylase, Am J Med (1961) 30: 502-517.
6. ^ http://www.preventiongenetics.com/ClinicalTesting/TestDescriptions/pygm.pdf
7. ^ Kazemi-Esfarjani P, Skomorowska E, Jensen TD, Haller RG, Vissing J (2002). "A nonischemic forearm exercise test for McArdle disease". Ann. Neurol. 52 (2): 153–9. doi:10.1002/ana.10263. PMID 12210784. 
8. ^ Pérez M, Moran M, Cardona C, et al. (January 2007). "Can patients with McArdle's disease run?". Br J Sports Med 41 (1): 53–4. doi:10.1136/bjsm.2006.030791. PMC 2465149. PMID 17000713. http://bjsm.bmj.com/cgi/pmidlookup?view=long&pmid=17000713. 
9. ^ Martín MA, Rubio JC, Wevers RA, et al. (2004). "Molecular analysis of myophosphorylase deficiency in Dutch patients with McArdle's disease". Ann. Hum. Genet. 68 (Pt 1): 17–22. doi:10.1046/j.1529-8817.2003.00067.x. PMID 14748827. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0003-4800&date=2004&volume=68&issue=Pt%201&spage=17. 

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