Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released

Condition: Glycogen Storage Disease 2
Mode(s) of Inheritance: Autosomal Recessive
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
GAA232300 (glycogen storage disease ii; gsd2)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: GAA (OMIM:232300)
Musculoskeletal morbidity / Comprehensive care by a multidisciplinary team (includes physical therapy/exercise program, early treatment of infections, appropriate surveillance, etc.)
Musculoskeletal morbidity / Enzyme replacement therapy
Impaired pulmonary function / Enzyme replacement therapy
Severe or life-threatening infections / Vaccination and aggressive prevention/treatment of infections

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The combined incidence of all forms of glycogen storage disease type II (GDS2, also known as Pompe disease) varies, depending on ethnicity and geographic region, from 1/14,000 in African Americans to 1/600,000 in Portugal. The combined incidence in the US is 1/40,000. The incidence of late-onset disease has been estimated as 1/57,000 in the Netherlands and 1/60,000 in individuals of European descent.
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Clinical Features
(Signs / symptoms)
GSD2 is a lysosomal storage disorder that results in the accumulation of glycogen in multiple tissues (most prominently skeletal, cardiac, and smooth muscle). GSD2 is progressive and can be classified into two general subtypes based on age of onset, clinical findings, severity, and rate of progression. In infantile-onset GSD2, GAA enzyme activity is completely or nearly completely absent (<1% of normal activity), while some residual activity (~2-40% of normal activity) is present in the late-onset form.
The classic infantile-onset form is more severe and is characterized by cardiomegaly with respiratory distress, muscular hypotonia, and feeding difficulties. The non-classic variant of the infantile-onset form is typically less severe and presents with motor delays and/or muscle weakness.
The late-onset form is characterized by progressive proximal muscle weakness, particularly in the trunk and lower limbs, and respiratory insufficiency without clinically apparent cardiac involvement. However, some adults with late-onset disease have been found to have arteriopathy. Ectasia of the basilar and internal carotid arteries has been noted, and may be associated with clinical signs, such as transient ischemic attacks and 3rd nerve paralysis. In addition, dilation of the ascending thoracic aorta has been noted. Intracranial aneurysms may be present in some patients leading to subarachnoid hemorrhage. Other features may include exercise intolerance, exertional dyspnea, orthopnea, sleep apnea, hyperlordosis and/or scoliosis (childhood and juvenile onset), hepatomegaly (childhood and juvenile onset), macroglossia (childhood onset), difficulty chewing and swallowing, weak cough, increased respiratory infections, decreased deep tendon reflexes, Gower sign, joint contractures, cardiac hypertrophy (childhood onset), and developmental delay in motor skills (childhood onset).
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Natural History
(Important subgroups & survival / recovery)
The classic infantile-onset form typically presents in the first 2 months of life. Without treatment by enzyme replacement therapy (ERT), it rapidly progresses and commonly results in death in the first year of life due to progressive left ventricular outflow obstruction. The non-classic variant of infantile-onset usually presents within the first year of life, has a slower progression, and typically results in death from ventilatory failure in early childhood.
The late-onset form can present at variable ages, from early childhood (after age one) into adulthood (as late at the 7th decade of life). The median age at diagnosis has been estimated as 38 years, though some affected adults often describe symptoms beginning in childhood. Progression of the disease is slower than the infantile-onset form and is often predicted by the age of onset and residual enzyme activity. The presenting symptom in 93% of patients is weakness of proximal extremities (generally preceded by myalgia and muscle cramps). Progression of skeletal muscle involvement eventually involves the diaphragm and accessory respiratory muscles. Roughly 60% of patients will have mild reduction in vital capacity and 30-40% will have moderate reduction. Affected individuals have a mean reduction in vital capacity of approximately 1.5% per year following diagnosis and the likelihood of needing either non-invasive or invasive ventilation increases by an average of 8% each year following diagnosis. Affected individuals often become wheelchair dependent because of lower limb weakness, with the probability of wheelchair use increasing, on average, 13% each year after diagnosis without treatment. Respiratory failure causes the major morbidity and mortality of this form of the disease. Male gender, severity of skeletal muscle weakness, and duration of disease are all risk factors for severe respiratory insufficiency. The median age at death in untreated adults has been estimated as 55 years (range 23-77 years).
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening:
The following evaluations should be performed at diagnosis:
• Echocardiogram
• 24-hour ambulatory ECG
• Assessment of pulmonary function and gas exchange
• Chest X-ray
• Polysomnography and detailed sleep history for sleep respiratory function
• Measure cardiorespiratory status and response to position and activity with pulse oximetry
• Screen for osteopenia/osteoporosis with dual-energy x-ray absorptiometry (DEXA)
• Assessment of musculoskeletal impairment and muscle strength
• Measures of function, disability, pain, and quality of life
• Perform neurology assessments including nerve conduction studies, needle electromyography (EMG) to determine presence of denervation as evidence of anterior horn cell involvement, and hearing tests. (Tier 2)
Management of patients should consist of a team including a physician with experience in managing GSD2 and specialists in the field of neurology, pulmonary, cardiology, orthopedics, metabolic dietician, general medicine, occupational therapists, and disease geneticists. (Tier 2)
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Though there are no established guidelines for muscle strengthening or therapeutic exercise for individuals with late-onset GSD2, a physical or occupational therapist should develop an exercise program with a focus on submaximal aerobic exercise and/or muscle strengthening, following guidelines for other degenerative muscle diseases. Functional activities should also be incorporated and strategies to optimize biomechanical advantage and use of energy conservation techniques. Although evidence is minimal (few studies with small sample sizes) in patients with GSD2, some studies suggest that submaximal exercise may increase muscle strength and function through improved clearance of accumulated glycogen in muscle. However, there is insufficient evidence that resistance training improves strength. (Tier 2)
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Little evidence is available for the effectiveness of muscle strengthening and therapeutic exercise in adult patients with GSD2. One study reported the results of a 12-week exercise intervention in adults mildly affected with GSD2 to improve aerobic fitness, muscle strength, and core stability. The study included 25 patients who had received ERT for at least one year and were not dependent on a ventilator and/or walking device. 23 patients completed the program and achieved decreased levels of fatigue and pain and improvements in endurance, muscle strength of the hip flexors and shoulder abductors, and core stability. However, no significant differences were observed in self-reported motor function or patient activity. (Tier 5)
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A systematic review of physiotherapy among patients with non-GSD2 neuromuscular disorders (e.g., muscular dystrophy) found that aerobic exercise (with or without strengthening exercises) had a positive effect on body function and activities and participation. However, inconsistent and insufficient evidence was found for the use of strengthening exercises alone. (Tier 5)
No established guidelines exist for management of secondary musculoskeletal impairments, including contracture and deformity, in late-onset GSD2, though general principles established for the management of other neuromuscular disorders can be applied. These principles should be applied early and include limiting contracture and deformity by gentle daily stretching, correction of improper positioning, judicious and timely use of splints and orthotic interventions, and provision of adequate support in all positions, including sitting and supported standing. Prevention of contracture and deformity is critical to preserve function and limit other secondary complications, such as skin breakdown and chronic musculoskeletal pain. (Tier 2)
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Little evidence is available for the effectiveness of measures that manage secondary musculoskeletal impairments in adult patients with GSD2. However, gentle stretching, splinting, and bracing are effective in patients with Duchenne muscular dystrophy in slowing the development of contractures, maintaining joint extension, and extending walking time. (Tier 5)
On the basis of a recent study showing a high prevalence of osteoporosis in patients with GSD2, all patients should undergo fall risk assessment. (Tier 2)
Nutrition needs to be adequate in terms of intake of calcium, Vitamin D, and protein intake. (Tier 2)
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ERT with alglucosidase is the only specific treatment available for late-onset GSD2 in adults and children. However, it is not recommended for patients with no symptoms or objective signs (proximal muscle weakness or reduced FVC). ERT is recommended at the earliest onset of symptoms or objective signs. No clinical studies have yet been conducted to show whether the treatment of asymptomatic patients can delay the onset of symptoms of the disease. The Late-Onset Treatment Study (LOTS) is a randomized controlled trial for ERT that has been conducted in 90 patients aged 8 years and older. The results of the study indicate that ERT has a positive effect on the disease process or processes that produce impaired ambulation and respiratory insufficiency in late-onset GDS2. At week 78, statistically significant findings were reported with improvements in the 6-minute walk test (this improvement occurred in the first 26 weeks of treatment and maintained for the next 52 weeks) and percent of predicted upright FVC results among those administered ERT compared to those on placebo. An open label extension study indicated that improvements in walking distance and stabilization of pulmonary function noted at week 78 were maintained at week 104. However, it is unclear how these study endpoints translate into functional improvements for patients. Quality-of-life measures collected in the same study found no associated improvements. (Tier 2)
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A systematic review of mostly uncontrolled clinical studies of symptomatic ERT treatment summarized outcomes of 368 patients with late-onset GSD2, including 251 adults (age ≥18). Creatine kinase levels decreased in 70% of patients, stabilized in 11%, and increased in 20%. Motor performances improved in 78% of patients, stabilized in 8%, and declined in 14%. Of patients with impaired ambulatory status 6% had improvements following ERT treatment. Respiratory dysfunction improved in 52% of patients, stabilized in 14% and declined in 35%. Following treatment, 8% of patients reported an improvement in quality of life outcomes. (Tier 1)
Given the increased risk of infections, strict hygiene and handwashing precautions should be implemented and medical attention should be sought for common symptoms such as a cough or fever. (Tier 2)
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Patients and other household contacts should stay up to date on vaccinations (particularly pneumococcus and influenza). (Tier 2)
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Early and aggressive treatment of bacterial and viral infections (particularly pulmonary infections) given the high risk for pneumonia and other infections that may lead to respiratory failure, intubation with ventilator dependence, and even death. Antivirals should be used for the flu. (Tier 2)
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General anesthesia must be performed by someone familiar with anesthesia in patients with GDS2 due to the risk of fatality. Surgical procedures must be grouped for a single anesthetic where possible. Intubation during surgery should be avoided, if possible. (Tier 2)
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Pregnant women should undergo careful respiratory and cardiac surveillance in consultation with a maternal fetal medicine specialist. A growing fetus may pose additional complications for women with myopathy and respiratory insufficiency. (Tier 4)
The following assessments should be performed at regular intervals:
• Chest X-ray
• Echocardiogram
• 24-hour ambulatory ECG to assess for life-threatening arrhythmias
• Monitor for arrhythmias
• Laboratory tests: serum creatinine kinase, transaminases, lactate dehydrogenase, and urinary hex4
• Assess respiratory status at each visit
• Assess pulmonary function and gas exchange annually
• Measurement of maximal clearance of airway secretions
• Spirometry, pulse oximetry, capnography should routinely be performed
• Detailed sleep history and assessment of symptoms associated with sleep-disordered breathing to assess for respiratory dysfunction during sleep
• Other assessments, such as swallowing and neurological exams. (Tier 2)
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Patients should be annually assessed for musculoskeletal impairments, functional deficits, levels of disability, and society participation. (Tier 2)
When a presymptomatic patient is confirmed to have GSD2 through newborn screening, sibling screening, or another screening program, it is recommended that such patients be examined every 6 months and that muscle strength and pulmonary function (including FVC in both upright and supine positions) be monitored at these visits for the onset of symptoms to guide initiation of ERT. (Tier 2)
All patients with GSD2 should be screened, regardless of age and wheelchair use, with DEXA with follow-up considered on a yearly basis. Low bone mineral density (BMD) is a common feature in patients, and a recent study demonstrated that 67% of the patients tested had a BMD z-score of -1 and that the decrease in BMD was present in both the infantile- and late-onset forms of the disease. (Tier 2)
Circumstances to Avoid
Patients with GDS2 should avoid overwork weakness, excessive fatigue, disuse, strenuous exercises, and eccentric contractions. Excessively strenuous resistance exercises have been discouraged in muscle disorders due to the potential for exacerbating muscle degeneration. In GSD2, there is additional theoretical concern that excessive muscle contraction might lead to increased leakage of glycogen from lysosomes or cause lysosomal rupture, thereby hastening muscle damage. (Tier 2)
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Avoid drastic changes in fluid status, either through dehydration or fluid overload. (Tier 2)
Patients should exercise caution when using some medications. Care should be taken with drugs that have a myorelaxant effect and central nervous system depressants. Some over the counter medications to treat cough, colds, and other symptoms often contain sympathomimetic agents which can be detrimental to the heart. The risk benefit ratio of use of medications such as steroids (risk of progressive muscle weakness and osteopenia) and loop diuretics (ototoxicity and calciuria) must be considered prior to administration. (Tier 2)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Variants
The risk of being a heterozygous carrier of a mutation in the gene that causes GSD2 is approximately 1/100. (Tier 4)
(Include any high risk racial or ethnic subgroups)
Penetrance for individuals detected based on genotype was not identified. Information for patients detected clinically is listed below:
Common findings in cases of infantile GSD2:
Hypotonia/muscle weakness= 52%-96%
Left ventricular hypertrophy=83%-100%
Respiratory distress=41%-78%
Absent deep tendon reflexes=33%-35%. (Tier 3)
Findings in late-onset GSD2:
Progressive proximal muscle weakness=93-95%
General fatigue and poor endurance=50-76%
Muscle pain and soreness=46%. (Tier 3)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available for the Adult context.
Intergenerational phenotypic variation has been reported in several families with GSD2.The clinical phenotype of late-onset GSD2 varies. (Tier 3)
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4. What is the Nature of the Intervention?
Nature of Intervention
Preventive stretching regimens are better tolerated and accepted if they are initiated before muscle tendon tightness and contractures develop, a point at which stretching often becomes painful. Aggressive stretching should be approached cautiously because, at least in severely affected children, a tendency for pathologic fracture has been observed.
In general, the use of ERT is safe. However, life-threatening anaphylactic reactions, severe allergic reactions, and immune-mediated reactions have been observed in some patients during ERT infusions. In the LOTS trial 5% of patients experienced an anaphylactic reaction. In an ERT trial, patients in the treatment and placebo groups had similar frequencies of adverse events, serious adverse events, and treatment-related adverse events. Most adverse events were mild to moderate and not considered to be related to the use of ERT. All ERT recipients tested negative for immunoglobulin G (IgG) anti-GAA antibodies at baseline, and all patients seroconverted by week 12. ERT is administered intravenously every 2 weeks; a device such as a ‘port-a-cath’ may be implanted to make access easier.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
The diagnosis of the late-onset form is often difficult because it can clinically resemble a myriad of other neuromuscular disorders. It can take several years to get a correct diagnosis, with one review finding a diagnostic delay ranging from 5 to 30 years. A high level of clinical suspicion is necessary for a timely and accurate diagnosis. (Tier 3)
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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.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. Barba-Romero MA, Barrot E, Bautista-Lorite J, Gutierrez-Rivas E, Illa I, Jimenez LM, Ley-Martos M, Lopez de Munain A, Pardo J, Pascual-Pascual SI, Perez-Lopez J, Solera J, Vilchez-Padilla JJ. Clinical guidelines for late-onset Pompe disease. Rev Neurol. (2012) 54(8):497-507.
2. Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. (2012) 45(3):319-33.
3. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J, Marsden D, Martins AM, Millington DS, Nicolino M, O'Grady G, Patterson MC, Rapoport DM, Slonim A, Spencer CT, Tifft CJ, Watson MS. Pompe disease diagnosis and management guideline. Genet Med. (2006) 8(5):267-88.
4. N Leslie, BT Tinkle. Glycogen Storage Disease Type II (Pompe Disease). 2007 Aug 31 [Updated 2013 May 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
5. Bhengu L, Davidson A, du Toit P, Els C, Gerntholtz T, Govendrageloo K, Henderson B, Mubaiwa L, Varughese S. Diagnosis and management of Pompe disease. S Afr Med J. (2014) 104(4):273-4.
6. Wang RY, Bodamer OA, Watson MS, Wilcox WR. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. (2011) 13(5):457-84.
7. Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol. (2013) 260(4):951-9.
8. Favejee MM, van den Berg LE, Kruijshaar ME, Wens SC, Praet SF, Pim Pijnappel WW, van Doorn PA, Bussmann JB, van der Ploeg AT. Exercise training in adults with Pompe disease: the effects on pain, fatigue, and functioning. Arch Phys Med Rehabil. (2015) 96(5):817-22.
9. van den Berg LE, Favejee MM, Wens SC, Kruijshaar ME, Praet SF, Reuser AJ, Bussmann JB, van Doorn PA, van der Ploeg AT. Safety and efficacy of exercise training in adults with Pompe disease: evalution of endurance, muscle strength and core stability before and after a 12 week training program. Orphanet J Rare Dis. (2015) 10:87.
10. Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, Munneke M, van Engelen BG, Hendricks HT, van der Wilt GJ, Oostendorp RA. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Arch Phys Med Rehabil. (2007) 88(11):1452-64.
11. McDonald CM. Limb contractures in progressive neuromuscular disease and the role of stretching, orthotics, and surgery. Phys Med Rehabil Clin N Am. (1998) 9(1):187-211.
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