Glycogen Storage Disease Type V

[Glycogenosis Type V, GSDV, McArdle Disease, Muscle Glycogen Phosphorylase Deficiency, Myophosphorylase Deficiency]

Clinical Diagnosis

Glycogen storage disease type V (GSDV) is suspected in individuals with the following:

• Exercise-induced muscle cramps and pain

• Episodes of myoglobinuria

• Supportive laboratory findings (i.e., an increased resting serum creatine kinase [CK] concentration and no change in plasma lactate concentration on the forearm non-ischemic or ischemic test)

The diagnosis is confirmed either by assay of myophosphorylase enzyme activity or by molecular genetic testing.

Testing

Serum creatine kinase (CK) activity. A wide range of persistently elevated activities is seen, with values usually approximately 1,000 IU/L (normal reference values: <170 IU/L).

Lactate forearm tests

• The non-ischemic lactate forearm test, the preferred lactate forearm test, relies on sampling plasma lactate concentration and plasma ammonia concentration 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 concentration and plasma ammonia concentration always occur within the first two minutes after exercise [Kazemi-Esfarjani et al 2002].
  
  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 concentration of lactate. (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.
  
  In controls, plasma lactate concentrations increase five to six times above basal values.
  
  In individuals with GSDV

  • The plasma lactate concentration does not increase (the so-called "flat lactate curve").

  • Post-exercise lactate-to-ammonia peak ratios are clearly decreased.

• The ischemic lactate forearm test was used until recently to assess the response of plasma lactate concentration to exercise in individuals with GSDV. Drawbacks to the lactate forearm ischemic test include:

  • False positive results in weak or unmotivated persons

  • Lack of specificity for GSDV (i.e., the test is positive with any block in glycogenolysis or glycolysis)

  • Pain and risk of local muscle damage resulting in myoglobinuria or compartment syndrome

Cycle test. This physiologic test in which only heart rate needs to be monitored takes advantage of the pathognomonic heart rate response of the second wind phenomenon manifest by all individuals with GSDV. A controlled case study [Vissing & Haller 2003a] indicates that cycling at a moderate, constant workload provides a specific, sensitive, and simple diagnostic test for GSDV.

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. The residual activity of myophosphorylase in GSDV is virtually undetectable.

For laboratories offering biochemical testing, see .

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. PYGM, encoding myophosphorylase (glycogen phosphorylase, muscle form), is the only gene associated with GSDV.

Clinical testing

• Targeted mutation analysis

  • p.Arg50X, a nonsense mutation at codon 50 in exon 1, is the most common mutation 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]. p.Arg50X has never been found in individuals of Japanese descent.

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

• Sequence analysis. Sequencing of the entire coding region of the PYGM gene is clinically available [Kubisch et al 1998].

Ethnic background must be taken into account when molecular genetic testing is performed because of the presence of relatively common mutations in specific populations (Table 1).

Table 1. PYGM Mutations Other than p.Arg50X and p.Gly205Ser with Relatively High Frequency in Specific Populations

Population	Mutation	Frequency
Japanese 1	p.Phe710del	64%
Spanish 2	p.Trp798Arg	17%
Central European 3	p.Tyr85X	25%

1. Tsujino et al [1994]

2. Fernández et al [2000], Rubio et al [2000], Martín et al [2001], Rubio et al [2007a]

3. Deschauer et al [2003], Martín et al [2004]

Table 2 summarizes molecular genetic testing for this disorder.

Table 2. Molecular Genetic Testing Used in Glycogen Storage Disease Type V

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PYGM	Targeted mutation analysis 2	p.Arg50X	32%-85%	Clinical
		p.Gly205Ser	9%-10%
	Sequence analysis	Sequence variants	97%-100%

1. 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]

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

• Clinical description of the type of exercise that precipitates the symptoms and a lactate forearm non-ischemic test

• If clinical findings and a lactate forearm test suggest a defect in muscle glycolysis or in glycogen metabolism, molecular genetic testing is recommended:

  • For the more common PYGM mutations (p.Arg50X and p.Gly205Ser);

  • If no mutation or only one mutation is identified, sequence analysis of the entire coding region can be considered;

  • In some specific populations (e.g., Spaniards) a molecular diagnostic flowchart has been proposed: sequential testing for the three common mutations in this population followed by sequence analysis of several PYGM hot-spot exons (i.e., 1, 14, 17, and 18) [Martín et al 2001, Rubio et al 2007a];

• If molecular genetic testing is not available or does not show homozygosity or compound heterozygosity for the common PYGM alleles, myophosphorylase enzyme activity should be analyzed histochemically and/or measured biochemically in muscle homogenates.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

Natural History

Glycogen storage disease type V is a metabolic myopathy with onset typically in the second to third 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-third of affected individuals is more likely to involve proximal muscles and is more common in individuals over age 50 years. Most individuals learn to adjust their daily activities and can lead 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., weight lifting) and sustained aerobic exercise (e.g., stair-climbing and 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 glucose and free fatty acids produced from extramuscular sources 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 weight lifting 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; approximately 50% of these individuals develop acute renal failure. Kidney failure is almost always reversible, but emergency treatment is required.

Other presentations of GSDV:

• Acute renal failure in the absence of exertion [Walker et al 2003, Sidhu & Thompson 2005]

• Hyper-CK-emia (asymptomatic elevations of serum creatine kinase) up to 17,000 IU/L in the infantile myopathy [Ito et al 2003]. Hyper-CK-emia has been reported in adolescents [Gospe et al 1998, Bruno et al 2000].

• Clumsiness, lethargy, and slow movement observed in eight pre-adolescents [Roubertie et al 1998]

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 are usually anaerobic. 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].

One study showed that an angiotensin converter enzyme (ACE) insertion/deletion (I/D) polymorphism, involving the insertion (allele I) or deletion (allele D) situated approximately 250 bp into intron 16 of the ACE gene, 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 McArdle syndrome that assessed the possible effect of several genotype modulators (ACE-I/D, AMPD1: p.Gln12X; PPARGC1A: p.Gly482Ser; ACTN3: p.Arg577X) 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 approximately one in 100,000 [Haller 2000].

Evaluations Following Initial Diagnosis

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

• Physical examination with emphasis on muscle strength/weakness

• Serum CK concentration

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 were observed, indicating that moderate aerobic exercise improves exercise capacity in individuals with McArdle disease [Haller et al 2006].

Nine individuals who underwent an eight-month supervised aerobic exercise training program including five weekly sessions of walking and/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 McArdle disease may exercise safely and may respond favorably to training [Maté-Muñoz et al 2007].

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]. The indication for symptomatic therapy with creatine monohydrate needs to be strengthened.

Ingestion of sucrose before exercise. In a single-blind, randomized, placebo-controlled crossover study in 12 individuals with GSDV, ingestion of sucrose markedly improved exercise tolerance [Vissing & Haller 2003b]. The treatment takes effect during the time when muscle injury commonly develops in GSDV. 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].

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.

• Avoid a totally sedentary life, which induces deconditioning.

• Engage in regular, moderate aerobic exercise, which improves circulatory capacity and increases delivery of blood-borne fuels, a sort of permanent "second wind" (i.e., a decrease in heart rate and perceived exertion during exercise) effect [Ollivier et al 2005].

Ramipril, an ACE inhibitor, used in a randomized, placebo-controlled, double-blind pilot trial in eight persons with McArdle disease, decreased disability and improved exercise physiology only in those individuals with the ACE genotype D/D [Martinuzzi et al 2008].

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 and may cause significant weight gain.

• 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.

Surveillance

Appropriate surveillance includes:

• Annual routine physical examination

• Annual review of diet

Agents/Circumstances to Avoid

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 seem 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 et al 2005].

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 mutations (p.Arg50X, 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 mutations 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 PYGM mutation carriers.

Testing 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 mutations are known, molecular genetic testing can be used; when the family-specific mutations 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.

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 one individual, but this requires confirmation [Phoenix et al 1998].

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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are generally asymptomatic. However, manifesting carriers for some mutations have been described.

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 his/her being a carrier is 2/3.

• Heterozygotes (carriers) are generally asymptomatic. In one study of eight individuals with GSDV, seven heterozygotes, and 11 individuals who are neither affected nor heterozygotes, the heterozygotes had values of exercise capacity indicators (maximal oxidative capacity and peak lactate response) identical to control subjects, 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 disease-causing mutation in the PYGM gene.

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 mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

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 ATP 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.

Pathologic allelic variants. p.Arg50X is a so-called "common" mutation in exon 1 of PYGM that results in a premature stop codon. This mutation was identified in approximately 32%-71% of all mutant alleles [Andreu et al 1998, Martín et al 2001, Bruno et al 2006, Aquaron et al 2007, Deschauer et al 2007, Rubio et al 2007a].

p.Gly205Ser is the second most frequent mutation in various European and US populations, representing approximately 9% of mutant alleles.

In an analysis of 95 individuals of Spanish origin, p.Trp798Arg accounted for 12% of mutant alleles.

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. Mutations 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]. It should be noted that 35% of all mutations in PYGM result in PTC. One study in 28 individuals harboring 17 different mutations with PTCs showed that the NMD mechanism occurred in 92% and that the common mutation p.Arg50X elicited decay in all genotypes tested [Nogales-Gadea et al 2008].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Reading

Acknowledgments

Supported by grants from the Fondo de Investigación Sanitaria (FIS PI040487, FIS PI040362, FIS PI0690088 and from Centro de Investigación Biomedica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain.

Revision History

• 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