BACKGROUND. Pompe disease is a lysosomal storage disorder that leads to the accumulation of glycogen and subsequently to muscle weakness, organ damage, and death. Pompe disease is detectable through newborn screening, and treatment has become available recently.
OBJECTIVE. Our goal was to review systematically all available evidence regarding screening for infantile Pompe disease to help policy makers determine whether Pompe disease should be added to their state's newborn screening battery.
METHODS. We searched online databases, including Medline, clinicaltrials.gov, and the Computer Retrieval of Information on Scientific Projects database, as well as Web sites maintained by federal organizations (eg, the Food and Drug Administration) and other nonprofit or private organizations (eg, the March of Dimes and Genzyme Corp), by using the terms “glycogen storage disease type II,” “Pompe disease,” and “Pompe's disease.” We also obtained preliminary findings from a screening program in Taiwan. Data were critically appraised and extracted by 2 investigators, one who is an expert in systematic review methods and the other who is an expert in Pompe disease.
RESULTS. The prevalence of Pompe disease has been estimated to be ∼1 case per 40000. Small studies suggest that enzyme therapy is highly efficacious in infantile Pompe disease and that earlier intervention leads to improved outcomes. Screening cannot distinguish between infantile and late-onset Pompe disease. The current screening program in Taiwan has a high false-positive rate; however, the threshold was purposely set low to ensure that no case would be missed.
CONCLUSIONS. Pilot studies of screening are needed to identify the most efficacious strategy for screening and determine how to manage cases of late-onset Pompe disease before screening for Pompe disease is adopted widely by newborn screening programs.
Pompe disease is an autosomal recessive disorder that leads to a deficiency of the enzyme acid α-glucosidase (GAA), resulting in the accumulation of lysosomal glycogen.1 All patients with Pompe disease share the same underlying lysosomal enzyme deficiency, and all patients have a steady accumulation of glycogen substrate, leading to progressive muscle damage and organ failure; however, the rates of substrate accumulation and tissue damage are variable, reflecting the amount of active enzyme that affected individuals produce. There is also variability in disease progression because of other, less-well understood factors, including modifier genes and the environment.
The American College of Medical Genetics classifies the condition into 2 broad categories: infantile and late-onset disease.1 The infantile category includes the classic infantile form of the disease, which is the most severe end of the disease spectrum. Individuals with classic infantile Pompe disease usually die in the first year of life, as a result of profound hypotonia and hypertrophic cardiomyopathy. The infantile variant, also referred to as the nonclassic infantile form, has a slower progression to morbidity and death than the classic infantile form. The late-onset category includes childhood and adult-onset forms of Pompe disease. As with infantile Pompe disease, late-onset Pompe disease is associated with progressive muscle weakness and death attributable to respiratory failure. However, hypertrophic cardiomyopathy is not typically associated with the late-onset form of Pompe disease. Age of onset does not always delineate subtypes well; so-called juvenile-onset or mild variant cases occasionally present before 12 months of age. Therefore, the clinical presentation must be considered with the age of onset in the classification of cases.
In 2006, the US Food and Drug Administration (FDA) approved licensure for Myozyme (alglucosidase alfa [Genzyme Corp., Cambridge, MA]), the first effective treatment for Pompe disease.2 The drug has been approved by the European Union (European Medicines Agency) as therapy for Pompe disease. Because infantile Pompe disease is uniformly lethal and screening is possible with dried blood spots, there has been significant interest in adding Pompe disease to the battery of conditions included on states' newborn screening panels.
The primary goal of this report is to review current evidence regarding the potential benefits and harm of expanding screening to include this lysosomal storage disorder. The secondary goal is to evaluate the feasibility of using systematic reviews to inform policymaking regarding screening for rare childhood conditions for which only few high-quality data are available. To address this important limitation, we considered not only published reports but also findings not available in peer-reviewed publications, such as preliminary results of screening programs. This report thus differs from other reviews designed to guide policy decisions, such as those produced by the US Preventive Services Task Force.3
Primary and Supplemental Data Sources
We searched Medline for all studies published in English from 1966 through July 2006, using the National Library of Medicine Medical Subject Headings term “glycogen storage disease type II” and the keywords “Pompe disease” and “Pompe's disease,” which identified 614 publications. To ensure completeness of the literature search, we reviewed reference lists and articles from the authors' libraries. Although no additional published articles were identified in these libraries, we did identify 1 study in press.4 We supplemented the primary literature search by searching the Web sites of the American College of Medical Genetics, the American Academy of Pediatrics, the National Newborn Screening Resource Center, the March of Dimes, the Acid Maltase Deficiency Association, the International Pompe Association, the Computer Retrieval of Information on Scientific Projects database of research projects and programs supported by the Department of Health and Human Services, a database of federally and privately supported clinical research (clinicaltrials.gov), the FDA, and Genzyme Corp. We also obtained preliminary data from a pilot project on screening newborns in selected Taiwanese hospitals.
We extracted data to answer key questions regarding the natural history and burden of suffering related to infantile Pompe disease, methods for screening and diagnosis, effectiveness of treatment, screening and treatment recommendations, and ongoing research. Although our focus was on infantile Pompe disease, we recognize that screening may detect late-onset Pompe disease; therefore, we also searched for data regarding the number of infants at risk for late-onset Pompe disease who would be detected and the benefit of intervention for asymptomatic infants at risk for late-onset Pompe disease. Because Pompe disease is a rare condition, we chose to consider a wide range of study designs, instead of restricting data on the basis of the quality of the study design (eg, randomized, controlled trials or other prospective designs). We considered case reports, case series, uncontrolled intervention trials, and expert consensus. However, we did exclude research studies that did not include human subjects. Two reviewers, one an expert in systematic reviews and policy issues related to newborn screening (Dr Kemper) and the other an expert in Pompe disease (Dr Kishnani), worked together to synthesize the data for this report. There was an insufficient number of studies to allow for meaningful meta-analysis.
What Is the Natural History of Infantile Pompe Disease and Its Burden of Suffering?
An international retrospective study based on chart reviews for children with infantile (classic or nonclassic) Pompe disease found that the median age at which children first became symptomatic was 2 months and the median age of diagnosis was ∼5 months.5 The median age of death was ∼9 months, with 9% of patients still alive at 24 months of age. Longer survival times were associated with higher skin fibroblast GAA activity. Similar morbidity results were found in an earlier retrospective cohort study.6 A review of the experience at 1 large medical institution identified 30 infants with Pompe disease.7 The average ages of diagnosis and death in that cohort were 5.1 month and 8.6 months, respectively. None of those infants survived past 12.4 months. Infants who survive into their second year of life most likely have the nonclassic form of the disease.8
The incidence of Pompe disease, on the basis of diagnosed cases, has been estimated to range from 0.17 to 1.31 cases per 100000.9–11 However, these estimates are highly dependent on disease recognition; therefore, the true incidence could be underestimated because of case ascertainment bias. Other studies have attempted to estimate the incidence on the basis of extrapolation from carrier frequency.
The gene for GAA is located on chromosome 17.12 Many different mutations have been described, and some specific mutations have been associated with a particular disease course.13 Approximately 3000 anonymous dried blood spots in the Netherlands were evaluated for 3 specific mutations, 2 associated with infantile Pompe disease and 1 associated with late-onset Pompe disease. These mutations represented 63% of those associated with Pompe disease among the Dutch.14 On the basis of the carrier frequency of these mutations (infantile form: 1 case per 284; late-onset form: 1 case per 154), the incidence of infantile Pompe disorder associated with these mutations only was estimated to be ∼1 case per 138000 (95% confidence interval: 1 case per 43000 to 1 case per 536000) and that of late-onset disease to be 1 case per 57000 (95% confidence interval: 1 case per 28000 to 1 case per 128000). An earlier study estimated the total incidence of Pompe disease, regardless of type, to be ∼1 case per 40000, on the basis of carrier testing of randomly selected individuals from New York for 7 mutations that were thought to be responsible for 29% of the cases of Pompe disease.15 No published data are available regarding the economic burden of infantile Pompe disease or the impact of the disease on families.
How Is the Diagnosis of Infantile Pompe Disease Established?
In addition to clinical history, selected tests for cardiomyopathy (eg, chest radiographs, electrocardiograms, and echocardiograms) and general myopathy (eg, creatine kinase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase measurements) are helpful. Elevation of urinary levels of a specific glucose tetrasaccharide or glucose tetrasaccharide and maltotetraose or serum levels of glucose tetrasaccharide and maltotetraose is sensitive but not specific for Pompe disease; therefore, measurements are used primarily to monitor treatment.16,17
A diagnosis of infantile Pompe disease is confirmed if the GAA enzyme activity in muscle tissue obtained through biopsy or cultured fibroblasts from children with symptoms of weakness is <1% of normal control values.18 Muscle biopsy is not typically recommended because the cardiomyopathy associated with Pompe disease poses a significant anesthesia risk.19 Unfortunately, because of the time required to grow fibroblasts from skin biopsies, the turnaround time for diagnosis from cultured fibroblasts is 4 to 6 weeks.
Recent reports suggest that measuring enzyme activity in mixed leukocytes, dried blood spots, and lymphocytes with the use of an appropriate inhibitor for maltase glucoamylase (which is present in blood), as opposed to using cultured fibroblasts, may be an acceptable alternative for diagnosis, greatly reducing the time to diagnosis.20–22 However, unlike assays based on cultured fibroblasts, these blood-based assays cannot distinguish infantile Pompe disease from late-onset Pompe disease. Direct DNA analysis is not typically used for diagnosis, because of the number of mutations associated with the condition.22
What Treatments Are Available for Pompe Disease?
Before the approval of alglucosidase alfa for enzyme replacement therapy, only supportive treatment was available. Although aggressive supportive care can improve nutrition and temporarily improve strength, the risk of morbidity is not altered.23 Oral supplementation with l-alanine or a diet high in branched-chain amino acids may improve the myopathy associated with nonclassic infantile Pompe disease by reducing protein turnover and resting energy expenditure.24–26 Bone marrow transplantation has not been effective, perhaps because it has not been performed sufficiently early in the disease course or because children with classic infantile Pompe disease die before engraftment can occur.27–29
Recombinant human GAA (rhGAA) for human clinical trials has been produced from rabbit milk30 and from Chinese hamster ovary cells. Alglucosidase alfa, the FDA-approved rhGAA form, is produced from Chinese hamster ovary cells. The recommended dose of alglucosidase alfa is 20 mg/kg, administered intravenously every 2 weeks in ∼4 hours. The current average wholesale price for the treatment is $720 per 50-mg vial.31
The first published phase I/II trial of rhGAA derived from Chinese hamster ovary cells included 3 infants (2.5, 3, and 4 months of age) with infantile Pompe disease who were given rhGAA (5 mg/kg) twice weekly.7 All patients survived beyond 1 year of life. After 1 year of therapy, 2 of the children had decreases in heart size related to improvement in cardiomyopathy, and the third maintained normal heart status despite hypertrophy. Two of the patients developed high and sustained anti-rhGAA antibody titers, which were associated with declines in motor development and pulmonary function. Those 2 patients became ventilator-dependent. However, the third patient, who is now almost 8 years of age, is ambulatory and does not require ventilator support or supplemental oxygen therapy (P.S.K., unpublished data).
A subsequent study of rhGAA from Chinese hamster ovary cells enrolled 8 children with classic infantile Pompe disease that was diagnosed between 1.8 and 6.5 months of age.32 Treatment with rhGAA began between 2.7 and 14.6 months of age. Six of the children survived a 52-week treatment period and 5 showed motor improvement, including 3 who gained the ability to walk. During the 52-week treatment period and a subsequent extension phase, a total of 6 of the 8 patients died, with a median age of death of 21.7 months. The 2 surviving children, both of whom began treatment before 6 months of age, are now >4 years of age.
A phase II trial of rhGAA derived from rabbit milk enrolled 2 infants (3.1 and 5.9 months of age) with classic Pompe disease.33 After 48 weeks, both children experienced improvements in motor development and cardiac function and neither required mechanical ventilation. Ten months after the study, these patients continued to experience improvements.34
Many factors (eg, age and disease severity at diagnosis and underlying genotype) may affect treatment outcomes. The development of antibodies to rhGAA may also be important. Patients who do not produce any active or inactive endogenous GAA (referred to as cross-reacting immunologic material [CRIM] negative) may be more likely to produce higher and more persistent titers of antibodies to rhGAA.32 The effect of CRIM status and the impact of high and persistently elevated anti-rhGAA antibody levels on clinical outcomes are unclear.7,32,35 However, it seems that being CRIM negative is a poor prognostic factor.32 We are not aware of any epidemiologic data regarding the proportion of children with classic Pompe disease who are CRIM negative or any published data regarding the effectiveness of interventions to decrease immune responses to rhGAA.
The most important adverse effects of rhGAA are related to hypersensitivity; across clinical trials and expanded-access programs, 3% of treated individuals (8 of 280 patients) developed severe or significant hypersensitivity reactions. Nephrotic syndrome was reported for 1 child who had received high doses of rhGAA for a long time and was also undergoing an immunotolerance regimen because of the development of antibodies to rhGAA.36 The nephrotic syndrome resolved with a decrease in the dose of rhGAA.
Is It Possible to Detect Pompe Disease Through Newborn Screening?
As with diagnosis, direct DNA screening for Pompe disease is not currently practical. However, it is possible to measure GAA activity in dried blood samples on filter paper.22,37–40 Different methods are available, including those based on fluorometric tests, immunocapture, and mass spectroscopy. Unlike with cultured fibroblasts or muscle tissue, tests using dried blood samples on filter paper cannot distinguish between infantile and late-onset disease. Data from those studies, based on retrospective comparisons of relatively small numbers of case and control subjects, suggest that such tests are highly sensitive and specific. A multiplex screening test for Fabry, Gaucher, Krabbe, Neimann-Pick A/B, and Pompe disease based on the use of tandem mass spectrometry has been developed,38 as has an antibody-based test for 11 different lysosomal proteins, including GAA.41 No published data are available regarding the costs of screening.
Does Treatment in the Presymptomatic or Early Symptomatic Phase of Pompe Disease Lead to Better Health Outcomes?
No data are available regarding treatment for presymptomatic children with Pompe disease. Data from the screening pilot study in Taiwan should provide this information. However, earlier treatment seems to confer benefit. In a trial with 18 children with classic infant Pompe disorder who began treatment by 26 weeks of age,4 the children seemed to have better survival rates and improved motor outcomes, compared with the children in the previously described studies in which children began therapy at an older age. In that study, all children survived the 52-week treatment period, 3 patients required invasive ventilatory support, none had cardiac failure, 7 could walk, 3 could stand independently, and 3 could sit independently.4
What Is the Potential Harm of Screening for Pompe Disease?
On the basis of the previously presented epidemiologic data, screening for Pompe disease may identify ≥2 cases of late-onset Pompe disease for each case of infantile Pompe disease. No data are available regarding the management of early-detected or presymptomatic late-onset disease, including when to begin enzyme replacement therapy. No data are available regarding the benefit or harm of such early detection on families. Although research on fragile X syndrome suggests that parents regard presymptomatic diagnosis as valuable,42 specific research is needed for Pompe disease.
As with any screening program, there would also be false-positive results. No data are available regarding the impact of these specific false-positive results on newborns and their families; false-positive newborn screening results have been associated with increased family stress and parent/child dysfunction.43
What Has Been the Experience of Screening Programs for Pompe Disease?
A Pompe disease newborn screening pilot program began in Taiwan in October 2005, using a fluorometric assay (W.-L.H., unpublished data). The program was designed to be highly sensitive, to ensure that no cases would be missed, although the false-positive rate would necessarily increase as a result. Complete details of this screening program will be presented elsewhere. However, as of July 2006, ∼0.9% of the nearly 71000 children who were screened were recalled for a second blood sample. Of those children, ∼9% (<0.1% of the initial cohort) had positive second-tier test results, from which 3 cases of classic infantile Pompe disease and no cases of late-onset disease were detected. In Taiwan, dried blood spots for newborn screening are collected on the third day of life. Earlier screening is not thought to affect test accuracy.
What Are the Recommendations of Professional Organizations Regarding Screening for Pompe Disease?
Professional organizations, including the American Academy of Pediatrics and the American Academy of Family Physicians, advocacy organizations, including the March of Dimes and the Genetic Alliance, and the Department of Health and Human Services Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children support the recommendations of the American College of Medical Genetics Newborn Screening Expert Group.44 The Newborn Screening Expert Group did not recommend screening for Pompe disease, primarily because neither enzyme replacement therapy nor a validated screening test was available at the time of its review.
What Ongoing Research Would Help Answer Questions About the Value of Newborn Screening for Pompe Disease?
Genzyme Corp, which manufactures alglucosidase alfa, continues to evaluate the safety and efficacy of the therapy. In addition, Genzyme maintains a registry of individuals diagnosed as having Pompe disease.45 This registry excludes individuals enrolled in a Genzyme-sponsored clinical trial. As of September 2006, there were 35 children with infantile Pompe disease in the registry (C. Dandrea, MBA, written communication, 2006). In addition, the International Pompe Association and the Erasmus Medical Center (Rotterdam, Netherlands) maintain a registry of individuals with late-onset Pompe disease. Findings from secondary analyses of data from these registries could lead to a better understanding of the course of treated Pompe disease and identify strategies to improve care. These registries may also be important for health system planning, by identifying the resources and services needed to provide care for those with Pompe disease. However, we are unaware of any ongoing health services research focusing on Pompe disease, including modeling of the potential impact on costs and benefits of newborn screening for Pompe disease.
There is significant ongoing basic science and early translational research in Pompe disease. For example, the National Institutes of Health are funding research into the pathogenesis (eg, Genetic Metabolic Myopathies [principal investigator: Dr Paul Plotz]) and the development of novel therapies, such as gene therapy (eg, “Correction of Inherited Cardiomyopathy Using Adeno-associated Virus Vectors” [principal investigator: Dr Barry Byrne] and “Gene Delivery to Striated Muscle by Systematic Adeno-associated Virus Vectors” [principal investigator: Dr Dwight Koeberl]).
Determination of whether to recommend that newborn screening should include a new condition, such as Pompe disease, is complex and involves assessment of the potential benefits and harm of screening from the perspectives of families and society.46 Although research into management is still underway, infantile Pompe disease is a uniformly fatal condition; enzyme replacement therapy improves both length and quality of life for affected children. However, there are still important unanswered questions about the harm of screening.
Current testing strategies identify those who have late-onset Pompe disease. This problem is not unique to Pompe disease. For example, individuals with short-chain acyl-coenzyme A dehydrogenase deficiency can have highly variable clinical outcomes, which cannot be predicted through identification in the newborn period.47 However, most states detect short-chain acyl-coenzyme A dehydrogenase in newborn screening.47 We think that parents who elect to have their children tested for Pompe disease should be informed that there is the possibility of detecting late-onset Pompe disease and that there is little knowledge about how to provide care for asymptomatic children with late-onset Pompe disease. It is important to recognize that no studies have been performed to determine how to communicate effectively this complex information about potential harm, including family anxiety, medicalization of a condition that may not cause problems for many years, and long-term consequences related to insurability and employability.
The recent data from the pilot project of screening in Taiwan showed a high rate of false-positive results. A high rate of false-positive results would overwhelm the ability of public health programs in the United States to ensure appropriate follow-up evaluation. Before screening for Pompe disease can be recommended to be added to states' newborn screening panels, pilot studies are needed to develop testing strategies to ensure that testing is adequately sensitive, while greatly decreasing the number of false-positive results.
No data are available regarding whether there is sufficient infrastructure to care for children who would require diagnostic confirmation or treatment. Without the availability of appropriate services first being ensured, some children and their families may also suffer harm.
Finally, no data are available regarding the costs associated with screening and treatment for Pompe disease. Such costs are not the only determinant of whether to initiate screening; however, it is important for policy makers to understand explicitly the trade-offs associated with any new public health initiative.
Most of the evidence gathered in this report is available in the peer-reviewed literature, but this review would be incomplete without the inclusion of data obtained through personal communication. We recognize that unpublished data may be less reliable, because they are not subjected to the important scrutiny of peer review. We also recognize that there may be important unpublished data of which we are unaware. Developing methods to incorporate non–peer-reviewed observations into systematic reviews that are both transparent and replicable will be central to developing reports to guide screening policy for the many rare conditions for which screening is becoming available.
On the basis of our experience in preparing this report, we also think that it would assist policy makers if a standardized recommendation scheme were developed. The system used by the US Preventive Services Task Force is a good model; screening recommendations are graded from A (“good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms”) through D (“at least fair evidence that [the service] is ineffective or that harms outweigh benefits”), with I for situations in which “evidence that the [service] is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined.”48 However, because of the lack of high-quality data, we think that many of the new conditions identifiable through newborn screening would receive a grade of I. We propose the following classification system. (1) Universal screening recommended: all newborn screening programs should implement screening for the condition once follow-up infrastructure is in place. (2) Targeted screening recommended: newborn screening programs should target high-prevalence population groups for screening once follow-up infrastructure is in place. An historical example of targeted screening would be testing for sickle cell disease among black children. There is significant concern about the ethics and feasibility of such targeted screening.49 Therefore, we think that the threshold for recommending targeted screening should be high. (3) Pilot study of screening recommended: although there is reasonable evidence to suggest that screening for the condition is likely to be beneficial, there are still important unanswered questions about the impact or performance of screening. Screening (either universal or targeted) has a high likelihood of being recommended once these questions are resolved. (4) Pivotal studies required: although there are many fundamental unanswered questions about the impact of screening, screening on balance may lead to greater benefits than harm. Additional research is needed to answer fundamental questions (eg, natural history and prevalence of the condition, effectiveness of treatment, and accuracy of screening). (5) No general recommendation: the evidence suggests that the potential benefits and harm of screening for the condition are closely balanced. (6) Recommended against: the evidence suggests that screening for the condition would lead to more harm than benefit.
This classification scheme, along with the underlying evidence synthesis, not only could help guide state newborn screening policy makers but also could facilitate coordination of the activities of researchers, screening advocates, private foundations, drug and device manufacturers, and the federal agencies involved in newborn screening (eg, the National Institutes of Health, the Health Resources and Services Administration, the Agency for Healthcare Research and Quality, and the FDA), to identify and to answer the key policy questions regarding newborn screening for any particular condition. Using this classification scheme, we would grade screening for Pompe disease as “pilot study of screening recommended,” because of the clear benefit of alglucosidase alfa for children with infantile Pompe disease. However, significant concerns remain about screening accuracy, the management of identified cases of late-onset Pompe disease, and the challenge of informing parents about the benefits and harm of newborn screening for Pompe disease. Until these concerns have been resolved with scientifically based screening pilot studies, we think that it is too soon to recommend that all states add Pompe disease to their newborn screening panels.
This project was funded by the Maternal and Child Health Bureau of the Health Resources and Services Administration.
- Accepted April 18, 2007.
- Address correspondence to Alex R. Kemper, MD, MPH, MS, North Pavilion, 2400 Pratt St, Room 0311, Terrace Level, Durham, NC 27705. E-mail:
This report does not necessarily reflect the views of the Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children. Opinions stated herein are those of the authors and not necessarily those of the Health Resources and Services Administration or the Department of Health and Human Services.
Financial Disclosure: Drs Hwu and Kishnani have received research grant support and honoraria from Genzyme and are members of the Pompe Disease Advisory Board for Genzyme; Duke University and inventors of the method of treatment and predecessors of the cell lines used to generate the enzyme (rhGAA) used in these clinical trials may benefit financially pursuant to the university's policy on inventions, patents, and technology transfer. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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- Copyright © 2007 by the American Academy of Pediatrics