Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: PYGM
Condition: Glycogen Storage Disease V
GENEDISEASE PAIRS: PYGM232600
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of Glycogen Storage Disease Type V (GSDV), also known as McArdle disease, has been estimated at 1:100,000-170,000. Recent data based on exome sequencing indicates that the prevalence may be closer to 1:50,000.
1 2 3
Clinical Features
(Signs / symptoms)
Symptoms of GSDV are caused by the inability to produce the enzyme muscle glycogen phosphorylase, which is critical for glycolysis. The usual presentation of GSDV is exercise intolerance in the first few minutes of exercise which is relieved by rest. Symptoms are usually precipitated by isometric or sustained vigorous aerobic exercise. Manifestations may include stiffness of muscles, myalgia, fatigue, tachycardia, and severe muscle pain. If exercise continues at the same intensity, muscle spasms may occur which can lead to muscle damage. Fixed muscle weakness, generally of proximal muscles, occurs in 25% of affected individuals and is more likely to occur in individuals over age 40. Other, less common, presentations of GSDV include: severe para-spinal wasting and weakness, severe obstructive hypertrophic cardiomyopathy, acute renal failure in the absence of exertion, hyper-CK-emia (elevations of serum creatine kinase (CK) activity) in infants and adolescents, and clumsiness in children.
 
Most individuals learn to improve exercise tolerance through exploiting the “second wind” phenomenon where relief of myalgia and rapid fatigue occur after a few minutes of rest due to a metabolic shift to fatty acid oxidation. The ability to develop a metabolic second wind is increased in those who keep physical fit through aerobic exercise (e.g., walking). However, those who undergo sustained or strenuous exercise (e.g., lifting heavy weights or sprinting) carry a high risk of muscle damage.
2 4 3
Natural History
(Important subgroups & survival / recovery)
Age of onset is frequently in the few decades of life but can vary, with some individuals manifesting progressive weakness starting in the sixth or seventh decade of life. However, many individuals remember painful symptoms from early childhood. The condition is relatively stable throughout life; however, a worsening of symptoms may occur in middle age accompanied by some muscle wasting. 50% have recurrent episodes of myoglobinuria following intense exercise that could eventually result in acute renal failure, although reported cases are rare. Renal failure is almost always reversible, but emergency treatment is required. Most individuals are able to have relatively normal lives through adjusting daily activities.
2 4 3
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with GSDV the following evaluations are recommended:
 
- Physical examination with emphasis on muscle strength/weakness
 
- Basal serum CK activity (Tier 4)
2
In some individuals, improvement in exercise and circulatory capacity has been reported following aerobic training, probably caused by the increased circulatory capacity, which facilitates delivery of blood-borne fuels. Therefore, it has been recommended that individuals engage in regular, moderate aerobic activity. (Tier 3)
2
In some individuals, improvement in exercise and circulatory capacity has been reported following aerobic training, probably caused by the increased circulatory capacity, which facilitates delivery of blood-borne fuels. Therefore, it has been recommended that individuals engage in regular, moderate aerobic activity. (Tier 1)
3
Some observational studies have examined the effect of aerobic exercise.
 
- 8 unrelated patients with GSDV underwent 14 weeks of exercise training on a stationary bike. Individuals showed increases in work capacity (50% increase in the first 6 minutes, 30% increase after “second wind”), oxygen uptake (14%), cardiac output (15%), and mitochondrial enzyme levels (citrate synthase: 80%, beta hydroxyacyl coenzyme A dehydrogenase: 62%). Patients did not experience pain or cramping. A “second wind” was present in patients before and after training.
 
- 9 individuals with GSDV underwent an eight-month supervised aerobic exercise program of walking or cycling. Individuals showed increases in peak power output (25%), VO2peak (44%), and ventilary threshold (27%). CK levels were lower at the end of the training period, suggesting that training did not induce muscle damage. No adverse events were reported from training. (Tier 3)
2 3
A systematic review of pharmacological and nutritional therapies for GSDV identified 13 studies including a total of 85 patients, but there are no related recommendations for use of these therapies. Literature was limited by the small number of patients included in these studies (range: 1-19 patients) and a lack of replication of interventions. Overall, no benefit was found with: D-ribose, glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatinine. Low quality of evidence suggested some benefit from the use of creatinine, oral sucrose, Ramipril, and a carbohydrate-rich diet in some measures; however, the significance of these clinical benefits is unclear. (Tier 1)
4
Surveillance
Appropriate surveillance includes annual routine physical examination and review of diet. (Tier 4)
2
Family Management
Early diagnosis of GSDV in relatives at risk may improve long-term outcome by heightened awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness. (Tier 4)
2
Circumstances to Avoid
Exercises that involve heavy static contractions or induce severe myalgia should be avoided. These may include:
 
- Static muscle contractions (e.g., handgrip exercises)
 
- Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting)
 
- 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. (Tier 3)
2
Individuals should avoid a totally sedentary life, which induces deconditioning. (Tier 3)
2
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 and GSDV does not appear to cause severe perioperative problem in routine anesthetics. Measures for preventing muscle ischemia and rhabdomyolysis should be taken in individuals with GSDV. One report of a 2 year old boy not previously recognized as having GSDV reported hyperthermia, pulmonary edema, and rhabdomyolysis following surgery for tetralogy of Fallot (patient had no prior surgeries). The patient died 10 days following surgery. While the clinicians believe that an adverse reaction to protamine was the likely cause of the adverse events, it is suggested that the presence of GSDV may have rendered the patient more susceptible to these adverse reactions. (Tier 3)
5 2
Clinicians should be cautious when recommending statins to individuals who have GSDV or are carriers for a PYGM pathogenic mutation due to a potentially increased risk of statin-induced myopathy. A study of 136 individuals with statin-induced myopathy identified 20-fold more PYGM heterozygotes than expected for the general population and 12-fold greater than the control group in the study (p=0.004). (Tier 3)
2
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
 
Prevalence of Genetic Mutations
Recent data based on exome sequencing indicates that the prevalence may be closer to 1:50,000 indicating that the disease may be underdiagnosed or the penetrance of some variants are overestimated. (Tier 5)
1
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on penetrance was identified for individuals detected based on genetic mutation.
 
Cross-sectional data from a registry of all 239 patients diagnosed with GSDV in the Spanish National Health system found 99.5% of patients reported a history of acute crises of exercise intolerance. 50% of cases reported recurrent myoglobinuria. 86% of patients reported experiencing the “second wind phenomenon”. (Tier 5)
6
No information on relative risk was identified.
 
 
Expressivity
There is considerable heterogeneity in the severity of symptoms, even in individuals who possess the same genetic mutation. This may be due the presence of modifying genes, differences in lifestyle, and aerobic capacity. (Tier 3)
4 3
4. What is the Nature of the Intervention?
Nature of Intervention
Potential interventions include aerobic exercise training, avoidance of static contractions, and caution with certain anesthetics and statins.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Many individuals remember painful symptoms from early childhood, but the disorder is rarely diagnosed before adulthood.
2
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Rhabdomyolysis, muscle damage, and fixed contractions / Training for an appropriate exercise regimen
1
3N
2C
3
9NC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. De Castro M, Johnston J, Biesecker L. Determining the prevalence of mcardle disease from gene frequency by analysis of next-generation sequencing data. Genet Med. (2015) 17(12):1002-6.
2. MA Mart?n, A Luc?a, J Arenas, AL Andreu. Glycogen storage disease type v. 2006 Apr 19 [Updated 2014 Jun 26]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1344
3. Quinlivan R, Vissing J, Hilton-Jones D, Buckley J. Physical training for mcardle disease. Cochrane Database Syst Rev. (2011)
4. Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for mcardle disease (glycogen storage disease type v). Cochrane Database Syst Rev. (2014)
5. Benca J, Hogan K. Malignant hyperthermia, coexisting disorders, and enzymopathies: risks and management options. Anesth Analg. (2009) 109(4):1049-53.
6. Lucia A, Ruiz JR, Santalla A, Nogales-Gadea G, Rubio JC, Garcia-Consuegra I, Cabello A, Perez M, Teijeira S, Vieitez I, Navarro C, Arenas J, Martin MA, Andreu AL. Genotypic and phenotypic features of mcardle disease: insights from the spanish national registry. J Neurol Neurosurg Psychiatry. (2012) 83(3):322-8.
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