Pompe disease …

Neuromuscular Disorders

Updated 01.18.2025
Released 01.04.1995
Expires For CME 01.18.2028

Pompe disease

Authors: Agnes Chen MD, Yun Cheong Chang MD

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Editor: Aravindhan Veerapandiyan MD

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Pompe disease

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Introduction

Overview

Pompe disease (also known as glycogen storage disease type II and acid maltase deficiency) is a chronic muscle-weakening neuromuscular disease that is often fatal (22). This rare autosomal recessive disorder is caused by a deficiency in the acid alpha-glucosidase enzyme, which is responsible for the hydrolysis of glycogen to glucose in the lysosome (15). Deficiencies in acid alpha-glucosidase lead to the lysosomal accumulation of glycogen in multiple tissues, with cardiac and skeletal muscles being the most severely affected (14). Pompe disease is a lysosomal storage disorder, a group of inherited diseases in which lysosomal enzymes are impaired, leading to functional deficits in substrate storage (22). Although Pompe disease was historically fatal in young children, enzyme replacement therapy is now improving survival while decreasing the risk of invasive ventilation. As of 2024, significant progress is being made towards curative therapies for Pompe disease (06).

Key points

	• Pompe disease is a rare autosomal recessive disorder caused by a deficiency in the acid alpha-glucosidase enzyme, which is responsible for the hydrolysis of glycogen to glucose in the lysosome.
	• Pompe disease is broadly divided into infantile-onset and adult-onset forms, with the former being characterized by faster progression.
	• Both forms of Pompe disease are characterized by heart and skeletal anomalies. Furthermore, CNS abnormalities often arise in children and adolescents with the infantile-onset form who have been treated with enzyme replacement therapy.
	• Although enzyme replacement therapy is the current standard of care for Pompe disease, clinical trials have also shown promising results for gene therapy.
	• Clinical trials have demonstrated the efficacy of enzyme replacement therapy for patients with infantile-onset, including sustained improvements in cardiac parameters and motor development.
	• Clinical trials of enzyme replacement therapy in patients with late-onset Pompe disease show moderate improvements in motor and respiratory function that tend to plateau over a couple of years.

Historical note and terminology

Pompe disease was first described in 1932 by Dutch pathologist Johannes Cassianus Pompe. He observed a 7-month-old child with general muscle weakness who died from idiopathic cardiac hypertrophy. A crucial observation at the time involved associating Pompe disease symptoms with glycogen storage in all tissues (22). In 1963, the Belgian biochemist Henri-Gery Hers discovered acid alpha-glucosidase, the missing intralysosomal glycogen-degrading enzyme in Pompe disease (14). This enzyme hydrolyses glycogen into glucose at acidic pH (22). Consequently, Pompe disease became the first of 50 disorders to be classified as a lysosomal storage disorder (22).

Clinical manifestations

Presentation and course

	• Pompe disease is generally classified into infantile-onset and late-onset forms.
	• Before the advent of modern therapies, the infantile form was typically deadly in infants. In contrast, the latter form progresses more slowly and is more variable in its presentation.
	• Both forms of Pompe disease are characterized by heart and skeletal anomalies.

Pompe disease presents as a continuum of clinical phenotypes that differ in age of onset, severity, rate of progression, and organ involvement (14; 17; 15). The clinical course largely depends on the specific mutation and the resulting level of residual acid alpha-glucosidase activity (14).

The disease is classified into infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) (22). IOPD is more severe than LOPD and begins at birth or within the first few months of life. It is characterized by cardiomyopathy and muscle weakness and often causes death in the first year of life in the absence of enzyme replacement therapy (22).

The classical form of IOPD usually presents in the first days or weeks of life and is associated with cardiomegaly and hypertrophic cardiomyopathy (15). In contrast, a small percentage of patients with IOPD show fewer clinical signs and non-severe cardiomyopathy during the first year of life. This form of Pompe disease is referred to as non-classic IOPD and is associated with less severe cardiac involvement and milder motor symptoms, allowing more prolonged survival (22; 15).

The signs and symptoms of IOPD include delays in motor development, hypotonia, feeding difficulties, alterations in the intestinal tract (including hepatomegaly and macroglossia), hypertrophic cardiomyopathy (including an ECG with a short PR interval), high QRS complex voltages, arrhythmias, and cardiorespiratory failure (22; 15). Many patients with IOPD need mechanical support to breathe (22). Brain MRI in patients with IOPD has also indicated abnormalities in white matter, ventricular size, and cerebrospinal fluid accumulations (see Prognosis and Complications section for CNS complications) (13). Death often occurs within the first 2 years of life due to progressive cardiac and respiratory insufficiency (15).

LOPD is applied to patients with onset between 12 months and adulthood (including childhood and adult forms) (15). The LOPD phenotype is highly variable, encompassing cases with mild muscle involvement as well as those with severe chronic respiratory failure and marked musculoskeletal weakness (15). LOPD is also sometimes applied to asymptomatic patients who harbor LOPD mutations in the GAA gene and were diagnosed because of family history, elevated serum creatine kinase levels, or newborn screening. The clinical expression for these individuals is generally not predictable at diagnosis (15).

Progressive limb-girdle weakness is one of the most frequent features reported by patients with adult-onset LOPD and is often the main reason for clinician evaluation (15). However, LOPD is also associated with isolated respiratory muscle involvement and isolated elevated serum creatine kinase levels (15). LOPD, which differs widely depending on the patient’s specific conditions, typically results in progressive muscle weakness, motor difficulties, and respiratory failure over time (22). The potential role of an angiotensin-converting enzyme polymorphism in modulating the clinical outcome was also shown in a group of patients with LOPD (08; 14).

Common signs and symptoms of LOPD include skeletal myopathy, exercise intolerance, weakness of limb muscles, low back pain, breathing failure, sleep apnea, dyspnea, and respiratory infections (22). Gastrointestinal symptoms such as macroglossia and hepatomegaly are much less common in LOPD. Some studies suggest that patients with LOPD may also manifest as CNS injury with brain alterations (22). However, contrary to the findings in IOPD, van den Dorpel and colleagues did not find evidence of substantial brain lesions or signs of general cognitive impairment in LOPD (26).

Prognosis and complications

	• Although children and adolescents with the infantile-onset form of the disease are living longer, they often show evidence of CNS complications involving white matter abnormalities and decreased cognitive ability. The underlying mechanisms (including CNS glycogen accumulation) are still poorly understood.
	• Some studies also suggest CNS abnormalities in the adult-onset form, although there is still controversy about this issue.

Before the era of enzyme replacement therapy, IOPD usually caused death in the first year of life (22). Based on studies published in the early 2000s (before the advent of enzyme replacement therapy), the mean age at death for classical IOPD was reported to be 8.7 months (02). Meanwhile, survival to 12 months of age was only 25.7% (02). In contrast, the prognosis for LOPD has always differed widely from patient to patient (15).

CNS complications of Pompe disease. Some autopsy studies of patients with IOPD have documented glycogen accumulation in the neurons, glial cells, basal ganglia, brainstem, cerebellum, and spinal cord (13). However, other autopsy studies have not shown any glycogen accumulation (28). How this glycogen accumulation leads to brain abnormalities in IOPD is not fully understood (25). One study indicated that the impairment of the hypoglossal nerve in acid alpha-glucosidase-deficient mice was caused by neural glycogen accumulation (16).

Van der Dorpel and colleagues performed a study on patients with IOPD treated with enzyme replacement therapy. They concluded that patients with white matter abnormalities showed decreased cognitive abilities with increased age (25). This decline was associated with further progression of MRI brain abnormalities. More specifically, they observed a significant (P < 0.01) decline with increasing age for full-scale IQ, performance IQ, and processing speed but not for verbal IQ (P = 0.17).

Ebbink and colleagues investigated brain MRIs in a cohort of 11 patients with IOPD receiving enzyme replacement therapy (09). The study observed a characteristic three-stage pattern of white matter involvement in patients up to 17 years of age. This pattern evolved from periventricular to subcortical regions in a superior-to-inferior direction over time (09).

Although controversial, there is also evidence of cognitive dysfunction in patients with LOPD. However, these patients do not appear to have the same progressive white matter disease as in IOPD (07). Although the question of auditory deficits in LOPD is controversial, studies have suggested that the prevalence of auditory deficits is not elevated in LOPD (28).

Wirsching and colleagues analyzed multimodal sensory evoked potentials in patients with LOPD (28). Only one patient demonstrated extended latencies for peak 1 on brainstem auditory evoked potentials, which was thought to be related to presbycusis. All patients had normal visual evoked potentials. There were minor abnormalities in median somatosensory evoked potentials, which may have been artifactual. None of the patients had clinical sensory symptoms.

Biological basis

Genetics

	• Pompe disease is known to be caused by defects in the GAA gene. A variety of such defects exist in different families and demographic groups.
	• Infantile-onset versions of the disease typically result in lower enzymatic activity of acid alpha-glucosidase.
	• The acid alpha-glucosidase enzyme undergoes a series of post-translational modifications before reaching the lysosome. The inability to hydrolyze glycosidic bonds in glycogen results in lysosomal dysfunction.

Pompe disease is an autosomal recessive disorder caused by pathogenic variants in both copies of the GAA gene. GAA is localized on the long arm of chromosome 17 and consists of 20 exons. The first exon is noncoding, whereas the other 19 exons encode a protein of around 1,000 amino acids (22).

The GAA gene is thought to be the only gene associated with Pompe disease (15). It encodes a 110-kDa precursor polypeptide that undergoes several post-translational modifications in the rough endoplasmic reticulum. Most mutations in GAA are found in single families or small populations, and most patients are compound heterozygotes (17). These variants may involve either point mutations or small and large deletions and insertions (22). The mutations are spread throughout the gene and affect different steps involved in the complex process of generating fully functional GAA, including protein synthesis, posttranslational modifications, and lysosomal trafficking and maturation (17).

The varying severity of Pompe disease is related to the residual activity of the acid alpha-glucosidase enzyme in tissues (15). Some GAA mutations are deleterious and cause a complete lack of enzyme activity, whereas other less severe mutations allow residual enzyme activity (15). Patients with infantile-onset Pompe disease (IOPD) typically carry mutations that alter all forms of GAA, causing low expression and enzymatic activity (22). Although acid alpha-glucosidase activity is generally less than 1% in patients with IOPD, those with late-onset Pompe disease typically have 2% to 30% of normal acid alpha-glucosidase activity (15). The same mutations are often found in patients with infantile-onset and late-onset Pompe disease, often with different incidences (22). However, genetics cannot alone determine the phenotypic variability in Pompe disease. Individuals carrying the same mutations often show significant variability in the age of onset and severity of the disease (15).

More than 500 mutations have been reported in Pompe disease, including insertions, deletions, splice sites, nonsense, and missense mutations (17). Several mutations are commonly found in patients of specific ethnic backgrounds, such as the Dutch, the Chinese from Taiwan, and African Americans (17). Among these, c.-32-13T>G (IVS1) is a common defect in White populations, whereas Chinese patients from Taiwan share a common c.1935C>A (p.Asp645Glu) mutation (21). Known mutations in the GAA gene are reported in the Pompe disease GAA variant database (15).

Cell biology

• The acid alpha-glucosidase enzyme undergoes a series of post-translational modifications before reaching the lysosome. The inability to hydrolyze glycosidic bonds in glycogen results in lysosomal dysfunction.

The acid alpha-glucosidase enzyme is synthesized as a 110-kD precursor glycosylated in the endoplasmic reticulum and phosphorylated on mannose residues in the Golgi apparatus. These modifications ensure its transport to the lysosomal system through a mannose-6-phosphate (M6P) receptor-mediated pathway (14; 17). The enzyme also undergoes extensive proteolytic processing to yield mature lysosomal forms (at 70 and 76 kD) with a higher affinity for glycogen (17). In patients affected by Pompe disease, the defective enzyme cannot catalyze the hydrolysis of the alpha-1,4 and alpha-1,6-glycosidic bonds in glycogen, leading to increased glycogen storage in lysosomes. This is responsible for lysosomal dysfunction, enlargement, and rupture (15).

Pathology

• Muscle biopsy specimens tend to show evidence of vacuolar myopathy, glycogen storage, fiber atrophy, and increased acid phosphatase reactivity. The extent of these findings is generally greater in infantile-onset cases.

Muscle biopsies are often performed using standard procedures in histological and histochemical studies. This includes periodic acid-Schiff staining to identify glycogen accumulation and acid phosphatase staining as a marker of lysosomal abnormalities (15). A typical pathological pattern is characterized by vacuolar myopathy with glycogen storage and increased acid phosphatase reactivity (15).

Fiber atrophy is more evident in IOPD and childhood forms, with type 1 and type 2 fibers being equally involved (15). The presence of internal nuclei and necrosis is also reported in adult cases (15). The number of vacuoles and amount of glycogen accumulation is variable and usually more prominent in IOPD than in LOPD, in which histological studies typically show mild involvement or a normal appearance (15). In LOPD, it is common to observe a pattern of normal-looking myofibers next to the affected ones within a single muscle bundle (17). In contrast, muscle morphology in patients with IOPD is more homogeneous, normal fibers are typically absent, and muscle architecture is lost in most cells (17).

Pathophysiology

	• From the perspective of pathophysiology, Pompe disease is viewed as a complex disorder involving excess glycogen storage and dysregulated autophagy (a recycling system involving the lysosomes).
	• Pompe disease results in the accumulation of autophagic debris, including glycogen, misfolded protein aggregates, and malfunctioning organelles.

Initially, the pathogenesis of Pompe disease was thought to occur in distinct stages, including the gradual accumulation of glycogen in the lysosomal lumen, lysosomal membrane rupture from increased mechanical pressure, the discharge of glycogen and potentially toxic materials into the cytoplasm, and finally, the destruction of muscle architecture (17).

However, it is now understood that the pathogenesis of Pompe disease (which involves defective autophagy, mitochondrial abnormalities, the dysregulation of lysosome-based signaling pathways, and oxidative stress) cannot solely be explained by damaged lysosomes (14; 15). Instead, the disease is also now viewed as a glycogen storage disorder and an autophagic myopathy (14).

Pompe disease was the first lysosomal storage disorder linked to autophagy (which means “self-eating”), a recycling system that harnesses the lysosome for the degradation of intracellular components (14). It is well-established that too much or too little autophagic activity can negatively affect muscle function, resulting in muscle wasting (17). Skeletal muscles rely heavily on autophagy because muscle fibers are terminally differentiated cells that cannot divide. Therefore, they cannot reduce the number of aberrant proteins through cell division (17).

The accumulation of autophagic debris (including glycogen, misfolded protein aggregates, and malfunctioning organelles such as aberrant mitochondria) is a prominent feature of many muscle disorders, including Pompe disease (17). An increase in autophagosomes, autophagy substrates, vacuolization, and inappropriate lysosomal acidification has been described in myotubes of patients with Pompe disease (22). Autophagy also influences acid alpha-glucosidase maturation and glycogen clearance (22).

Differential diagnosis

Associated or underlying disorders

The differential diagnosis of Pompe disease depends on whether the patient has infantile-onset disease or onset after 12 months of age.

For infantile-onset Pompe disease (IOPD), the differential diagnosis consists of other diseases that present with severe weakness and cardiomyopathy. For example, spinal muscular atrophy type I would not be in the differential for IOPD because of the lack of cardiac involvement in spinal muscular atrophy. The differential includes a few other glycogen storage diseases (GSD) and mitochondrial or respiratory chain disorders with early infantile presentation.

Glycogen storage diseases in the differential diagnosis for IOPD:

	• Lysosome-associated membrane protein 2 (LAMP2) deficiency (GSDIIb, Danon disease)
	• Debrancher deficiency (GSDIII, Cori or Forbes disease), congenital form, which would have more severe liver involvement than in Pompe disease
	• Glycogen branching enzyme deficiency (GSD IV, Andersen disease), congenital form

Differential diagnosis for late-onset Pompe disease:

Neuromuscular disorders affecting the limb-girdle and respiratory muscles, such as muscular dystrophies and other metabolic myopathies.
Muscular dystrophies, including Duchenne-Becker muscular dystrophy and limb-girdle muscular dystrophies, dystroglycanopathies, LAMA2-related muscular dystrophy laminopathies, mitochondrial DNA depletion syndrome 2, neutral lipid storage disease with myopathy.
Metabolic myopathies, such as mitochondrial diseases, fatty acid oxidation disorders, and the other glycogen storage diseases.
	Other glycogen storage diseases involving muscle are in the differential for Pompe disease but often have a more obvious exertional fatigue aspect with cramping and myoglobinuria, which are less present in Pompe disease.
		• Glycogen branching enzyme deficiency (GSD IV, Andersen disease)
		• Glycogen storage disease type V (McArdle disease; muscle glycogen phosphorylase deficiency)
		• Phosphofructokinase deficiency (GSD VII, Tarui disease)
		• Phosphorylase kinase deficiency (GSD IX)
	Lipid metabolism disorders are also in the differential but generally have a prominent exercise component, in addition to symptoms being worsened by fasting, which is not a factor in Pompe disease.
	Mitochondrial myopathies are in the differential but often have other systemic symptoms.

Diagnostic workup

An infant with poor feeding, severe weakness, and hypotonia, in addition to cardiomyopathy, should undergo further testing for possible infantile-onset Pompe disease (IOPD). The evaluation consists of the following laboratory tests:

	• CXR: cardiomegaly, lung volume reduction, atelectasis
	• EKG: huge R wave, short PR interval, and broad QRS complex
	• Echocardiogram: cardiomyopathy
	• Serum creatine kinase: elevated
	• Hepatic transaminases (ALT and AST): elevated
	• Lactate dehydrogenase: elevated
	• Acid alpha-glucosidase activity in dried blood spots or white blood cells: decreased (usually less than 1% of normal controls in IOPD)

Results obtained as above, in addition to the clinical findings, should prompt immediate inquiry into procuring enzyme replacement for the patient because the timing of initiation of treatment has profound consequences on survival (see Management section).

Further confirmatory testing:

	Urinary glucose tetrasaccharide: elevated
		Urinary glucose tetrasaccharide (Glc4) is also often elevated in patients with Pompe disease and other glycogen storage diseases (11). The level of Glc4 is correlated with disease severity; therefore, it is less sensitive in patients with late-onset Pompe disease. The level of Glc4 is also correlated with the age of diagnosis, the extent of glycogen accumulation, the stage of disease, and the severity of the pathogenic variants (19).
	Molecular genetic testing
		GAA sequencing is performed to confirm the diagnosis of Pompe disease. There are more than 900 variants of GAA listed in the Pompe disease variant database, with over 400 variants identified as pathogenic. Additionally, pseudodeficiency alleles have been described, which can result in misleading low levels of acid alpha-glucosidase activity (04).

Newborn screening, which involves analysis of acid alpha-glucosidase enzyme activity in dried blood spots, has affected how Pompe disease is diagnosed. Pompe disease is on the newborn screen in 32 of the 50 United States and the District of Columbia (HRSA: Newborn Screening in Your State). Positive tests should prompt confirmatory testing by molecular testing (GAA gene sequencing), although there is some variability depending on the state and country. Infants with positive newborn screens should be evaluated for clinical signs and symptoms of Pompe disease before the confirmatory testing has resulted. The Pompe Disease Newborn Screening Working Group, a group of international experts on newborn screening and Pompe disease, has published two management algorithms based on whether the NBS laboratory protocol includes DNA sequencing or not (04).

Diagnostic algorithm for evaluation after a positive newborn screen for Pompe disease with DNA sequencing

Part of the NBS laboratory protocol. (Modified from: Burton BK, Kronn DF, Hwu WL, Kishnani PS; Pompe Disease Newborn Screening Working Group. The Initial Evaluation of Patients After Positive Newborn Screening: Recommended Algo...
Diagnostic algorithm for evaluation after a positive newborn screen for Pompe disease without DNA sequencing

Part of the NBS laboratory protocol. (Modified from: Burton BK, Kronn DF, Hwu WL, Kishnani PS; Pompe Disease Newborn Screening Working Group. The Initial Evaluation of Patients After Positive Newborn Screening: Recommended Algo...

Late-onset Pompe disease has a wide spectrum of presentation and should be suspected in children and adults with progressive limb-girdle weakness, especially in combination with respiratory muscle involvement. Often overlooked is a history of poor exercise tolerance and difficulty climbing stairs. Testing consists of some of the same studies as for IOPD, and more frequently, electromyography, muscle MRI, and muscle biopsy.

	• CXR: less cardiomegaly, but there may be reduced lung volume and atelectasis
	• Electrocardiogram and echocardiogram: evidence of cardiac hypertrophy, less severe than in IOPD
	• Serum creatine kinase: often normal, some patients will have a mild increase
	• Hepatic transaminases (ALT and AST): often elevated
	• EMG and nerve conduction study: myopathic pattern with spontaneous activity, there may be myotonic discharges, often isolated to the paraspinal muscles in adults (12)
	• Acid alpha-glucosidase activity in dried blood spots or white blood cells: decreased (usually less than 30% of normal controls)
	• Muscle MRI: paravertebral and abdominal muscle
	• Muscle biopsy: vacuolated fibers filled with glycogen on periodic acid Schiff or acid phosphatase staining

In the last decade, it has become common practice to move to next-generation sequencing-based disease-specific gene panels to diagnose patients who present with muscle weakness, oftentimes prior to, or in lieu of, muscle biopsy. In the United States, molecular testing is sometimes done before acid alpha-glucosidase enzyme assay as part of the diagnostic workup in a patient who presents with progressive muscle weakness. Gene panels for neuromuscular disease generally do include the diseases that are in the differential for Pompe disease, in addition to many other neuromuscular diseases.

Management

The management of Pompe disease requires an extensive multidisciplinary team to address multisystem manifestations to assess cardiology, respiratory function, speech and language, physiotherapy, neurology, genetics, and metabolism (07). Furthermore, the long-term monitoring of patients with Pompe disease requires serial multisystem evaluations. This will include measures of cardiac function, swallow function, and respiratory parameters (eg, pulmonary function tests, polysomnography, and exercise tests) (07).

Two emerging treatments for patients with Pompe disease include enzyme replacement therapy and various gene replacement therapies. Additional experimental therapies have targeted oxidative stress, the inhibition of autophagy, the stimulation of lysosomal exocytosis, the modulation of mTORC1 signaling, splicing dysfunction, and substrate reduction (17; 15).

Enzyme replacement therapy

	•⁠ ⁠Enzyme replacement therapy is the current standard of care for Pompe disease.
	•⁠ ⁠Some patients develop antibodies to intravenous recombinant human acid alpha-glucosidase and have a poorer response to treatment. However, immune tolerance induction protocols have been developed to overcome this obstacle

Enzyme replacement therapy, which involves exogenously administered functional enzymes, is currently the standard of care for treating Pompe disease (14; 22; 15). It also represents the first instance of using a recombinant enzyme to treat skeletal muscle (14). In 2006, enzyme replacement therapy in the form of recombinant human acid alpha-glucosidase was approved for clinical use in patients with Pompe disease in Europe and the United States (14; 22). It is typically administered intravenously every 2 weeks at a recommended dose of 20 mg/kg. However, higher doses (up to 40 mg/kg) are recommended for infantile-onset Pompe disease (IOPD) (22).

The most reliable effect of enzyme replacement therapy has been on cardiac pathology and function regardless of disease severity. In contrast, the skeletal muscle response is variable and less impressive (14). Furthermore, novel recombinant human acid alpha-glucosidases, such as avalglucosidase, have been produced to increase the affinity for key receptors (Lab). Avalglucosidase was approved for treating late-onset Pompe disease in 2021 (15).

Patients who are identified with IOPD should be treated with enzyme replacement therapy as soon as possible because skeletal and cardiac muscle injury has already occurred at birth. A fetus with IOPD was treated with alglucosidase alfa through the umbilical vein beginning at a gestational age of 24 weeks (05).

Patients with IOPD who have detectable acid alpha-glucosidase protein are categorized as cross-reactive immunologic material positive (CRIM+), whereas those who do not are categorized as cross-reactive immunologic material negative (CRIM-). Most CRIM- patients develop antibodies to intravenous recombinant human acid alpha-glucosidase and have a poorer response to treatment. A small subset of CRIM+ patients also develop high, sustained antibody titers and have a worse treatment outcome (01).

Due to the negative effect of high, sustained antibody levels on treatment response, immune tolerance induction protocols have been used after the development of a high antibody response. They are also used prophylactically on patients with CRIM- IOPD who are expected to mount an antibody response to acid alpha-glucosidase (18).

Treatment on the horizon: gene replacement strategies

	• Although gene therapy has the potential to be a more convenient form of therapy for Pompe disease (that can also potentially treat CNS complications), clinical trials are still in progress.
	• Two potential forms of gene therapy for Pompe disease include adeno-associated virus vectors and lentiviral vector-mediated gene therapy.

Because Pompe disease is caused by defects in a single gene, it is an ideal target for gene replacement strategies (22). Gene therapy involves the delivery of a functional copy of a gene into a patient’s tissue without replacing or removing the mutated copy of the gene harbored within the patient’s own genome (14).

In comparison to enzyme replacement therapy, gene therapy could offer several benefits to patients with Pompe disease (14; 17). Because gene therapy may require only a single treatment, it has the potential to be more convenient and cheaper than enzyme replacement therapy. Both adeno-associated virus vectors and lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy can potentially provide effective therapy for Pompe disease (24).

Adeno-associated virus vectors are the preferred form of gene therapy in preclinical studies and clinical trials because they are nonpathogenic and have low immunogenicity compared with other vectors (14). However, animal studies of adeno-associated virus vector therapy have been somewhat disappointing, with minimal improvements in motor function despite increased acid alpha-glucosidase activity in the injected muscle (15).

As an alternative to adeno-associated virus-based therapy, lentiviral vectors are also being used in ex-vivo hematopoietic stem cell gene therapy for lysosomal storage disorders (24). Based on mouse studies, treatment with lentiviral vectors shows systemic acid alpha-glucosidase expression and the correction of neurologic deficits (24). An additional benefit of lentiviral-hematopoietic stem and progenitor cell gene therapy is the ability of modified hematopoietic stem and progenitor cells to differentiate into microglial cells and engraft into the CNS compartment (24).

Outcomes

	• Clinical trials of enzyme replacement therapy have shown promising results for infantile-onset patients, including sustained improvements in cardiac parameters and motor development. However, enzyme replacement therapy is not likely to improve CNS impairments.
	• Clinical trials of enzyme replacement therapy in late-onset patients show moderate improvements in motor and respiratory function that tend to plateau over a couple of years.
	• Adeno-associated virus gene therapy for infantile-onset and late-onset Pompe disease has also been investigated in several early-phase clinical trials. Despite concerns about adverse events, the partial restoration of acid alpha-glucosidase enzymatic activity has been demonstrated.

Although clinical trials in patients with IOPD have shown variable results, recombinant human acid alpha-glucosidase treatment appears to improve survival while decreasing the risk of invasive ventilation and preserving cardiac function (14; 22; 15). Many patients with IOPD on enzyme replacement therapy have demonstrated sustained improvements in cardiac parameters with marked decreases in left ventricular mass index and left ventricular wall thickness, correction of abnormal ECG parameters, and improvements in cardiac function (14). Other patients have achieved major milestones in motor development (14). Despite these promising results, the data suggest that IOPD remains a life-threatening condition even with the emergence of enzyme replacement therapy (14; 02). Furthermore, enzyme replacement therapy cannot cross the blood-brain barrier, which is problematic for patients with IOPD and associated CNS impairments that tend to accrue with prolonged survival (14; 13).

Clinical trials have also demonstrated that enzyme replacement therapy stabilizes motor and respiratory function in patients with late-onset Pompe disease (23; 14; 22). In most patients, the treatment was associated with improved ambulation, modest motor function improvements, increased walking distance, and a modest increase or stabilization of pulmonary function (23; Kohler et 2018). However, follow-up studies revealed significant variability in response to therapy for patients with late-onset Pompe disease (23; 14). More specifically, a mild or moderate response is often observed during the first 2 to 3 years of treatment, followed by a plateau or slight decline (22).

A disadvantage of enzyme replacement therapy for patients is that it is often inconvenient and painful. For instance, enzyme replacement therapy is often delivered biweekly via intravenous drip over the course of 6 to 7 hours per treatment (14). Enzyme replacement therapy may also cause allergic reactions due to immunoglobulin G antibodies (02). However, in general, these are mild or moderate reactions. Rarely, severe anaphylactic reactions may occur as isolated events due to immunoglobulin E antibodies (02).

As of 2024, gene therapy using the intravenous delivery of adeno-associated virus vectors is in phase I/II clinical trials for late-onset and infantile-onset Pompe disease. The first trial evaluating the adeno-associated virus gene therapy approach was published in 2009. A partial restoration of acid alpha-glucosidase enzymatic activity was observed in bone marrow and peripheral blood cells, with less efficacy in reducing glycogen storage in the heart (15). Several modifications to adeno-associated virus serotypes have been used in gene therapy trials with enhanced safety and long-term efficacy across target organs to correct the pathophysiology across the CNS, heart, and skeletal muscles (14; 24). Promising data from late-onset Pompe disease trials indicate that most participants met the criteria to discontinue enzyme replacement therapy after several months of gene therapy (06). Nevertheless, there are ongoing concerns about the potential of adeno-associated virus vector infusions to cause inflammatory toxicities, complement activation, cytopenias, and marked hepatotoxicity (24).

References

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20: Rohman PJ, Scott E, Richfield L, Ramaswami U, Hughes DA. Pregnancy and associated events in women receiving enzyme replacement therapy for late-onset glycogen storage disease type II (Pompe disease). J Obstet Gynaecol Res 2016;42(10):1263-71. PMID 27384519
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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Agnes Chen MD

Dr. Chen of Harbor-UCLA Medical Center received a research grant from Takeda.
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Yun Cheong Chang MD

Dr. Change of Morsani College of Medicine at the University of South Florida has no relevant financial relationships to disclose.
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Editor

Aravindhan Veerapandiyan MD

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
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Former Authors

Seiichi Tsujino MD
George M Hadjigeorgiou MD
Priya S Kishnani MD
Aditi Korlimarla MBBS

Patient Profile

Age range of presentation: IOPD: 0 month to 65+ years

LOPD: 12 months to 65+ years
Sex preponderance: male=female
Heredity: autosomal recessive
Population groups selectively affected: French Guiana (1 in 2000)

Taiwan (1 in 15,000)
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Pompe disease: E74.02
ICD-11: Glycogen storage disease: 5C51.3

Familial-genetic hypertrophic cardiomyopathy: BC43.10
OMIM: Pompe disease: 232300

Glycogen storage disease: 237967002

The GAA gene: 606800

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Pompe disease

Associated Disorders

Acid alpha-1,4- and alpha-1,6-glucosidase deficiency
Acid maltase deficiency
Pompe disease, myopathic form
Cardiomegalic Pompe disease
Intracranial aneurysms
- Infantile Pompe disease
- Late-onset Pompe disease
- Pompe disease
- Respiratory insufficiency

Differential Diagnosis

Lysosome-associated membrane protein 2 deficiency
Debrancher deficiency
Glycogen branching enzyme deficiency
Duchenne-Becker muscular dystrophy
limb-girdle muscular dystrophies
- dystroglycanopathies
- LAMA2-related muscular dystrophy laminopathies
- mitochondrial DNA depletion syndrome 2
- neutral lipid storage disease with myopathy
- mitochondrial diseases
- fatty acid oxidation disorders
- glycogen storage diseases
- glycogen branching enzyme deficiency
- glycogen storage disease type V
- phosphofructokinase deficiency
- phosphorylase kinase deficiency
- lipid metabolism disorders
- mitochondrial myopathies

Also Relevant

Congenital muscle fiber-type disproportion
Neurogenetics and genetic and genomic testing
Paraspinal neuromuscular syndromes
Screening of newborns for neurogenetic abnormalities
Sleep and neuromuscular and spinal cord disorders
- Spinal muscular atrophy
- Spontaneous carotid and vertebral artery dissection

Pompe disease

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Genetics

Cell biology

Pathology

Pathophysiology

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Enzyme replacement therapy

Treatment on the horizon: gene replacement strategies

Outcomes

Special considerations

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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