Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.2.6
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: GAA
• Condition: Glycogen Storage Disease 2
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• GAA ⇔ 0009290 (glycogen storage disease ii): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric, given the variability in presentation in the adult setting, as well as the uncertainty regarding effectiveness of early onset treatment initiation.

Final Consensus Scores

Gene Condition Pairs: GAA ⇔ 0009290 (OMIM:232300)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality due to acid alpha-glucosidase deficiency / Evaluation by specialists to guide management including enzyme replacement therapy	2	3C	2A	2	9CA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The incidence of glycogen storage disease type II (GSD2) also known as Pompe disease (PD) varies, depending on ethnicity and geographic region. The combined incidence of all forms is commonly reported to be 1/40,000. The incidence of infantile-onset PD (IOPD) ranges from 1/100,000 to 1/138,000. The incidence of late-onset PD (LOPD) ranges from 1/57,000 to 1/60,000. Data from newborn screening indicate an overall birth prevalence of 1/25,000. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]

Clinical Features

PD is a lysosomal storage disorder that results in the accumulation of glycogen in multiple tissues (most prominently skeletal, cardiac, and smooth muscle). PD is progressive and can be classified into two general subtypes based on age of onset, organ involvement, severity, and rate of progression; these classifications tend to be useful in determining prognosis and treatment options. In IOPD, 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 LOPD.
IOPD (defined as individuals with onset before age 12 months with cardiomyopathy) typically presents with hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, cardiomegaly, and hypertrophic cardiomyopathy. Additional presenting symptoms can include frequent infections, hepatomegaly, macroglossia, and loss of early milestones. Children with a small amount of natural GAA enzyme are termed cross-reactive immunological material (CRIM)-positive. Children who are unable to produce native enzyme are termed CRIM-negative.
LOPD (defined as individuals with onset before age 12 months without cardiomyopathy and all individuals with onset of myopathy after age 12 months) is characterized by progressive proximal muscle weakness, particularly in the trunk and lower limbs, and respiratory insufficiency without clinically significant 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, hepatomegaly, macroglossia, difficulty chewing and swallowing, weak cough, increased respiratory infections, decreased deep tendon reflexes, Gower sign, joint contractures, cardiac hypertrophy, and developmental delay in motor skills. [1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13]

Natural History

IOPD may be apparent in utero, but typically presents before age 12 months and includes cardiomyopathy. Without treatment by enzyme replacement therapy (ERT), it rapidly progresses and is uniformly lethal, commonly by age 2 years due to progressive cardiorespiratory failure. In a retrospective review of 168 patients with IOPD, the median age at symptom onset was 2 months (range 0-12 months), the median age at first ventilator support was 5.9 months (range 0.1-31.1 months), and the median age at death was 8.7 months (range 0.1-31.1 months).
LOPD can present at any age, as late at the 7th decade of life. Symptom onset with LOPD occurs on average around age 27-35 years of age, with symptoms often preceding definitive diagnosis by 7 to 10 years. 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 IOPD 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. Reduction in forced vital capacity (FVC) is common in LOPD. 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). [1, 2, 4, 6, 7, 10, 11, 12, 13]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/Pompe.pdf [14]

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
•Consideration of non-invasive respiratory support in all children
•Screen for osteopenia/osteoporosis with dual-energy x-ray absorptiometry (DEXA)
•Assessment of musculoskeletal impairment and muscle strength (baseline 6-minute walk test)
•Swallowing assessment and evaluation for GE reflux to guide management of feeding (oral/gavage)
•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
•Audiology assessment. (Tier 2) [2, 3, 6, 8, 10, 12]

PD is best managed by a multidisciplinary team led by a physician with experience managing this disorder. Team members should include a metabolic disease specialist/biochemical geneticist in addition to the specialists dictated by the disease manifestations, which might include a cardiologist, pulmonologist, neurologist, neuromuscular specialist, intensivist, orthopedist, respiratory therapist, physical therapist, occupational therapist, otolaryngologist speech therapist, audiologist, genetic counselor, and a metabolic dietitian. (Tier 2) [4, 8, 11, 12]

Prior to commencement of ERT for IOPD, it is important to determine CRIM status and whether a clinical trial of immune tolerance induction should be part of the treatment plan. CRIM status is an important predictor of response to ERT. In a retrospective study of CRIM+ and CRIM- patients with IOPD receiving alglucosidase alfa, after 1 year of treatment, 4.8% of CRIM+ and 54.5% of CRIM- patients were deceased. (Tier 2) [10, 12]

ERT with alglucosidase alfa was the first specific treatment available for PD in adults and children. ERT should be initiated promptly in patients with IOPD. Respiratory assessment is recommended in conjunction with starting ERT for patients with IOPD. However, ERT is not recommended for patients with LOPD with no symptoms or objective signs (proximal muscle weakness or reduced FVC). Trial of ERT is recommended at the earliest onset of symptoms or objective signs for LOPD. Definition of outcome parameters that ERT is intended to target is recommended prior to starting therapy. The individual response to ERT may vary due to development of rhGAA specific antibodies, age of presentation, rate of progression of disease, muscle fiber type, defective autophagy, and underlying genotype. The probability of developing high titers of antibodies is primarily affected by CRIM status. (Tier 2) [2, 3, 4, 6, 8, 10, 12, 13]

A systematic review evaluating alglucosidase alfa in IOPD found one small, randomized trial (n=18) comparing different doses of ERT. Results revealed that long term alglucosidase alfa treatment (both dosing groups – median duration of treatment being 2.3 years) markedly improved cardiomyopathy and extended overall survival and ventilation-free survival (low-quality evidence). Results demonstrated that, compared to a historical control group of 61 children, ERT reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92% and reduced the risk of death or any type of ventilation by 88% in 52 weeks. (Tier 1) [5]

Three systematic reviews assessing effectiveness of ERT in LOPD identified one RCT (n=90, ages 10 to 70 years). Patients were randomly assigned to receive alglucosidase alfa or placebo. Primary findings included:
•ERT was associated with improved walking distance and stabilization of pulmonary function over an 18-month period.
•At week 78, statistically significant findings were reported with improvements in the 6-minute walk test (6-MWT) (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.
Three SR meta-analyses performed to assess the effectiveness of ERT in LOPD demonstrated the following:
•One meta-analysis modeled mortality (6 studies) and found that patients treated with ERT had nearly a five-fold lower mortality rate than untreated patients.
•All meta-analyses found significant improved walking distance on 6-MWT compared to distance at baseline.
•One meta-analysis found initial FVC improvement with ERT followed by slow regression to baseline and slight decline thereafter. Two meta-analyses suggested that there was little effect of ERT on FVC.
•One meta-analysis showed that the proportion of patients on a ventilator remained relatively constant over time for those on ERT.
•One meta-analysis evaluated muscle strength and showed a tendency towards better muscle strength after ERT, but the difference was not statistically significant. (Tier 1) [15, 16, 17]

One systematic review assessed the effectiveness of ERT on LOPD in patients (specifically limited to symptom onset of age 2-18 years) and included 1 case series and 16 case reports. Low level evidence found that respiratory function may improve or be maintained in early months of therapy. Improved muscle function in the first 6-12 months was suggested, but results may be confounded by natural development. Patients with less severe baseline status and treated at a younger age showed more response than patients with more severe baseline status, treated as adults. (Tier 1) [18]

Though there are no established guidelines for muscle strengthening or therapeutic exercise for individuals with LOPD, 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. Evaluation by cardiologist and pulmonologist prior to physical therapy and aerobic exercise is recommended. 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 PD, 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) [2, 6, 8, 10]

Little evidence is available for the effectiveness of muscle strengthening and therapeutic exercise in adult patients with PD. One study reported the results of a 12-week exercise intervention in adults (median age 46 years) mildly affected with PD to improve aerobic fitness, muscle strength, and core stability. The study included 23 patients who had received ERT for at least one year and were not dependent on a ventilator and/or walking device. Patients achieved significantly 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 the amount of physical activity. (Tier 5) [19, 20]

No established guidelines exist for management of secondary musculoskeletal impairments, including contracture and deformity, in LOPD, 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) [2, 6, 8]

Little evidence is available for the effectiveness of measures that manage secondary musculoskeletal impairments in adult patients with PD. A systematic review on the effectiveness of stretching programs in children with neuromuscular disabilities identified five studies with conflicting findings. Two of five identified limited/weak evidence to support the effectiveness of passive stretching for improving range of motion and spasticity. (Tier 1) [21]

On the basis of a study showing a high prevalence of osteoporosis in patients with PD, all patients should undergo fall risk assessment and walking assistance equipment to reduce falls. (Tier 2) [6, 8]

Nutrition needs to be adequate in terms of intake of calcium, Vitamin D, and protein intake. (Tier 2) [2, 4, 6, 8, 10]

Provide oral stimulation and non-nutritive sucking for infants who are nonoral feeders. (Tier 2) [2]

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) [2, 4, 11]

Patients and other household contacts should stay up to date on vaccinations (particularly pneumococcus – the 23 valent vaccine after age 2 and for older patients who have not previously received it, and influenza during influenza season). Furthermore, palivizumab (Synagis) should be used during respiratory syncytial virus season, in infants and young children as this can be life-threatening. (Tier 2) [2, 4, 6, 11]

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) [2, 4, 6, 8, 11]

General anesthesia must be performed by someone familiar with anesthesia in patients with PD due to the risk of fatality. Surgical procedures must be grouped for a single anesthetic where possible. Monitoring respiratory function is recommended. Intubation during surgery should be avoided, if possible. (Tier 2) [2, 4, 8, 11]

Continuation of ERT in pregnancy and lactation can be considered (Tier 2) [13]

It is recommended that pregnant individuals with PD have a cesarean delivery under local instead of general anesthesia. (Tier 2) [8]

Pregnant individuals should undergo close respiratory and cardiac surveillance in consultation with a maternal fetal medicine specialist. A growing fetus may pose additional complications for individuals with myopathy and respiratory insufficiency. (Tier 4) [7]

Surveillance

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
•Monitor growth parameters carefully
•Assess pulmonary function and gas exchange every 6-12 months for patients with LOPD
•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
•Regular assessment of swallowing for all infants
•Motor and functional assessments should be repeated at 3–6-month intervals for children under age 5 years, and should be part of routine management in older patients with LOPD
•Hearing tests should be repeated annually, as clinically indicated, and following medical/surgical intervention. (Tier 2) [2, 3, 4, 6, 8, 10, 12]

Guidelines on monitoring antibody status in patients with LOPD receiving ERT vary. One guideline recommends that IgG antibody levels monitored every 3 months for up to 2 years, and then annually. Another recommends baseline antibody status prior to initiation of ERT and again if patients show a poor response to ERT. (Tier 2) [3, 6, 8, 10]

Patients should be annually assessed for musculoskeletal impairments, functional deficits, levels of disability, and society participation (Tier 2) [2]

Presymptomatic patients (those without any symptoms or objective signs of LOPD) should be examined every 6 months in the first year and then every 6 to 12 months (interval varies per guideline) to identify disease progression early. Monitoring should consistent of at least a minimal set of clinical assessments, including manual muscle testing using the Medical Research Council grading scale, 6-MWT, timed tests (10-m walk, climb four steps, stand up from supine and stand from chair), FVC in a sitting and supine position and ventilation use. (Tier 2) [6, 8, 10, 12, 13]

All patients with PD 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 IOPD and LOPD. (Tier 2) [2, 3, 6, 8]

Circumstances to Avoid

Patients with PD 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 PD, 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) [2, 6, 8]

Avoid drastic changes in fluid status, either through dehydration or fluid overload. (Tier 2) [2, 10]

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) [2, 4, 6]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 2, 3, 4, 6, 7, 8, 9, 10, 11]

Prevalence of Genetic Variants

On sequence analysis a pathogenic variant in GAA can be detected in 83-93% of patients with confirmed or reduced enzyme activity associated with PD. Deletion of exon 18 comprises 5-7% of alleles. (Tier 3) [7]

The chance of being a heterozygous carrier of a pathogenic variant in the GAA gene that causes GSD2 is estimated to be approximately 1/100. (Tier 3) [1]

The genetic prevalence of PD was estimated based on the proportion of individuals who have a causative genotype in a general population database (gnomAD). Total carrier frequency and predicted genetic prevalence were 1 in 77 and approximately 1:23,000, respectively. The predicted genetic prevalence varied widely by population ranging from approximately 1:12,000 to 1:1,000,000. (Tier 5) [22]

Penetrance

Penetrance for individuals detected based on genotype was not identified.
Information for patients detected clinically is listed below:
Common findings at presentation of IOPD:
•Hypotonia/muscle weakness= 52%-96%
•Cardiomegaly=92%-100%
•Hepatomegaly=29%-90%
•Left ventricular hypertrophy=83%-100%
•Cardiomyopathy=88%
•Respiratory distress=41%-78%
•Macroglossia= 29-62%
•Feeding difficulties = 57%
•Failure to thrive = 53%
•Absent deep tendon reflexes=33%-35%. (Tier 3) [7]

Findings in LOPD:
•Progressive proximal muscle weakness=93-95%
•General fatigue and poor endurance=50-76%
•Muscle pain and soreness=46%
•Mild reduction in FVC=60%
•Moderate reduction in FVC=30-40%
•Supraventricular and ventricular tachyarrhythmias=29%
•Dysphagia= 25% (Tier 3) [2, 3, 6, 7, 10]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

All patients with PD share the same general disease course. Severity varies by age of onset, organ involvement including degree and severity of muscular involvement (skeletal, respiratory, cardiac), and rate of progression. IOPD includes the most severe end of the disease spectrum often referred to as classic IOPD. Patients with non-classic IOPD have slower progression and less severe cardiomyopathy but presenting in the first year of life. (Tier 4) [2]

The clinical phenotype of LOPD varies with respect to the age of onset, organ involvement, degree of myopathy, and rate of progression. (Tier 3) [4, 6]

GAA pathogenic variants that introduce mRNA instability, such as nonsense variants, are more commonly seen in IOPD as they result in nearly complete absence of GAA enzyme activity. GAA pathogenic missense and splicing variants may result in either complete or partial absence of GAA enzyme activity and therefore may be seen in both IOPD and LOPD. (Tier 3) [7]

A pathogenic variant analysis study of 243 patients with IOPD showed that 25.1% were identified as being CRIM-. Most patients were either homozygous or compound heterozygotes for nonsense and/or frame-shift pathogenic variants, resulting in premature stop codons or multi-exon deletions. In contrast, most of the CRIM+ patients had 1 or 2 missense or in-frame deletion pathogenic variants that predicted the synthesis of some GAA protein. (Tier 3) [10]

4. What is the Nature of the Intervention?

Nature of Intervention

In general, the use of alglucosidase alfa is safe. However, life-threatening anaphylactic reactions, severe allergic reactions, and immune-mediated reactions have been observed in some patients during ERT infusions. Infants at high risk for development of antibodies to the therapeutic enzyme are likely to need immunomodulation early in the treatment course. In a trial evaluating ERT in IOPD, infusion related events were mild or moderate and could be controlled by slowing or interrupting infusions. A systematic review found that adverse events after ERT in patients with LOPD were typically mild. In a randomized trial in LOPD 5% of patients (n=3) experienced an anaphylactic reaction. A systematic review found that although most patients with LOPD on ERT presented with elevated antibody titers, few showed a reduction in response to treatment or higher incidence of adverse events. ERT is administered intravenously every 2 weeks and may take as long as 4-6 hours per infusion. More recent evidence suggests that administration of ERT weekly improves survival in IOPD. A device such as a ‘port-a-cath’ may be implanted to make access easier. Treatment costs are high. An increasing number of patients are receiving their ERT in their own home through home infusion programs. [3, 4, 5, 6, 7, 8, 10, 11, 13, 15, 23]

5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?

Chance to Escape Clinical Detection

PD was added to the Recommended Uniform Screening Panel (RUSP) in 2015 but has not yet been adopted by all state newborn screening programs in the US. The diagnosis of PD often poses a diagnostic dilemma due to the rarity of the condition and the relatively nonspecific nature of the phenotypic features that may only in aggregate lead to suspicion of PD. LOPD can remain clinically silent for years. In patients with LOPD, respiratory failure may be mild and go unnoticed. Other serious complications are those resulting from the presence of intracranial aneurysms, which may be underdiagnosed and cause death. 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) [2, 3, 4, 6, 10, 13, 24]

Date of Search: 11.10.2016 (updated 05.12.2023)

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