Pompe Disease

Ethan Sperry; Nancy Leslie; Lisa Berry; Loren Pena

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Pompe Disease

Synonyms: Acid Alpha-Glucosidase Deficiency, Acid Maltase Deficiency, GAA Deficiency, Glycogenosis Type II, Glycogen Storage Disease Type II (GSD II)

Ethan Sperry, MD, PhD, Nancy Leslie, MD, Lisa Berry, MS, and Loren Pena, MD, PhD.

Author Information and Affiliations

Initial Posting: August 31, 2007; Last Update: August 21, 2025.

Estimated reading time: 50 minutes

Summary

Clinical characteristics.

Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression into infantile-onset Pompe disease (IOPD) (i.e., individuals with onset before age 12 months with cardiomyopathy) and late-onset Pompe disease (LOPD) (i.e., individuals with onset before age 12 months without cardiomyopathy, and all individuals with onset after age 12 months). Untreated individuals with IOPD typically have hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress. Cardiomegaly and hypertrophic cardiomyopathy is usually identified in the first weeks of life and progress to left ventricular outflow obstruction and diminished lung volume. Progressive deposition of glycogen results in conduction defects with shortening of the PR interval on EKG. In untreated infants, death commonly occurs in the first two years of life from cardiopulmonary insufficiency. In those in whom enzyme replacement therapy (ERT) is initiated before age six months and before the need for ventilatory assistance, a majority have improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to untreated individuals.

LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs, which may require use of a wheelchair. Respiratory insufficiency progressing to respiratory failure is a significant cause of morbidity and mortality. Some adults have developed arteriopathy, including dilatation of the ascending thoracic aorta. Scoliosis is also frequent.

Diagnosis/testing.

The diagnosis of Pompe disease is established in a proband who has deficiency of acid alpha-glucosidase (GAA) enzyme activity in isolated lymphocytes or mixed leukocytes and/or by identification of biallelic pathogenic (or likely pathogenic) variants in GAA by molecular genetic testing in a proband with an out-of-range newborn screening result and/or suggestive clinical features.

Management.

Targeted therapies: Although ERT should be initiated as soon as the diagnosis of IOPD or symptomatic Pompe disease is established, it is appropriate to determine cross-reactive immunologic material (CRIM) status prior to initiating ERT, as individuals who do not produce CRIM (i.e., who are CRIM negative) generally develop high titer anti-rhGAA antibodies during ERT and require modified therapy protocols using immunomodulation early in the treatment course, optimally before the first infusion. ERT options include alglucosidase alfa for both IOPD and LOPD; avalglucosidase for individuals with LOPD who are older than age one year; and cipaglucosidase alfa with miglustat for adults with LOPD who weigh at least 40 kg and are not improving on their current ERT regimen.

Supportive care: Medical intervention for cardiomyopathy needs to be individualized as use of standard drugs may be contraindicated in certain stages of the disease process. Management of conduction disturbances includes avoidance of stress, infection, fever, dehydration, and anesthesia; medical therapy, if indicated, often necessitates a careful balance of ventricular function and should be undertaken by a cardiologist familiar with Pompe disease. Speech therapy and augmented communication devices may be helpful for those with communication difficulties. Feeding therapy and consideration of a gastrostomy tube is recommended for those who have feeding/nutritional difficulties. Respiratory support for those with respiratory insufficiency may include CPAP and BiPAP; tracheostomy may be considered in those with macroglossia and severe respiratory insufficiency. Standard treatment for arteriopathy, muscle weakness, scoliosis, osteoporosis, and hearing loss.

Surveillance: At each visit, measure growth parameters and evaluate nutritional status and safety of oral intake; monitor those with seizures as clinically indicated; assess for new manifestations (seizures, changes in tone, movement disorders); monitor developmental progress and educational needs; assess mobility and self-help skills; assess for scoliosis; monitor for evidence of aspiration and respiratory insufficiency; assess respiratory status with regard to cough, difficulty breathing, wheezing, fatigability, and exercise intolerance; obtain electrolytes, BUN, creatinine, liver function tests, CK level, and urine total glucotetrasaccharide (Hex4) level. At least annually, bone mineral density screening (DXA) in those with LOPD (in those with IOPD, DXA scan every two to three years until puberty, then every one to two years); pulmonary function tests; echocardiography (to include assessment for aortic dilatation in those with LOPD); EKG; audiology evaluation; BNP level (if there are concerns for evolving cardiomyopathy). At least every five years, MR cerebral angiography to evaluate for progressive dilation of cerebral vasculature. As clinically indicated, brain imaging to evaluate for intracranial vasculopathy (in those with LOPD); chest radiograph; whole-body MRI to evaluate muscle disease burden; polysomnography; videofluoroscopic swallow study; 24-hour ambulatory EKG (Holter monitoring).

Agents/circumstances to avoid: The use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in later stages of the disease; hypotension and volume depletion should be avoided. Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment with ERT. If a molecular diagnosis has been established in the proband, molecular genetic prenatal testing of a fetus at risk may be performed; for at-risk newborn sibs (when prenatal testing was not performed), in parallel with newborn screening, either test for the familial GAA pathogenic variants or measure GAA enzyme activity.

Pregnancy management: Several women with LOPD have been treated with ERT during pregnancy and lactation with no reported adverse effects on the fetus and no adverse events during infusions.

Genetic counseling.

Pompe disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GAA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GAA pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression:

Infantile-onset Pompe disease (IOPD). Individuals with onset before age 12 months with cardiomyopathy
Late-onset Pompe disease (LOPD)
- Individuals with onset before age 12 months without cardiomyopathy
- All individuals with onset after age 12 months

Suggestive Findings

A diagnosis of Pompe disease may be suspected due to an out-of-range newborn screening (NBS) result prior to onset of suggestive findings or may be considered because of symptoms of Pompe disease.

Out-of-Range NBS Result

NBS for Pompe disease is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify acid alpha-glucosidase (GAA) enzyme activity. Pompe disease is included in the United States (US) Secretary of Health and Human Services Recommended Uniform Screening Panel. For information on NBS by state in the US, see www.newbornscreening.hrsa.gov/your-state.

In the US most NBS laboratories determine their own cut-off levels for test results that are considered to be out of range and require further laboratory testing. For Pompe disease, follow-up testing typically includes molecular genetic testing (see Establishing the Diagnosis). A single abnormal NBS result is not regarded as sufficient for a diagnosis of Pompe disease.

Further evaluations following an out-of-range NBS result while awaiting confirmatory testing may also include physical examination, echocardiography to assess for cardiac hypertrophy, a serum creatine kinase (CK) level, and urinary glucotetrasaccharide (Hex4).

Symptomatic Individual

A symptomatic individual can have either typical findings associated with later-onset Pompe disease or untreated infantile-onset Pompe disease resulting from any of the following: NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result.

Clinical findings

Infantile-onset Pompe disease (IOPD)
- Poor feeding with poor growth
- Motor delay / muscle weakness
- Respiratory infections/difficulty
- Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
Late-onset Pompe disease (LOPD)
- Proximal muscular weakness
- Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy

Supportive laboratory findings

Elevated serum CK concentration as high as 2000 IU/L (normal: 60-305 IU/L)
- Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
- Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
Urinary glucotetrasaccharide (Hex4). This is a highly sensitive finding in individuals with IOPD; however, it is also seen in other glycogen storage diseases.
- The sensitivity of this assay is diminished in individuals with LOPD.
- Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Biochemical/Enzymatic Diagnosis

The diagnosis of Pompe disease is established in a proband who has deficiency of GAA enzyme activity in isolated lymphocytes or mixed leukocytes, although other tissues such as muscle can be used.

As a general rule, the lower the GAA enzyme activity, the earlier the age of onset of disease:

Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.

Molecular Diagnosis

The molecular diagnosis of Pompe is established in a proband with an out-of-range NBS result and/or suggestive clinical features by identification of biallelic pathogenic (or likely pathogenic) variants in GAA by molecular genetic testing (see Table 1). Because of its relatively high sensitivity, GAA molecular genetic testing can obviate the need for enzymatic testing and, thus, is increasingly the preferred confirmatory test for Pompe disease.

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic GAA variants of uncertain significance (or of one known GAA pathogenic variant and one GAA variant of uncertain significance) does not establish or rule out the diagnosis. (3) Molecular genetic testing or blood-based enzyme testing is preferred over analysis of GAA enzyme activity in cultured skin fibroblasts because of longer turnaround times for the latter. However, GAA enzyme activity in cultured skin fibroblasts may be helpful when LOPD is suspected or when asymptomatic individuals are ascertained through screening tests.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Pompe disease, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of GAA is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
A multigene panel that includes GAA and other genes of interest (see Differential Diagnosis) is likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Exome or genome sequencing can be used. Rapid exome or genome sequencing may be considered when newborns or infants are critically ill, or when the differential diagnosis is most efficiently interrogated by broad genomic testing. To date, most GAA pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing [Stenson et al 2020].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Pompe Disease

Gene ¹	Method	Proportion of Pathogenic Variants ² Identified by Method
GAA	Sequence analysis ³	95%-96% ^4, 5
GAA	Gene-targeted deletion/duplication analysis ⁶	4% ⁷

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020], Peruzzo et al [2019], and Moschetti et al [2024]
5.: Several complex rearrangements in GAA have been reported but these generally are detectable through sequence analysis [Stenson et al 2020].
6.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
7.: Deletion of exon 18 comprises approximately 5%-7% of alleles [Van der Kraan et al 1994]. Although other exon and multiexon deletions have been reported, they are rare [McCready et al 2007, Pittis et al 2008, Bali et al 2012, Amiñoso et al 2013].

Clinical Characteristics

Clinical Description

Traditionally, Pompe disease has been separated into two major phenotypes – infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) –based on age of onset, organ involvement (i.e., presence of cardiomyopathy), severity, and rate of progression. As a general rule, the earlier the onset of manifestations, the faster the rate of progression; thus, the two general classifications – IOPD and LOPD – tend to be clinically useful in determining prognosis and treatment options.

Although LOPD has been divided into childhood-, juvenile-, and adult-onset disease, many individuals with adult-onset disease recall symptoms beginning in childhood and, thus, late onset is often the preferred term for those presenting after age 12 months. Most likely, LOPD represents a clinical continuum in which age of onset cannot reliably distinguish subtype [Kishnani et al 2013].

Newborn screening (NBS) and the availability of enzyme replacement therapy (ERT) for affected individuals is changing the clinical course of individuals with Pompe disease.

Most of the literature on long-term clinical outcomes after initiation of ERT does not include significant numbers of individuals treated very early (those ascertained by NBS or known family history).
In those in whom ERT was initiated before age six months and before the need for ventilatory assistance, a majority had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to an untreated cohort.
Predictors of a poor response to ERT include increase in muscle glycogen during therapy, high IgG titers to alpha-glucosidase, and a negative cross-reactive immunologic material (CRIM) status. An individual is considered CRIM negative when that individual is unable to synthesize non-functional but immunoreactive protein; in this situation, providing ERT may induce an immune response in the affected individual, resulting in significantly decreased efficacy of ERT.

IOPD with Prompt Initiation of Appropriate Management

Prenatal IOPD

Prenatal ERT was carried out in a single individual with predicated IOPD based on family history and who was CRIM negative [Cohen et al 2022].

Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.

Postnatal IOPD

Motor function. Initiation of ERT before age two weeks is associated with significantly improved gross motor function at age 12 months [Prater et al 2012, Yang et al 2016] (see also Management, Targeted Therapies for discussion of determining CRIM status prior to starting ERT).

Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].

Cardiac function. In addition to improved motor function, longer-term survivors who underwent early ERT may show sustained improvement in cardiac function [Prater et al 2012].

ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].

Respiratory function. Pivotal trials of ERT on IOPD show convincing delay in the onset of dependence on ventilator support, but most affected individuals who are ventilator dependent remain so, even after starting ERT.

Cognition. While the long-term prognosis is as yet unknown, available studies suggest better cognitive outcomes for those treated with ERT than had been predicted.

Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].

Hearing loss. In one study of 19 infants with IOPD identified on NBS who all started ERT prior to 23 days of age, two had abnormal newborn hearing screens [Hsueh et al 2021]. At follow up between the ages of 2 and 9.5 years, two individuals had sensorineural hearing loss. Other long-term follow-up studies report higher frequencies of sensorineural, mixed, and conductive hearing loss than those reported by Hsueh et al [2021], but methodologic inconsistencies make it difficult to make robust comparisons.

Untreated IOPD

IOPD may be apparent in utero but, prior to NBS, was more often clinically recognized at a median age of four months in individuals with hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress (see Table 2).

Table 2.

Common Findings at Presentation of Infantile-Onset Pompe Disease in Individuals Who Were Not Diagnosed Through Newborn Screening

Physical Signs	Proportion of Individuals ¹
Normal cognition	95%
Cardiomegaly	92%-100%
Left ventricular hypertrophy	83%-100%
Hypotonia / muscle weakness	52%-96%
Cardiomyopathy (most typically hypertrophic)	88%
Hepatomegaly	29%-90%
Respiratory distress	41%-78%
Heart murmur	46%-75%
Enlarged tongue (macroglossia)	29%-62%
Feeding difficulties	57%
Poor growth	53%
Absent deep tendon reflexes	33%-35%

1.: Hirschhorn & Reuser [2001], van den Hout et al [2003]

Cardiac function. Without treatment by ERT, the cardiomegaly and hypertrophic cardiomyopathy that may be identified in the first weeks of life by echocardiography progress to left ventricular outflow obstruction.

Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see Respiratory function).
Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.

Respiratory function. Many untreated individuals require ventilatory support with disease progression.

Feeding difficulties may result from facial hypotonia, macroglossia, tongue weakness, and/or poor oral motor skills.

Motor function. Untreated individuals with IOPD typically have hypotonia and developmental delay, along with feeding difficulties and respiratory insufficiency.

Electrophysiologic studies

Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
Nerve conduction velocity is typically normal for both motor and sensory nerves.
However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.

Cognition. Information regarding cognitive function in individuals with untreated IOPD is not available.

Hearing loss is common, possibly reflecting cochlear or conductive pathology or both.

Prognosis in untreated individuals with IOPD. In untreated infants, death commonly occurs in the first two years of life from cardiopulmonary insufficiency. Death from ventilatory failure typically occurs in early childhood.

LOPD Treated with ERT

ERT approaches are the standard of care for individuals with LOPD. Several ERTs are approved for LOPD (see Management, Targeted Therapies).

Alglucosidase alfa has been approved for the longest period of time and thus there is more data on longer-term outcomes in individuals who have received this product. The major morbidities are motor disability and respiratory insufficiency, and long-term data has concentrated on these clinical outcomes.
- In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
- Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
Next-generation ERTs, including avalglucosidase alfa and cipagluosidase alfa with miglustat as a stabilizer, have been more recently approved for treatment, so there is less data on long-term outcomes.
- Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
- In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
- In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].

Untreated LOPD

LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs and respiratory insufficiency. Disease progression is often predicted by the age of onset, as progression is more rapid if symptoms are evident in childhood.

Table 3.

Clinical Manifestations in Untreated Late-Onset Pompe Disease

Physical Signs	Comments
Progressive proximal muscle weakness	Found in about 95% of affected persons
Respiratory insufficiency
Exercise intolerance
Exertional dyspnea
Orthopnea
Sleep apnea
Hyperlordosis &/or scoliosis
Hepatomegaly	In childhood- & juvenile-onset forms
Macroglossia	In childhood-onset form
Difficulty chewing & swallowing
Gastrointestinal symptoms	Incl irritable bowel-like symptoms
Chronic pain
↑ respiratory infections
↓ deep tendon reflexes
Gower sign
Joint contractures

: Based on Hirschhorn & Reuser [2001]

Motor function. Progression of skeletal muscle involvement is slower than in the IOPD and eventually involves the diaphragm and accessory respiratory muscles.

Affected individuals often become wheelchair users because of lower-limb weakness.
Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.

Electrophysiologic studies

EMG. Myopathy can be documented by EMG in all forms of Pompe disease, although some muscles may appear normal. In adults, needle EMG of the paraspinal muscles may be required to demonstrate abnormalities [Hobson-Webb et al 2011].
NCV studies are normal for both motor and sensory nerves, particularly at the time of diagnosis. EMG and NCV findings do not appear to be impacted by ERT.

Cardiac function. Significant conduction abnormalities were found in four of 131 adults with LOPD [Sacconi et al 2014], so Holter monitoring may be indicated (see Management). While initial manifestations in late childhood- to adolescent-onset Pompe disease do not typically include cardiac complications, some adults with late-onset disease have developed arteriopathy, including dilatation of the ascending thoracic aorta [El-Gharbawy et al 2011, Malhotra et al 2017].

Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
- Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
- Vertebral dolichoectasia was found in 17/30.
- Arterial stenosis was found in 14/30.
- Aneurysms were found in 7/30.
Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].

Respiratory function. Respiratory failure causes the major morbidity and mortality [Güngör et al 2011]. Male sex, severity of skeletal muscle weakness, and duration of disease are all risk factors for severe respiratory insufficiency [van der Beek et al 2011].

Skeletal. Scoliosis is frequent, particularly in individuals with infantile- or childhood-onset disease. Prompt management of scoliosis is recommended, as individuals with Pompe disease and scoliosis are at increased risk of dependence on invasive respiratory support [Roberts et al 2011]. Evidence of advanced osteoporosis in adults with LOPD is accumulating, the causes of which are still being elucidated. There may be benefit from ERT on bone mineral density [Sheng et al 2017, Avanti et al 2023] (see Management).

Prognosis for untreated LOPD. In an untreated cohort of individuals with LOPD, the median age at diagnosis was 38 years, the median survival after diagnosis was 27 years, and the median age at death was 55 years (range: 23-77 years) [Güngör et al 2011].

Genotype-Phenotype Correlations

Combinations of pathogenic variants that result in complete absence of acid alpha-glucosidase (GAA) enzyme activity are seen more commonly in IOPD, whereas combinations of pathogenic variants that result in partial enzyme activity are seen more commonly in LOPD.

GAA pathogenic variants that introduce mRNA instability, such as nonsense pathogenic 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 [Zampieri et al 2011].

Observations about genotype-phenotype correlations with specific pathogenic variants (see Table 4) include:

The pathogenic variant p.Glu176ArgfsTer45 (c.525delT) is an especially common pathogenic variant among the Dutch [Van der Kraan et al 1994]. It results in negligible GAA enzyme activity and is one of the more severe alterations. Whether in the homozygous state or in the compound heterozygous state with another severe pathogenic variant, this variant is associated with IOPD, although this correlation is not absolute.
Deletion of exon 18 (p.Gly828_Asn882del [c.2482_2646del]) is also a common pathogenic variant, particularly among the Dutch [Van der Kraan et al 1994]. It results in negligible GAA enzyme activity and is one of the more severe pathogenic variants. Deletion of exon 18, either in the homozygous state or in the compound heterozygous state with another severe pathogenic variant, predicts IOPD.
The pathogenic variant c.336-13T>G is seen in 36%-90% of LOPD and is not associated with IOPD [Hermans et al 2004, Montalvo et al 2006]. This pathogenic variant leads to a leaky splice site resulting in greatly diminished but not absent GAA enzyme activity.
The pathogenic variant p.Asp645Glu is seen in a high proportion (≤80%) of IOPD in Taiwan and China and is associated with a haplotype, suggesting a founder effect [Shieh & Lin 1998].
The pathogenic variant p.Arg854Ter is frequently associated with IOPD. Although present in several different ancestral backgrounds, this pathogenic variant has been observed in up to 60% of individuals of African descent who have a common haplotype, suggesting a founder effect [Becker et al 1998].

Table 4.

Proportion of Persons with Selected GAA Pathogenic Variants

GAA Pathogenic Variant	% of Affected Persons	Reference(s)
p.Glu176ArgfsTer45	34% of Dutch population	Van der Kraan et al [1994]
p.Glu176ArgfsTer45	9% of US population	Hirschhorn & Huie [1999]
p.Gly828_Asn882del	25% of Dutch & Canadian infants	Van der Kraan et al [1994]
p.Gly828_Asn882del	5% of US population	Hirschhorn & Huie [1999]
c.336-13T>G	36%-90% of persons w/LOPD	Hermans et al [2004], Montalvo et al [2006]
p.Asp645Glu	40%-80% of Taiwanese & Chinese infants	Shieh & Lin [1998], Su et al [2020]
p.Arg854Ter	43%-60% of persons of African descent w/common phenotype	Becker et al [1998]

: LOPD = late-onset Pompe disease

Nomenclature

Historically, IOPD (now defined as onset before age 12 months with cardiomyopathy) was further divided into the classic form (severe with onset age <12 months with clinically significant cardiomyopathy) and the "non-classic" or infantile form (onset age <12 months but without cardiomyopathy) [Slonim et al 2000]. Most children with "non-classic IOPD" are now classified as LOPD (i.e., onset age <12 months without cardiomyopathy as well as all individuals with onset of myopathy age >12 months).

Prevalence

Since inclusion in NBS, new data suggests that Pompe disease is more common than previously thought. The birth prevalence from the state of California is estimated at 1:25,2000 (IOPD and LOPD combined), with the prevalence of LOPD being ~1:37,500 [Tang et al 2020]. The birth prevalence for African American infants continues to be the highest observed and is estimated to be 1:18,700 [Tang et al 2020]. Data from 206,741 newborns screened by NBS in northeast Italy estimated an overall incidence 1:18,795 (IOPD: 1:68,914; LOPD: 1:25,843) [Gragnaniello et al 2022]

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in GAA.

Differential Diagnosis

Infantile-Onset Pompe Disease (IOPD)

Table 5.

Genes of Interest in the Differential Diagnosis of Infantile-Onset Pompe Disease

Gene	Disorder	MOI	Clinical Features / Comment
AGL	Glycogen storage disease type IIIa (debrancher deficiency)	AR	Hypotonia, cardiomegaly, muscle weakness, & ↑ serum CK concentration w/more dramatic liver involvement than typically seen in Pompe disease
GBE1	Glycogen storage disease type IV (glycogen branching enzyme deficiency)	AR	Hypotonia, cardiomegaly, muscle weakness, & ↑ serum CK concentration w/more dramatic liver involvement than typically seen in Pompe disease (similar to GSD IIIa)
LAMP2	Danon disease	XL	Hypotonia, hypertrophic cardiomyopathy, & myopathy as a result of excessive glycogen storage Males are more severely affected than females & typical age of presentation w/cardiomyopathy & weakness is in mid-adolescence, although a few persons w/infantile onset have been reported. ID may be present, which is unusual in Pompe disease.
Many genes incl: MYBPC3 MYH7 TNNI3 TNNT2 ¹	Hypertrophic cardiomyopathy	AD ²	Typically defined by presence of unexplained LVH. Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of ↑ LV wall thickness, such as pressure overload or storage/infiltrative disorders. Not assoc w/hypotonia or pronounced muscle weakness
SLC22A5	Primary carnitine deficiency	AR	Muscle weakness & cardiomyopathy w/o ↑ serum CK concentration Phenotypes vary widely, incl asymptomatic females ascertained through NBS of their newborns. Acutely symptomatic infants may have encephalopathy or coma, which is unusual in Pompe disease.
SMN1	Spinal muscular atrophy I	AR	Hypotonia, feeding difficulties, progressive proximal muscle weakness, & areflexia No cardiac involvement Lack of cardiomegaly should help distinguish SMA I from IOPD.
>350 genes ³	Primary mitochondrial disorders	MT AR AD XL	Mitochondrial / respiratory chain disorders show wide variation in clinical presentation & may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, & ↑ serum CK concentration. Mitochondrial disorders are often distinguishable from Pompe disease by absence of hypotonia & presence of cognitive involvement.

: AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; ID = intellectual disability; IOPD = infantile-onset Pompe disease; LVH = left ventricular hypertrophy; MT = mitochondrial; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked
1.: See Table 1 in Nonsyndromic Hypertrophic Cardiomyopathy Overview for a current list of known HCM-related genes.
2.: Nonsyndromic hypertrophic cardiomyopathy is typically inherited in an autosomal dominant manner; pathogenic variants in genes associated with autosomal inheritance have been reported in rare families.
3.: McCormick et al [2018]

Myocarditis can also be considered in the differential diagnosis of IOPD. Myocarditis is characterized by inflammation of the myocardium leading to cardiomegaly without hypotonia or muscle weakness.

Late-Onset Pompe Disease (LOPD)

The early involvement of the respiratory muscles is often useful in distinguishing LOPD from many neuromuscular disorders.

Table 6.

Genes of Interest in the Differential Diagnosis of Late-Onset Pompe Disease

Gene	Disorder	MOI	Clinical Features / Comment
DMD	Duchenne-Becker muscular dystrophy (See Dystrophinopathies.)	XL	Progressive proximal muscle weakness, respiratory insufficiency, & difficulty ambulating Primarily affects males.
PYGL	Glycogen storage disease type VI	AR	Hypotonia, hepatomegaly, muscle weakness, & ↑ serum CK concentration
PYGM	Glycogen storage disease type V (McArdle disease; muscle glycogen phosphorylase deficiency)	AR	↑ serum CK concentration & muscle cramping w/exertion
>35 genes ¹	Limb-girdle muscular dystrophy (OMIM PS253600 & PS603511)	AR AD	Progressive muscle weakness is seen in legs, pelvis, & shoulders w/sparing of truncal muscles

: AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; MOI = mode of inheritance; XL = X-linked
1.: See OMIM Phenotypic Series Muscular dystrophy, limb-girdle, autosomal recessive and Muscular dystrophy, limb-girdle, autosomal dominant.

Polymyositis can also be considered in the differential diagnosis of LOPD. Polymyositis is characterized by progressive, symmetric, unexplained muscle weakness.

Management

Clinical practice guidelines for Pompe disease have been published:

Guidelines for individuals ascertained by newborn screening [Kronn et al 2017]
Guidelines for infantile-onset Pompe disease (IOPD) [American College of Medical Genetics expert panel; see Kishnani et al 2006]
Guidelines for late-onset Pompe disease (LOPD) [Cupler et al 2012]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Pompe disease, the evaluations summarized in Table 7 for IOPD and Table 8 for LOPD (if not performed already) are recommended.

Table 7.

Infantile-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Constitutional	Measurement of weight, length, & head circumference	To assess for poor growth
Respiratory	Assess for signs/symptoms of respiratory insufficiency.	Incl for cough, wheeze, labored breathing, dyspnea, energy level, exercise tolerance, and fatigability feeding difficulties, or sleep disturbance
	Chest radiograph	To assess for cardiomegaly, apparent lung volume reduction, areas of atelectasis, & any pulmonary fluid
	Consider pulmonary function tests.	Most affected persons demonstrate pulmonary insufficiency. Assessing ventilatory capacity in supine position can detect early ventilatory insufficiency.
	Pulse oximetry, respiratory rate, & venous bicarbonate &/or pCO₂ should be obtained to assess for alveolar hypoventilation. ¹
Mouth	Assess for macroglossia.
Cardiovascular	EKG & echocardiography	To assess for cardiac hypertrophy or evidence of cardiomyopathy
Gastrointestinal/ Feeding	Gastroenterology / nutrition / feeding team eval	Incl for facial hypotonia, macroglossia, tongue weakness, &/or poor oral motor skills Consider videofluoroscopic swallow study. Assess for signs/symptoms of GERD.
Hearing	Baseline hearing eval incl tympanometry is appropriate.	See Genetic Hearing Loss Overview for discussion of age-related methods of hearing eval.
Development	Developmental assessment	To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education
Neurologic	Assessment for hypotonia, muscle weakness, & absent deep tendon reflexes
	Assessment of motor skills & overall functioning	To guide subsequent therapies
	Assessment of risk for falls
Musculoskeletal	Consider baseline DXA scan.	In those who are at least age 2 yrs
Musculoskeletal	Baseline CK level
Genetic counseling	By genetics professionals ²	To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of Pompe disease to facilitate medical & personal decision making
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

: CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; pCO₂ = partial pressure of carbon dioxide
1.: van der Beek et al [2011], Cupler et al [2012]
2.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Table 8.

Late-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Respiratory	Chest radiograph	To obtain baseline eval of lungs & cardiac silhouette Cardiomegaly is rare.
Respiratory	Assess for signs/symptoms of sleep apnea.	Consider a polysomnogram.
Mouth	Assess for evidence of macroglossia.
Hearing	Baseline hearing eval incl tympanometry is appropriate.	See Genetic Hearing Loss Overview for discussion of age-related methods of hearing eval.
Cardiac	EKG w/consideration of Holter monitor	A minority of persons have significant conduction abnormalities. ¹
Cardiac	Echocardiogram	To include assessment for dilatation of ascending thoracic aorta
Gastrointestinal/ Nutrition	Assessment of nutritional status
	Assessment of swallowing difficulty by videofluoroscopic swallow study	To assess for barriers to adequate nutrition & risk for aspiration
	Assessment for signs/symptoms of non-specific GI symptoms such as constipation & GERD	Although affected persons do not typically have irritable bowel syndrome, they may have similar symptoms.
Neurologic	Assessment for signs/symptoms of transient ischemic attacks & third nerve palsy
	Assessment for muscle weakness
	Assessment of motor skills & overall functioning	To guide subsequent therapies Difficulty w/communication is common.
	Assessment of risk for falls
Musculoskeletal	Orthopedics / physical medicine & rehab / PT & OT eval	To incl assessment of: Gross motor & fine motor skills Contractures and scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
	Consider DXA scan.	To assess for osteoporosis
	Baseline CK level
	Consider whole-body MRI.	To evaluate muscle disease burden
Genetic counseling	By genetics professionals ²	To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of Pompe disease to facilitate medical & personal decision making
Family support & resources	By clinicians, wider care team, & family support organizations	Assessment of family & social structure to determine need for: Community or online resources such as Parent to Parent Social work involvement for parental support Home nursing referral

: ADL = activities of daily living; CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
1.: Sacconi et al [2014]
2.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for Pompe disease.

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Although enzyme replacement therapy (ERT) should be initiated as soon as the diagnosis of IOPD or symptomatic Pompe disease is established, it is appropriate to determine cross-reactive immunologic material (CRIM) status prior to initiating ERT, as individuals who do not produce CRIM (i.e., who are CRIM negative) generally develop high titer anti-recombinant human acid alpha-glucosidase (anti-rhGAA) antibodies during ERT and require modified therapy protocols using immunomodulation early in the treatment course, optimally before the first infusion [Winchester et al 2008, Kishnani et al 2010, Messinger et al 2012]. An individual who is CRIM negative is unable to synthesize non-functional but immunoreactive GAA protein.

Table 9.

Targeted Treatment of Pompe Disease

Targeted Treatment ¹	Pompe Disease Phenotype ²	Dosage	Consideration
Alglucosidase alfa (Myozyme^®, Lumizyme^®)	IOPD & LOPD	20mg/kg every other week
Avalglucosidase (Nexviazyme^®)	LOPD	Weight <30kg: 40mg/kg every other week Weight ≥30kg: 20mg/kg every other week	Approved for persons w/LOPD who are older than age 1 yr
Cipaglucosidase alfa (Pombility^®) / miglustat (Opfolda^®)	LOPD	Cipaglucosidase alfa: 20mg/kg every other week Miglustat dosing is by weight category; refer to product insert	Approved for adults w/LOPD who weigh at least 40 kg & are not improving on their current ERT regimen

: IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
1.: Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs in cases of CRIM-negative IOPD (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
2.: In utero alglucosidase alfa therapy (20 mg/kg of estimated fetal weight) was given to an affected fetus every two weeks from 24 5/7 weeks' gestation to 34 5/7 weeks' gestation as part of a clinical trial (see Therapies Under Investigation) with good results [Cohen et al 2022].

CRIM Status

Determining CRIM status prior to initiating ERT is recommended. Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].

Two ways to determine the CRIM status of an individual with Pompe disease are as follows:

GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]

Geographic areas in which CRIM-negative status is common include the United States and the Middle East [Messinger et al 2012].

Complications of ERT

Infusion-associated reactions are not uncommon, occurring in at least 5% of affected individuals, depending on the ERT regimen used, the clinical phenotype (IOPD vs LOPD) of the affected individual, and the CRIM status of the individual.

Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.

Pretreatment / infusion modulation. It is reasonable to consider premedication with antipyretics, antihistamines, or glucocorticoids for individuals who experience recurrent pyrexia and hypersensitivity symptoms.

For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see Establishing the Diagnosis).

For these reasons – and because many individuals with IOPD have preexisting compromise of respiratory and cardiac function – initiation of therapy in centers equipped to provide emergency care is recommended.

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 10). Guidelines for the management of IOPD have been published [Kronn et al 2017].

Table 10.

Pompe Disease: Supportive Treatment of Manifestations

Manifestation/Concern	Treatment	Considerations/Other
Cardiomyopathy	Medical intervention needs to be individualized as use of standard drugs may be contraindicated in certain stages of the disease process (see Agents/Circumstances to Avoid).	For persons receiving ERT, improvement in heart muscle thickness has been observed; individualized treatment plans are necessary to maximize quality of life (incl liberation from certain medications or screening). ¹
Arteriopathy	Standard treatment per cardiologist
Conduction disturbances	Mgmt includes avoidance of stress, infection, fever, dehydration, & anesthesia.	Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death. It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
Conduction disturbances	Medical therapy, if indicated, often necessitates a careful balance of ventricular function & should be undertaken by a cardiologist familiar w/Pompe disease.
Muscle weakness	PT is appropriate to maintain range of motion & assist in ambulation.	Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery. Untreated persons often progress to requiring a wheelchair.
Scoliosis	Standard treatment per orthopedist	Prompt mgmt of scoliosis is recommended, as persons w/Pompe disease & scoliosis are at ↑ risk of dependence on invasive respiratory support. ²
Osteoporosis	Standard treatment per endocrinologist
Communication difficulties	Speech therapy as well as use of augmented communication devices may be helpful.
Feeding/nutritional difficulties	Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues.	Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia Untreated infants may require specialized diets & maximal nutritional support. Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
Respiratory insufficiency	Respiratory support incl CPAP & BiPAP may be required.	Inspiratory/expiratory training has improved respiratory muscle strength in adults w/LOPD. ³
Respiratory insufficiency	Tracheostomy may be considered in those w/macroglossia & severe respiratory insufficiency.
Hearing loss	Hearing aids may be helpful per otolaryngologist. ⁴	Community hearing services through early intervention or school district
Family/Community	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.	Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics.

: BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; ERT = enzyme replacement therapy; LOPD = late-onset Pompe disease; OT = occupational therapy; PT = physical therapy
1.: Kronn et al [2017]
2.: Roberts et al [2011]
3.: Jones et al [2011]
4.: van Capelle et al [2010]

Surveillance

Updated management and surveillance guidelines have been published by the Pompe Disease Newborn Screening Working Group [Kronn et al 2017], summarized in Table 11.

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 11 are recommended. Given the wide age range in individuals with LOPD, most of the recommendations can be applied to both IOPD and LOPD; however, there are some differences highlighted in Table 11.

Table 11.

Pompe Disease: Recommended Surveillance

System/Concern	Evaluation	Frequency
Constitutional	Measurement of growth parameters Eval of nutritional status & safety of oral intake	At each visit
Neurologic	Monitor those w/seizures as clinically indicated.
	Assess for new manifestations such as seizures, changes in tone, & movement disorders.
	Brain imaging to evaluate for intracranial vasculopathy	As clinically indicated for persons w/LOPD
Development	Monitor developmental progress & educational needs.	At each visit
Musculoskeletal	Physical medicine, OT/PT assessment of mobility, self-help skills
	Clinical assessment for scoliosis
	DXA scan	IOPD: every 2-3 yrs until puberty, then every 1-2 yrs LOPD: Consider annual screening.
	CK level	At each visit, particularly in those persons identified on NBS w/LOPD & very early clinical symptoms
Respiratory	Monitor for evidence of aspiration & respiratory insufficiency.	At each visit
	Assessment of respiratory status w/regard to cough, difficulty breathing, wheezing, fatigability, & exercise intolerance	At each visit
	Chest radiograph	As clinically indicated
	Whole-body MRI to evaluate muscle disease burden	As clinically indicated
	Pulmonary function tests	At least annually, or as clinically indicated
	Polysomnography	As clinically indicated
Gastrointestinal	Videofluoroscopic swallow study	As clinically indicated
Gastrointestinal	Liver function studies	At each visit
Cardiovascular	Echocardiography, incl assessment for aortic dilatation in persons w/LOPD	Annually
	24-hour ambulatory EKG (Holter monitoring) ¹	As clinically indicated
	MR cerebral angiography to evaluate for progressive dilation of cerebral vasculature	IOPD: consider initial screening prior to starting ERT & then every 5 yrs thereafter. ² LOPD: at initial visit & at least every 5 yrs thereafter. ³
	EKG	Annually
	BNP level	At least annually if concern for evolving cardiomyopathy
Metabolic assessments	Electrolytes, BUN, & creatinine ⁴	At each visit
Metabolic assessments	Urinary total glucotetrasaccharide (Hex4) level	At each visit
Hearing	Audiology eval	Annually
Family/Community	Assess family need for social work support (e.g., home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	At each visit

: BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
1.: Sacconi et al [2014] noted that ERT did not prevent development of significant conduction abnormalities in four of 131 adults with LOPD. Pfrimmer et al [2024] noted that around half of individuals with IOPD in their study on long-term ERT developed cardiac arrhythmias.
2.: Viamonte et al [2020]
3.: Hensel et al [2015]
4.: To monitor for secondary complications related to cardiac and/or pulmonary impairment as well as medication effects

Agents/Circumstances to Avoid

Use of standard drugs for treatment of cardiac manifestations may be contraindicated in certain stages of the disease. The use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in later stages of the disease.

Hypotension and volume depletion should be avoided.

Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks.

Exposure to infectious agents is to be avoided.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If a molecular diagnosis has been established in the proband, molecular genetic prenatal testing of a fetus at risk may be performed via amniocentesis or chorionic villus sampling to facilitate institution of treatment at birth.

Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment with ERT. For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening, either test for the familial GAA pathogenic variants or measure GAA enzyme activity.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Most individuals with IOPD have not reproduced.

Many adults with LOPD have reproduced. Several women have been treated with ERT during pregnancy and lactation with no reported adverse effects on the fetus and no adverse events during infusions [de Vries et al 2011, Holbeck-Brendel & Poulsen 2017, Goker-Alpan et al 2020]. As would be expected in a woman with a myopathy and respiratory insufficiency, the growing fetus may pose additional complications to the mother's health. Close respiratory and cardiac surveillance should be initiated in consultation with maternal-fetal medicine specialists.

Therapies Under Investigation

In utero therapy. In utero alglucosidase alfa therapy (20 mg/kg of estimated fetal weight) was given to an affected fetus every two weeks from 24 5/7 weeks' gestation to 34 5/7 weeks' gestation as part of a clinical trial. After birth, the infant received immunotolerance induction and alglucosidase alfa ERT at various doses. Follow up through approximately age 12 months noted normal cardiac function and attainment of appropriate gross motor milestones [Cohen et al 2022].

Gene therapy to correct the underlying enzyme defect is under investigation [Raben et al 2002, DeRuisseau et al 2009, Mah et al 2010]. A Phase I/II trial to investigate the ability of adeno-associated virus (AAV)-mediated delivery of GAA to improve ventilation reported outcomes of children with IOPD treated with ERT. In this trial of phrenic nerve-injected AAV-mediated GAA and ventilatory training, the rate of ventilatory decline was attenuated in a subset of children, particularly those who were not already dependent on ventilatory assistance full time at the time of intervention [Smith et al 2017].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pompe disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected individual are presumed to be heterozygous for a GAA pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GAA pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
- Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for a GAA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Sib pair concordance in IOPD is high in children with null pathogenic variants [Hirschhorn & Reuser 2001]. Age and severity of manifestations in LOPD may vary among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with Pompe disease are obligate heterozygotes (carriers) for a pathogenic variant in GAA.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a GAA pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the GAA pathogenic variants in the family.

Note: Measurement of acid alpha-glucosidase enzyme activity in skin fibroblasts, muscle, or peripheral blood leukocytes is unreliable for carrier determination because of significant overlap in residual enzyme activity levels between obligate carriers and the general (non-carrier) population.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The American College of Medical Genetics and Genomics includes Pompe disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the GAA pathogenic variants have been identified in an affected family member, molecular genetic prenatal testing and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Acid Maltase Deficiency Association (AMDA)
Phone: 210-494-6144
Email: info@amda-pompe.org
amda-pompe.org
Association for Glycogen Storage Disease
agsdus.org
MedlinePlus
Pompe disease
Muscular Dystrophy Association (MDA) - USA
Phone: 800-572-1717
Email: ResourceCenter@mdausa.org
mda.org
Newborn Screening in Your State
Health Resources & Services Administration
newbornscreening.hrsa.gov/your-state
RegistryNXT!
Phone: 888-404-4413
Email: RegistryNXTHelpDesk@nof1health.com
registrynxt.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Pompe Disease: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
GAA	17q25.3	Lysosomal alpha-glucosidase	Glucosidase, alpha, acid (Pompe disease) (GAA) @ LOVD CCHMC - Human Genetics Mutation Database (GAA)	GAA	GAA

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Pompe Disease (View All in OMIM)

232300	POMPE DISEASE, INFANTILE-ONSET; IOPD
606800	GLUCOSIDASE, ALPHA, ACID; GAA
621314	POMPE DISEASE, LATE-ONSET; LOPD

Molecular Pathogenesis

Acid alpha-glucosidase (GAA) is a lysosomal enzyme that catalyzes α-1,4- and α-1,6-glucosidic linkages at acid pH. There are seven glycosylation sites. The immature protein consists of 952 amino acids with a predicted non-glycosylated weight of 105 kd. The mature enzyme exists in either 76-kd or 70-kd form as a monomer. Pathogenic variants in GAA result in mRNA instability and/or severely truncated GAA or an enzyme with markedly decreased activity leading to a markedly abnormal accumulation of glycogen in lysosomes causing damage to several organs including heart, muscle, and others.

Mechanism of disease causation. Loss of function

GAA-specific laboratory technical considerations. Several pseudodeficiency alleles, including c.1726G>A (p.Gly576Ser) and c.2065G>A (p.Glu689Lys), which interfere with enzyme activity toward artificial substrates, are relatively common in individuals of Asian ancestry as well as other populations studied as part of newborn screening (NBS) programs [Labrousse et al 2010, Hopkins et al 2015, Lin et al 2017]. Additional pseudodeficiency alleles are likely to be discovered through NBS.

Table 12.

GAA Variants Discussed in This GeneReview

Reference Sequences	Variant Classification	DNA Nucleotide Change	Predicted Protein Change	Notes
NM_000152.3 NP_000143.2	Pseudodeficiency	c.1726G>A	p.Gly576Ser	Variants that lead to ↓ GAA enzyme activity w/o causing Pompe disease These two variants are common in persons of Asian ancestry.
	Pseudodeficiency	c.2065G>A	p.Glu689Lys
	Pathogenic	c.525delT	p.Glu176ArgfsTer45	Common variants in Dutch population, assoc w/almost negligible enzyme activity & thus severe manifestations (See Genotype-Phenotype Correlations.)
		c.2482_2646del (Exon 18 del)	p.Gly828_Asn882del
		c.336-13T>G (IVS1-13T>G ¹)	--	Variant leads to a leaky splice site & diminished but not absent enzyme activity, seen in 36%-90% of LOPD (See Genotype-Phenotype Correlations.)
		c.1935C>A	p.Asp645Glu	Variant seen in a high proportion (≤80%) of IOPD in Taiwan & China, suggesting a founder effect (See Genotype-Phenotype Correlations).
		c.2560C>T	p.Arg854Ter	Variant frequently assoc w/IOPD Although present in several different ancestral backgrounds, this variant has been observed in up to 60% of persons of African descent with a common haplotype, suggesting a founder effect (see Genotype-Phenotype Correlations).

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
1.: Variant designation that does not conform to current naming conventions

Chapter Notes

Author Notes

Web page: STAR Center for Lysosomal Diseases

Author History

Laurie Bailey, MS; Cincinnati Children's Hospital Medical Center (2017-2025)
Lisa Berry, MS (2025-present)
Nancy Leslie, MD (2007-present)
Loren Pena, MD, PhD (2025-present)
Ethan Sperry, MD, PhD (2025-present)
Brad Tinkle, MD, PhD; Advocate Children’s Hospital, Illinois (2007-2017)

Revision History

21 August 2025 (ma) Comprehensive update posted live
11 May 2017 (bp) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
12 August 2010 (me) Comprehensive update posted live
31 August 2007 (me) Review posted live
8 January 2007 (bt) Original submission

References

Published Guidelines / Consensus Statements

American College of Medical Genetics. Pompe disease diagnosis and management guideline. Available online. 2006. Accessed 10-28-21.
Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-Onset Pompe Disease. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45:319-33.
Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, Swoboda KJ, Kishnani PS; Pompe Disease Newborn Screening working group. management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics. 2017;140:S24-S45.

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Sperry E, Leslie N, Berry L, et al. Pompe Disease. 2007 Aug 31 [Updated 2025 Aug 21]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
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GeneReviews® [Internet].

Pompe Disease

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Out-of-Range NBS Result

Symptomatic Individual

Establishing the Diagnosis

Biochemical/Enzymatic Diagnosis

Molecular Diagnosis

Option 1

Option 2

Table 1.

Clinical Characteristics

Clinical Description

IOPD with Prompt Initiation of Appropriate Management

Prenatal IOPD

Postnatal IOPD

Untreated IOPD

Table 2.

LOPD Treated with ERT

Untreated LOPD

Table 3.

Genotype-Phenotype Correlations

Table 4.

Nomenclature

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Infantile-Onset Pompe Disease (IOPD)

Table 5.

Late-Onset Pompe Disease (LOPD)

Table 6.

Management

Evaluations Following Initial Diagnosis

Table 7.

Table 8.

Treatment of Manifestations

Targeted Therapies

Table 9.

CRIM Status

Complications of ERT

Supportive Care

Table 10.

Surveillance

Table 11.

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Pregnancy Management

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Carrier Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Table 12.

Chapter Notes

Author Notes

Author History

Revision History

References

Published Guidelines / Consensus Statements

Literature Cited

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