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Glycogen Storage Disease Type V

Synonyms: Glycogenosis Type V, GSDV, McArdle Disease, Muscle Glycogen Phosphorylase Deficiency, Myophosphorylase Deficiency

, PhD, , MD, PhD, , PhD, and , MD, PhD.

Author Information
, PhD
Hospital 12 de Octubre Research Institute (i+12) and
Center for Biomedical Research in Rare Diseases Network (CIBERER)
Madrid, Spain
, MD, PhD
European University of Madrid (UEM) and
Hospital 12 de Octubre Research Institute (i+12)
Madrid, Spain
, PhD
Hospital 12 de Octubre Research Institute (i+12)
Madrid, Spain
, MD, PhD
Hospital Universitari Vall d’Hebron Institut de Recerca (VHIR)
Barcelona, Spain

Initial Posting: ; Last Update: June 26, 2014.

Summary

Disease characteristics. Glycogen storage disease type V (GSDV, McArdle disease) is a metabolic myopathy characterized by exercise intolerance manifested by rapid fatigue, myalgia, and cramps in exercising muscles. Symptoms usually are precipitated by isometric exercise or sustained aerobic exercise. Most individuals improve their exercise tolerance by exploiting the "second wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest. Age of onset is frequently in the first decade of life but can vary. Fixed muscle weakness occurs in approximately 25% of affected individuals, is more likely to involve proximal muscles, and is more common in individuals of advanced age. Approximately 50% of affected individuals have recurrent episodes of myoglobinuria that could eventually result in acute renal failure, although reported cases are rare.

Diagnosis/testing. GSDV is diagnosed by clinical findings, supportive laboratory findings (i.e., increased resting serum creatine kinase [CK] activity and no change in plasma lactate concentration on the forearm non-ischemic or ischemic test), and the cycle test (a specific, sensitive, and simple test that is based on the pathognomonic heart rate response observed in the second wind phenomenon). The diagnosis is confirmed by molecular genetic testing of PYGM (encoding glycogen phosphorylase, muscle form), the only gene known to be associated with GSDV. Targeted mutation analysis identifies the most common pathogenic variants, p.Arg50Ter and p.Gly205Ser. Assay of myophosphorylase enzyme activity confirms the diagnosis when genetic diagnosis is unclear.

Management. Treatment of manifestations: Although no cure for GSDV is available, affected individuals benefit from moderate-intensity aerobic training (e.g., walking or brisk walking, bicycling) to increase cardiorespiratory fitness and muscle oxidative capacity. Pre-exercise ingestion of sports drinks containing simple carbohydrates improves exercise tolerance and may protect against exercise-induced rhabdomyolysis.

Prevention of secondary complications: Caution with general anesthesia because it may cause acute muscle damage.

Surveillance: Annual routine physical examination and review of diet.

Agents/circumstances to avoid: To prevent occurrence of cramps and myoglobinuria, avoid intense isometric exercise and maximal aerobic exercise.

Evaluation of relatives at risk: When the family-specific pathogenic variants are known, early detection of GSDV in relatives at risk ensures proper management to prevent muscle injury leading to rhabdomyolysis and to improve long-term outcome – particularly by adoption of a healthy lifestyle (i.e., regular exercise practice such as brisk walking) in childhood.

Genetic counseling. GSDV is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of being a carrier is 2/3. Heterozygotes are asymptomatic. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.

Diagnosis

Suggestive Findings

Glycogen storage disease type V (GSDV) is suspected in individuals with the following supportive clinical and laboratory findings.

Clinical findings:

  • Exercise-induced muscle cramps and pain, especially during the first ~10 minutes, that improve after a brief rest period or when exercise intensity is reduced (i.e., the so-called ‘second wind phenomenon’).
  • Episodes of myoglobinuria

Laboratory findings:

  • Increased resting serum creatine kinase [CK] activity. A wide range of persistently elevated activities are seen, with mean values frequently exceeding 1,000 IU/L (normal reference values: <200 IU/L).
  • No change in plasma lactate concentration on the forearm non-ischemic test, which relies on determination of plasma lactate and ammonia concentrations at baseline and within the first two minutes following exercise consisting of repeated maximal one-second handgrips every other second for one minute (~30 contractions). Diagnostic changes in plasma lactate and ammonia concentrations always occur within the first two minutes after exercise [Kazemi-Esfarjani et al 2002].
    • In controls: plasma lactate concentrations increase five to six times above basal values.
    • In individuals with GSDV: plasma lactate concentration does not increase (the so-called "flat lactate curve") and post-exercise lactate-to-ammonia peak ratios are clearly decreased.
      Note: (1) Persons with a glycogen storage disease have exaggerated responses of plasma ammonia concentration to exercise; therefore, measuring plasma ammonia concentration is as informative as measuring plasma lactate concentration. (2) The non-ischemic lactate forearm test [Kazemi-Esfarjani et al 2002] has the same diagnostic power as the ischemic lactate forearm test but eliminates the cramps, pain, and potential muscle injury produced by the ischemic test. (3) The ischemic lactate forearm test is no longer used. Click here (pdf) for more information.

Cycle and walking test. A cycle test is a physiologic test in which only heart rate needs to be monitored to detect the pathognomonic heart rate response of the second wind phenomenon, manifest by all individuals with GSDV (i.e., marked increase in heart rate [>+30-40 beats/min] during the first ~10 minutes of a cycle test at moderate intensity [~40 watts for adults] together with frequent symptoms of myalgia and cramps, followed by a decrease in heart rate and muscle symptoms [Vissing & Haller 2003a]). This test provides a sensitive, specific, and simple diagnostic test for GSDV with no possibility of false positive results. A walking test can also be performed in less specialized clinical settings to detect the second wind in persons with GSDV [Buckley et al 2014].

Confirming the Diagnosis

The diagnosis of GSDV is confirmed in a proband by identification of biallelic pathogenic variants in PYGM on molecular genetic testing or – if genetic testing results are unclear – by assay of muscle myophosphorylase enzyme activity with biochemical or histochemical methods.

Molecular genetic testing of PYGM, encoding myophosphorylase (glycogen phosphorylase, muscle form) (Table 1):

Table 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type V

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
PYGMTargeted mutation analysis p.Arg50Ter 2, 332%-85% 4
p.Gly205Ser 59%-10% 4
Sequence analysis 697%-100% 7
Deletion/duplication analysis 8<1% 9

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. p.Arg50Ter, a nonsense mutation at codon 50 in exon 1, is the most common pathogenic variant causing GSDV among individuals of European and US descent [Andreu et al 1998, Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007, Rubio et al 2007a, Lucia et al 2012]. p.Arg50Ter has never been found in individuals of Japanese descent.

3. p.Lys543Thr is included in some panels but is not commonly seen in individuals with GSDV.

4. Percentages taken from Bartram et al [1993], Tsujino et al [1993], el-Schahawi et al [1996], Andreu et al [1998], Martín et al [2001], Bruno et al [2006], Aquaron et al [2007], Deschauer et al [2007], Rubio et al [2007a]

5. p.Gly205Ser is the second most common pathogenic variant, accounting for approximately 9% of mutant alleles in various European and US populations.

6. Sequence analysis detects all the common variants discussed above as well as other variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Kubisch et al [1998]

8. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Large deletions of PYGM are very rare; a 1094 bp deletion, c.1969+214_2177+369del, extending from intron 16 to intron 17 has been reported [García-Consuegra et al 2009].

Myophosphorylase enzyme activity. Myophosphorylase E.C. 2.4.1.1 is the muscle isoenzyme of glycogen phosphorylase. Qualitative histochemistry or quantitative biochemical analysis in a muscle biopsy or muscle homogenate is diagnostic. In persons with GSDV the residual activity of myophosphorylase in GSDV is virtually undetectable.

Clinical Description

Natural History

Glycogen storage disease type V (GSDV) is a metabolic myopathy with onset frequently in the first decade of life. Clinical heterogeneity exists; some individuals have mild symptoms manifesting as fatigue or poor stamina without cramps, whereas a severe, rapidly progressive form manifests shortly after birth. In some individuals, progressive weakness manifests in the sixth or seventh decade of life [Wolfe et al 2000]. The fixed weakness that occurs in approximately one fourth of affected individuals is more likely to involve proximal muscles and is more common in individuals over age 40 years. Most individuals learn to adjust their daily activities and can have relatively normal lives.

The usual presentation of GSDV is exercise intolerance, including stiffness or weakness of the muscles being used, myalgia, and fatigue in the first few minutes of exercise. These symptoms are usually precipitated by isometric exercise (e.g., carrying weights) and sustained vigorous aerobic exercise (e.g., stair-climbing, jogging), and typically are relieved by rest. Any skeletal muscle can be affected.

Many individuals remember painful symptoms from early childhood, but the disorder is rarely diagnosed before adulthood. Some people notice a worsening of their symptoms in middle age that may be accompanied by some muscle wasting. Presentation with exertional dyspnea has been described [Voduc et al 2004].

Most individuals learn to improve their exercise tolerance by exploiting the "second wind" phenomenon, a unique feature of GSDV, that is, relief of myalgia and rapid fatigue after a few minutes of rest. The metabolic events underlying the second wind are the increased supply of blood-borne glucose and free fatty acids as exercise progresses, leading to a switch in metabolic pathways from endogenous glycolysis to oxidative phosphorylation of blood-borne fatty acids [Haller & Vissing 2002]. The ability to develop a second wind is greatly increased in those who keep physically fit through aerobic exercise, such as walking. In contrast, sustained or strenuous exercise, such as lifting heavy weights or sprinting, carries a high risk of muscle damage. Continuing to exercise in the presence of severe pain also results in muscle damage (rhabdomyolysis) and myoglobinuria, with the attending risk of acute renal failure.

Myoglobinuria occurs in approximately 50% of individuals following intense exercise; however, very few develop acute renal failure. Kidney failure is almost always reversible, but emergency treatment is required [Lucia et al 2012].

Other presentations of GSDV:

Pathophysiology. The two types of exercise:

  • Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors including: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen.
  • Anaerobic exercise is intense but cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP anaerobically.

The first few minutes of any exercise have an anaerobic component. Depending on intensity and duration of the exercise, muscle uses different fuel sources such as anaerobic glycolysis, blood glucose, muscle glycogen, and aerobic glycolysis, followed by fatty acid oxidation.

At rest the main energy source is blood free fatty acids. These molecules are oxidized in the mitochondrial beta-oxidation pathway to produce acetyl-CoA, which is further metabolized through the Krebs cycle and the mitochondrial respiratory chain resulting in ATP production.

Genotype-Phenotype Correlations

Several studies in European populations did not observe any apparent correlation between severity of clinical findings and genotype [Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007, Vieitez et al 2011].

One study showed that an insertion/deletion (I/D) benign variant in ACE (encoding angiotensin converting enzyme), involving the insertion (allele I) or deletion (allele D) situated approximately 250 bp into intron 16 of ACE, could play a significant role as a phenotype modulator in individuals with GSDV [Martinuzzi et al 2003]. The ACE I allele has been associated with a higher functional capacity in affected females [Gómez-Gallego et al 2008].

In the study of 99 individuals with GSDV that assessed the possible effect of several genotype modulators (ACE-I/D, AMPD1: p.Gln12Ter; PPARGC1A: p.Gly482Ser; ACTN3: p.Arg577Ter) on clinical severity, no significant relationships were detected except for the ACE D allele and the disease severity score described by Martinuzzi et al [2003] and Rubio et al [2007b].

Prevalence

The prevalence of GSDV in the Dallas-Fort Worth, Texas area was estimated at 1:100,000 [Haller 2000].

The Spanish McArdle Disease patient registry reported a minimum prevalence in that country of nearly 1:170,000 [Lucia et al 2012].

Differential Diagnosis

The differential diagnosis of glycogen storage disease type V (GSDV) includes the following:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type V (GSDV), the following evaluations are recommended:

  • Physical examination with emphasis on muscle strength/weakness
  • Basal serum CK activity

Treatment of Manifestations

Aerobic training (on a regular diet). In some individuals, improvement in exercise and circulatory capacity has been reported, probably caused by the increased circulatory capacity, which facilitates delivery of blood-borne fuels [Haller 2000].

In eight individuals who underwent a 14-week aerobic conditioning program in which they pedaled a cycloergometer for 30-40 minutes a day, four days a week at an intensity corresponding to 60% to 70% of maximal heart rate, an increase in work capacity, oxygen uptake, cardiac output, citrate synthase activity, and beta-hydroxyacyl coenzyme A dehydrogenase activity was observed, indicating that moderate aerobic exercise improves exercise capacity in individuals with GSDV [Haller et al 2006].

Nine individuals who underwent an eight-month supervised aerobic exercise training program including five weekly sessions of walking or cycling for no more than 60 minutes, improved their peak power output, peak oxygen uptake, and ventilatory threshold with no evidence of negative outcomes, suggesting that under carefully controlled conditions individuals with GSDV may exercise safely and may respond favorably to training [Maté-Muñoz et al 2007].

A systematic review of physical training for GSDV published in the Cochrane Database concluded that there are no randomized or quasi-randomized controlled trials of aerobic training in people with GSDV; however, three studies using small numbers of participants provided some evidence that aerobic training improves fitness without adverse events in people with GSDV. They suggested that it would be safe and worthwhile to conduct larger controlled trials of aerobic training in patients with GSDV [Quinlivan et al 2011].

In a subcohort of 63 patients (out of 239 registered) interviewed for their physical activity habits and whose peak oxygen uptake (and index of peak cardiorespiratory fitness and peak muscle oxidative capacity) were measured, the 32% who were physically active had higher levels of peak oxygen uptake (by 23%, p=0.003) and were more likely to improve their clinical course over a four-year period compared with inactive patients (odds ratio = 225; 95% confidence intervals 20.3 to 2496.7) after controlling for age. Moreover, for 81% of patients in the physically active cohort, clinical disease was reclassified as less severe. Mean peak oxygen uptake was very low, especially in women, where it barely reached the limit (13 mL O2/kg/min or 3.7 metabolic equivalents (METs, with 1MET equaling 3.5 mL O2/kg/min) necessary for independent living. Age also had a negative effect on peak oxygen uptake. However, the peak oxygen uptake in patients who were physically active was 1.5METs higher than in those who were not active. Seven patients (6 physically active) had a peak oxygen uptake of 8 METs, which is the minimum threshold for optimal health.

Three daily habits recommended by Haller [2000] to improve the quality of life:

  • Avoid intense isometric exercise and maximal aerobic exercise, which triggers cramps and, potentially, myoglobinuria (see Agents/Circumstances to Avoid).
  • Avoid a totally sedentary life, which induces deconditioning.
  • Engage in regular, moderate aerobic exercise, which improves cardiorespiratory capacity and increases delivery of blood-borne fuels, a sort of permanent "second wind" (i.e., decrease in heart rate and perceived exertion during exercise) effect [Ollivier et al 2005].

Pharmacologic and Nutritional Treatments

Two systematic reviews of pharmacologic and nutritional treatments for GSDV were published in the Cochrane Database [Quinlivan & Beynon 2004, Quinlivan et al 2008]. The authors' conclusions:

  • There is no evidence of significant benefit from any specific nutritional or pharmacologic treatment for GSDV.
  • Low-dose creatine supplementation demonstrated a statistically significant benefit, albeit modest, in ischemic exercise in a small number of individuals.
  • Ingestion of oral sucrose immediately prior to exercise reduces perceived ratings of exertion and heart rate and improves exercise tolerance. This treatment does not influence sustained or unexpected exercise.
  • A carbohydrate-rich diet was of benefit.
  • Because of the rarity of GSDV, multicenter collaboration and standardized assessment protocols are needed for future treatment trials.

Pharmacologic treatments

  • Creatine monohydrate in a placebo-controlled crossover trial with nine affected individuals improved symptoms and increased their capacity for ischemic, isometric forearm exercise [Vorgerd et al 2000]. This positive effect did not result from increased levels of phosphocreatine in muscle. Rather, creatine may have a quenching effect on the potassium-mediated changes in membrane excitability. A subsequent clinical trial with high doses of creatine monohydrate in 19 individuals lowered exercise intolerance [Vorgerd et al 2002]. Thus, the indication for symptomatic therapy with creatine monohydrate needs to be strengthened.
  • Ramipril, an ACE inhibitor, used in a randomized, placebo-controlled, double-blind pilot trial in eight persons with GSDV, decreased disability and improved exercise physiology only in those individuals with the ACE D/D genotype (see Genotype-Phenotype Correlations) [Martinuzzi et al 2008].

Nutritional treatments

  • In a single-blind, randomized, placebo-controlled crossover study in 12 individuals with GSDV, Vissing & Haller [2003b] found that ingestion of 75 g of sucrose markedly improved exercise tolerance.
  • Ingesting simple carbohydrates (adult dose: 30-40 g glucose, fructose, or sucrose, or ~440 mL of most commercially available sport drinks; pediatric dose: 20 g) about five minutes before engaging in strenuous exercise such as brisk walking (or physical education classes in the younger individuals) can be helpful [Perez et al 2007, Andersen et al 2008]. In addition to increasing exercise capacity and sense of well-being, the treatment may protect against exercise-induced rhabdomyolysis.
  • Ingestion of sucrose before exercise combined with an aerobic conditioning program is reasonable [Amato 2003].
  • Individuals with GSDV can also benefit from adopting a diet rich in complex carbohydrates (i.e., with a high proportion (65%) of complex carbohydrates such as those found in vegetables, fruits, cereals, bread, pasta, and rice) and a low proportion (20%) of fat [Andersen & Vissing 2008].

Prevention of Primary Manifestations

See Treatment of Manifestations and Agents/Circumstances to Avoid.

Prevention of Secondary Complications

To prevent muscle breakdown (rhabdomyolysis) and myoglobinuria-induced renal damage: follow the exercise and nutritional measures described in Treatment of Manifestations.

Surveillance

Appropriate surveillance includes:

  • Annual routine physical examination
  • Annual review of diet

Agents/Circumstances to Avoid

Exercises that involve heavy static contractions or induce severe myalgia should be avoided [Quinlivan et al 2011, Lucia et al 2012].

Exercises that should be avoided in patients with GSDV [Lucia et al 2008] are the following:

  • Static muscle contractions (e.g., handgrip exercises)
  • Static muscle contractions or heavy loads on low muscle mass (e.g., weightlifting)
  • Dynamic exercises at a high-intensity level (e.g., competitive ball games)
  • Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps)
  • Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in individuals who are very fit and well habituated

General anesthetics. Risk of acute muscle damage is reported with certain general anesthetics (usually muscle relaxants and inhaled anesthetics), although in practice, problems appear to be rare. One report showed hyperthermia, pulmonary edema, and rhabdomyolysis [Lobato et al 1999]; however, GSDV does not appear to cause severe perioperative problems in routine anesthetic care. Nonetheless, measures for preventing muscle ischemia and rhabdomyolysis should be taken in individuals with GSDV [Bollig 2013].

Lipid-lowering drugs. A study in which 136 individuals with myopathy induced by one of the three lipid-lowering drugs atorvastatin, cerivastatin, and simvastatin were tested for the two more frequent PYGM pathogenic variants (p.Arg50Ter, p.Gly205Ser) revealed 20-fold more PYGM heterozygotes than expected for the general population [Vladutiu et al 2006]. These findings provide preliminary evidence that PYGM heterozygotes may be predisposed to statin-induced myopathy; however, because only two pathogenic variants were assessed, some individuals in this study who were presumed to be carriers could actually be compound heterozygotes. Thus, clinicians should be cautious when recommending statins to individuals who have GSDV or are carriers for a PYGM pathogenic variant.

Evaluation of Relatives at Risk

Early diagnosis of GSDV in relatives at risk may improve long-term outcome by heightening awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness.

  • When the family-specific PYGM pathogenic variants are known, molecular genetic testing can be used.
  • When the family-specific PYGM pathogenic variants are not known, a reliable and accurate diagnosis of GSDV could be reached following the criteria described in Diagnosis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The condition does not appear to adversely affect pregnancy and childbirth outcomes [Quinlivan et al 2010, Lucia et al 2012].

Therapies Under Investigation

Gene therapy. An adenoviral recombinant containing the full-length human myophosphorylase cDNA was efficiently transduced into phosphorylase-deficient sheep and human myoblasts, where it restored enzyme activity [Pari et al 1999].

Adenovirus and adeno-associated virus-mediated delivery of human phosphorylase cDNA and LacZ cDNA to muscle in the ovine (sheep) model of McArdle disease showed expression of functional myophosphorylase and some re-expression of the non-muscle glycogen phosphorylase isoforms (liver and brain isoforms) in regenerating fibers [Howell et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Vitamin B6 has been used because the overall body stores of pyridoxal phosphate are depleted in GSDV. A beneficial effect has been documented in two individuals, but this requires confirmation [Phoenix et al 1998, Sato et al 2012].

Branched-chain amino acids (BCA). Administration of BCA as alternative fuels to glycogen to six individuals worsened bicycle exercise capacity, possibly because of the free fatty acid-lowering effect of the amino acids [MacLean et al 1998].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Glycogen storage disease type V (GSDV) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one PYGM pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic. Note: manifesting heterozygotes were reported before genetic testing was available [Manfredi et al 1993]; such observations could be attributable to lack of identification of the second pathogenic variant.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic. Manifesting heterozygotes were reported before the availability of genetic testing [Manfredi et al 1993]. However, in one study including eight individuals with GSDV, seven heterozygotes, and 11 controls (individuals who are neither affected nor heterozygotes), the heterozygotes had values of exercise capacity indicators (maximal oxidative capacity and peak lactate response) identical to controls, suggesting that they are not prone to developing symptoms of GSDV [Andersen et al 2006].

Offspring of a proband. The offspring of an individual with GSDV are obligate heterozygotes (carriers) for a pathogenic variant in PYGM.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the PYGM pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the PYGM pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Biochemical testing. Biochemical testing cannot be done on fetal tissue as myophosphorylase is expressed only in differentiated muscle cells.

Requests for prenatal testing for conditions such as GSDV are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the PYGM pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Glycogen Storage Disease (AGSD)
    PO Box 896
    Durant IA 52747
    Phone: 563-514-4022
    Email: maryc@agsdus.org
  • Medline Plus
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Glycogen Storage Disease Type V: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PYGM11q13​.1Glycogen phosphorylase, muscle formPYGM databasePYGM

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Glycogen Storage Disease Type V (View All in OMIM)

232600GLYCOGEN STORAGE DISEASE V; GSD5
608455GLYCOGEN PHOSPHORYLASE, MUSCLE; PYGM

Molecular Genetic Pathogenesis

The muscle glycogen phosphorylase (PYGM, glycogen phosphorylase, α-1,4-glucan orthophosphate glycosyltransferase, EC 2.4.1.1.) initiates glycogen breakdown by removing α-1,4-glucosyl residues with phosphate ion ('inorganic phosphate') consumption (i.e., phosphorylytically) from the outer branches of glycogen with liberation of glucose-1-phosphate. The enzyme exists as a homodimer containing two identical subunits of 97 kd each. The dimers associate into a tetramer to form the enzymatically active phosphorylase A.

Gene structure. PYGM spans 14 kb containing 20 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Five single-nucleotide benign variants in the coding region have been annotated: three nonsynonymous and two synonymous changes have been identified (see Table 4). Ideally, synonymous exonic allelic variants found in symptomatic individuals in whom no other PYGM pathogenic variant was identified should be tested for their potential effect on mRNA splicing [Cartegni et al 2002]. The synonymous mutations at lysine residues 205 and 609 were found to severely alter PYGM transcripts in symptomatic individuals [Fernandez-Cadenas et al 2003, García-Consuegra et al 2009].

Pathogenic allelic variants. To date, more than 140 pathogenic variants causing PYGM deficiency have been identified. See Table 2 for classes of mutations observed [Andreu et al 2007; HGMD, accessed June 2, 2014].

Note that the synonymous mutation c.1827G>A at lysine residue 609 was found to severely alter PYGM transcripts [Fernandez-Cadenas et al 2003] (see Table 3). Another synonymous variant, c.645G>A at lysine amino acid 215, is also predicted to be pathogenic by affecting PYGM transcription [García-Consuegra et al 2009].

Table 2. Classes of Mutations Observed in PYGM

Genetic MechanismNumber of Mutations
Nucleotide substitutions (missense/nonsense)86
Nucleotide substitutions (splicing)14
Small deletions20
Small insertions (including duplications)5
Small indel mutations 13
Gross deletions4
Total144

From Bruno et al [2006], Andreu et al [2007], Aquaron et al [2007], Deschauer et al [2007], Rubio et al [2007a], Lucia et al [2012], and The Human Gene Mutation Database (HGMD)

1. Indel mutations (also called "indels") are the simultaneous insertion and deletion of nucleotide sequence(s) at the same site in a gene.

Table 3. Selected PYGM Allelic Variants

Variant
Classification
DNA Nucleotide ChangeProtein Amino Acid Change 1
(Alias 2)
Reference Sequences
Benignc.564C>Ap.Asn188LysNM_005609​.2
NP_005600​.1
c.1240C>Gp.Arg414Gly
c.1289C>Tp.Ser430Leu
c.1365C>Tp.=
c.1494C>Tp.=
Pathogenicc.148C>Tp.Arg50Ter
(Arg49*)
c.255C>Ap.Tyr85Ter
(Tyr84*)
c.613G>Ap.Gly205Ser
(Gly204Ser)
c.645G>A p.=
(Lys215Lys)
c.1628A>Cp.Lys543Thr
(Lys542Thr)
c.1827G>Ap.=
(Lys608Lys)
c.2128_2130delTTCp.Phe710del
(708/709del)
c.2392T>Cp.Trp798Arg
(Trp797Arg)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. p.= indicates that no amino acid change is expected.

2. Variant designation that does not conform to current naming conventions. For PYGM, the alias for a pathogenic protein amino acid change was in the past one residue less, as it follows a convention of designating the second amino acid (Ser) as residue number one, rather than the standard of using the initiating Met residue as number one.

Recurrent pathogenic variants (Table 4) include the following:

Table 4. PYGM Pathogenic Variants Other than p.Arg50Ter and p.Gly205Ser with Relatively High Frequency in Specific Populations

PopulationPathogenic VariantFrequency
Japanese 1p.Phe710del 64%
Spanish 2p.Trp798Arg 12%
Central European 3p.Tyr85Ter 25%

Normal gene product. The size of monomeric PYGM is 841 amino acids in human skeletal muscle. PYGM protein has a molecular weight of 97 kd.

Abnormal gene product. Pathogenic variants in PYGM reduce or abolish myophosphorylase enzyme activity in muscle [Dimauro et al 2002]. Missense mutations may affect contact dimer pairs, which are involved in the propagation of allosteric effects of this regulatory protein. Mutations can also disrupt hydrogen bond interactions and affect substrate or effector-/inhibitor-binding sites. Mutations yielding premature stop codons (PTC) predict truncated proteins but may also produce deep effects at the transcriptional level (i.e., nonsense-mediated decay (NMD), disruption of splicing machinery yielding aberrant transcript) [Martín et al 2001, Fernandez-Cadenas et al 2003, Garcia-Consuegra 2009]. It should be noted that 35% of all pathogenic variants in PYGM result in PTC. One study in 28 individuals harboring 17 different pathogenic variants with PTCs showed that the NMD mechanism occurred in 92% and that the common pathogenic variant p.Arg50Ter elicited decay in all genotypes tested [Nogales-Gadea et al 2008].

A knock-in mouse model for the common variant p.Arg50Ter has been shown to recapitulate most of the signs and symptoms of GSDV, and consequently could be of great value for in-depth studies of molecular pathogenesis and for exploring new therapeutic approaches for genetic disorders caused by premature stop codons [Nogales-Gadea et al 2012].

References

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Suggested Reading

  1. Rommel O, Kley RA, Dekomien G, Epplen JT, Vorgerd M, Hasenbring M. Muscle pain in myophosphorylase deficiency (McArdle's disease): the role of gender, genotype, and pain-related coping. Pain. 2006;124:295–304. [PubMed: 16793208]

Chapter Notes

Acknowledgments

Supported by grants from the Fondo de Investigación Sanitaria (FIS PI12/00914, PI10/00036, European Union, Executive Agency for Health and Consumers (EUROMAC) no. 318081, and from Centro de Investigación Biomedica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain.

Revision History

  • 26 June 2014 (me) Comprehensive update posted live
  • 12 May 2009 (me) Comprehensive update posted live
  • 8 May 2006 (cd) Revision: sequence analysis of PYGM clinically available
  • 19 April 2006 (me) Review posted to live Web site
  • 26 August 2005 (ja) Original submission
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