Author(s): Sara Flores, MD, Kristen Clark, MD, Sneh Patel, MD
Originally published: November 21, 2024 Last updated: November 21, 2024
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Disease/Disorder

Definition

Pompe Disease (PD), also referred to as Type 2 Glycogenesis or Acid Maltase Deficiency, is a glycogen storage disease that occurs due to an inherited deficiency in lysosomal acid-α-glucosidase (GAA, or acid maltase), an enzyme encoded on chromosome 17q25 and which is found in several cell types, including skeletal and cardiac myocytes. This disorder is inherited in an autosomal recessive manner, and the enzymatic defect results in glycogen spillage and accumulation in several tissues of the body, leading to widespread systemic manifestations due to tissue dysfunction.1

Etiology

Because the process of glycogen storage is multifaceted, PD has multiple areas of underlying dysfunction. Acid maltase is synthesized in the rough endoplasmic reticulum and undergoes posttranslational modifications (e.g. glycosylation, folding, mannose 6-phosphate (M6P) modification, and cleavage) before fusing with the endocytosed glycogen-containing lysosome. Normally, once fused, this leads to glycogen uptake and eventual metabolism; when deficient, the lysosome is unable to relieve itself of its accumulated glycogen, leading to progressive enlargement of the lysosome, eventual rupture, and glycogen spillage and buildup across different organs of the body.2

Epidemiology

Previously, the incidence of PD was estimated near 1/40,000 live births, with approximately 25% of these cases being infantile onset and 75% being late-onset.3 Incidence varies across the globe, with certain higher risk populations with higher incidence rates having been identified, including those of African American, Taiwanese, Dutch, or Israeli descent.4 More recently, with the advent of newborn screening for PD, these estimates have been adjusted – PD may be more common than previously thought. For example, screening programs in California reported a rate of approximately 1/25,000 live births,5 while in an incidence Japan closer to 1/37,000 was noted.6 

Interestingly, mutations vary across ethnicity and region. For example, c.-32-13T>G (IVS1), which leads to low residual enzyme activity, is common in Caucasians. In comparison, c.del525, del exon18, and c.925G>A (p.Gly309Arg) mutations are frequent in Dutch people, while individuals with Taiwanese heritage more often share a c.1935C>A (p.Asp645Glu) mutation. Individuals of Central African descent and African Americans are more likely to have the c.2560C>T (p.Arg854Ter) mutation.1,7

Patho-anatomy/physiology

PD is a glycogen storage disease that occurs due to an inherited deficiency in lysosomal acid-α-glucosidase. Several mutations have been identified to underlie this phenomenon. Mutations can affect GAA protein synthesis, posttranslational modifications, or lysosomal trafficking. Depending on its phenotype, PD can be of variable age of onset and severity of disease, and this is partly dependent on the underlying mutation in question.  The underlying mutation may determine the amount of residual enzymatic activity.1

Disease progression

PD is classified into two forms according to age of onset. The infantile form (infantile-onset PD, or IOPD) manifests within the first few years of life, while the adult form (late-onset PD, or LOPD) presents closer to mid-life, around 30 years of age.1  

For IOPD, two subtypes are recognized: classic IOPD, which is more severe, and non-classic IOPD, which is less severe and tends to present in slightly older children. Classic IOPD manifests within the first year of life, and is marked by progressive hypertrophic cardiomyopathy, along with the more common symptoms of muscle weakness, hypotonia, motor milestone delay, and respiratory distress. Given its devastating effects on the cardiovascular system, it is unsurprising than only a small percent of classic IOPD patients survive beyond 1 year of age. In comparison, non-classic IOPD has a lower risk for cardiomyopathy (and if present, often lacks left ventricular outflow obstruction), and is associated with a lower risk of death due to cardiac arrest. However, its patients also have a high risk of childhood mortality, often due to respiratory arrest.1

In either form of IOPD, symptoms start early in life, and death can occur very soon if the disease remains untreated. In comparison, for LOPD, symptoms are similar but less severe and more insidious in progression, leading to longer average lifespan. LOPD has a much lower rate of severe cardiac manifestations than non-classic IOPD. Regardless, LOPD still causes muscle weakness, loss of ambulation, and respiratory distress when the diaphragm becomes involved. As such, an older individual with a history of limb-girdle weakness that slowly progresses over years is more suggestive of LOPD. This proximal weakness is often accompanied by postural changes such as lordosis, camptocormia, and scapular winging.1,4  

Essentials of Assessment

History

PD can manifest at varying severity levels and at varying age of onset. Glycogen buildup can lead to different manifestations – most commonly observed are involvement of the musculoskeletal system, but other affected systems include the cardiovascular system (cardiomyopathy and arrythmia), respiratory system (respiratory insufficiency), and other systemic manifestations (dysarthria/dysphagia, bony abnormalities like osteopenia and scoliosis, central nervous system irregularities e.g. intracranial aneurysms, and incontinence secondary to sphincter involvement).1,4

Physical examination

Infantile-onset PD manifests early in childhood and is marked by muscle weakness, hypotonia, motor milestone delay, respiratory distress, and progressive hypertrophic cardiomyopathy. Late-onset PD presents closer to mid-life with muscle weakness, loss of ambulation, and respiratory distress when the diaphragm becomes involved. An older individual with limb-girdle weakness that slowly progresses over years is suggestive of LOPD. In either form, proximal muscle weakness is often accompanied by postural changes such as lordosis, camptocormia, and scapular winging.

Functional assessment

General recommendations include frequent evaluations for respiratory and cardiac status, with a goal to promote continued independence and function without inducing muscle soreness or prolonged recovery times after activity.4 The following assessments are recommended for patients with PD: pulmonary function assessments (6 minute walk test, pulmonary function test), cardiac evaluation (echocardiogram, ECG, chest x-rays), occupational and physical therapy evaluations (e.g. bracing for contractures and scoliosis) and functional evaluations for durable medical equipment (e.g. wheelchair).32

It is important to note that while these recommendations seem comprehensive, they do have their limitations. For example, the 6-minute walk test, which is a mainstay in functional evaluation, is often not sensitive in younger patients. Similarly, forced vital capacity, often used to assess diaphragm health, does not change till much later in the disease. As such, continued care with routine and repeat assessments is often needed to follow the progressive course of the disease.1 Furthermore, these recommendations should be tailored to age and stage of the disease.26

Laboratory studies

Generally, workup of symptoms consistent with PD begins with bloodwork. Several enzymes may be elevated, with perhaps the most commonly tested enzyme being creatine kinase (CK). CK will typically not be higher than 2000 U/L, instead averaging at the moderately elevated level of 600–700 U/L. Of note, normal CK levels do not preclude the diagnosis. Besides CK, elevations in aminotransferases (ALT/AST) and lactate dehydrogenase (LDH) may also be observed. A more specialized lab test is urinary glucose tetrasaccharide (Glc4), which can be elevated in PD, and is sometimes followed as a response to active treatment of PD.1,4

Imaging and supplemental assessment tools

Besides bloodwork, assessment of affected organ systems is also an important step.

One can consider magnetic resonance imaging (MRI) to assess the extent of muscle dysfunction, or to identify potential target areas for biopsy. Muscle biopsies with periodic acid-Schiff (PAS) and acid phosphatase can be used as a supportive tool.  Under histological examination, slides may show evidence of vacuolar myopathy secondary to glycogen deposition, or acid phosphatase-positive lipofuscin inclusions. Other assessments include echocardiogram and electrocardiogram (ECG) to assess for cardiomyopathy and resultant arrythmias, pulmonary function tests to assess for restrictive respiratory disease, and electromyography (EMG) which could show an irritable myopathic pattern disproportionately affecting the proximal muscles with associated myotonic discharges in affected muscles.1,4

Gold standard diagnosis involves assessing for GAA enzymatic activity levels, which can be tested with dried blood, skin fibroblasts, or muscle biopsy. GAA enzymatic activity is measured using a fluorometric method, tandem mass spectrometry, or microfluidics combined with fluorometry. In classic IOPD, enzyme activity is near absent (< 1%), whereas residual levels (up to 30% of normal) may be appreciated in the later onset form.1,4

Of note, newborn screening now includes GAA activity testing. Because clinical manifestations of PD can be delayed for several months to years, newborn screening provides a chance for early diagnosis and initiation of treatment. This is especially important for severe cases of IOPD, as initiating treatment early before irreversible changes occur is an important prognostic factor.8

Early predictions of outcomes

Younger age, better clinical status at time of initiation, and female gender have appeared to be positive prognostic factors for the effect of enzyme replacement therapy in the treatment of PD.13

Social role and social support system

A major consideration is the mental health aspect of this progressive disorder. Studies have shown increased prevalence of anxiety and depression in patients and families of patients affected by PD.28 Involving mental health specialists in the multidisciplinary team approach is an important factor in the treatment of patients with PD.

Professional issues

There are significant challenges in the management of patients with PD. The currently available treatments lose effectiveness over the long run and have inconsistent penetration in certain muscles. More definitive gene therapy and enzyme replacement strategies are currently in development and testing.4

Another challenging situation arises when PD is diagnosed genetically at birth with newborn screening panels (NBS) before any symptoms are present. This occurs often because LOPD is much more common than IOPD with LOPD accounting for 75% of all cases of PD. Currently, there is no clear consensus on how to manage these patients.4 The optimal time to initiate enzyme replacement therapy in pre-symptomatic and asymptomatic patients has not been determined.4

Rehabilitation Management and Treatments     

Available or current treatment guidelines

Until a few decades ago, PD was only treated via supportive care. While there is no cure for PD, enzyme replacement therapy (ERT) can reduce or slow the progression of the disease. A turning point came in 2006, when ERT with alglucosidase alfa was approved for human use. The trailblazing research that led to approval for ERT began from clinical trials that focused on applying enzyme replacement to patients with other lysosomal storage disease (namely, Hunter syndrome and Hurler syndrome). Treatment with exogenously administered culture fibroblasts was able to correct the two enzymatic deficiencies.9,10 Subsequent studies paved the way for approval of ERT for other functional enzyme deficiencies to alleviate symptoms, including that of PD.1

Studies focusing on the effects of ERT have suggested an overwhelmingly positive response. One major study, the “Late Onset Treatment Study” (LOTS) was a randomized, double-blind, placebo-controlled, multicenter study that demonstrated the safety and efficacy of alglucosidase alfa in 90 children and adults with late-onset Pompe disease. Specifically, it found that enzyme replacement therapy with alglucosidase alfa in LOPD led to significant improvements in slowing the decline of ambulation, extremity function, and respiratory function, findings which were supported by later studies with similar objectives.11,12 Such studies also suggest that ERT tends to promote gains with respect to the cardiovascular system, more-so than the musculoskeletal system.1

Unfortunately, despite the initial effectiveness of therapy, this responsiveness to ERT seems to wear off at the 2–3 year mark, and many patients tend to return to their slow decline.1,4 Demonstrating this finding, one clinical trial of 18 infants <6 months of age that were treated for 52 weeks reported improvements in cardiac function in the short term with associated improved survival rate (reduced mortality by 99%) and ventilator dependence (reduced risk by 92%), but during the 3 year follow-up period, survival rate (67.5%) and ventilation dependence rate (50%) drastically decreased and increased, respectively. Furthermore, only 40% of those who initially were able to walk in the early stage of the study were still functionally capable of walking at 3 years.14 Because of this lack of a sustained response, two new forms of ERT with modified chemical compositions that were theorized to help with cell targeting and cellular uptake were tested in clinical trials compared to alglucosidase alfa. The new forms of ERT included avalglucosidase alfa (COMET trial)15 and cipaglucosidase alfa plus miglustat (PROPEL trial).16 While both new forms of ERT were shown to be non-inferior to alglucosidase alfa, neither met the criteria for superiority. However, data is still being followed for long term differences, beyond 2-3 years post treatment.

Given these considerations, the effects of ERT prolonging life in patients with severe PD up to 2-3 years further should be considered, as many patients do not survive ventilator free beyond 3 years of age, and respiratory infections and invasive ventilation come with its own risks and benefits beyond the manifestations of PD.1,4 Thus, while the advent of ERT has made a profound impact on the natural course of PD, many patients will continue to be burdened by the disease despite treatment. However, the limitations of ERT have sparked new research towards emerging therapies, with a goal to be used as an alternative to or in conjunction with ERT.

Coordination of care

In addition to the disease-modifying treatments, overall management of PD requires symptomatic management and screening for complications. To date, various treatment guidelines for PD have been recommended, and while all differ to some degree, nearly all agree that patients benefit most from a team management perspective that involves a multidisciplinary approach. The suggested approach involves some combination of therapists (physical therapy, speech therapy, respiratory therapy, occupational therapy, and dieticians), genetic counselors, and physicians for proper management. Coordination and communication between different medical teams such as neurology, genetics, physiatry, pulmonology, gastroenterology, and cardiology can be crucial.

Patient & family education

Patient and family education for PD depends on which type of the disease the patient has. Patient education for the infantile forms of the disease is more beneficial for the caregivers of the baby born with PD. In general, later disease onset correlates with slower disease progression and longer life expectancy.30,31 Therefore, patients with the late onset form of PD may benefit from therapeutic, dietary and exercises recommendations to slow disease progression.30,31

Without diagnosis and early treatment with ERT, infantile forms of PD are often fatal within the first year of life due to heart failure.30 It is critical that PD in infants is quickly diagnosed and ERT initiated prior to the onset of severe symptoms. Studies suggest ERT can improve life expectancy, but more research is still needed.30

For individuals diagnosed with LOPD, doctors may recommend support therapies in addition to ERT. Physical therapy, occupational therapy, and speech therapy may improve muscle strength and caloric intake.30 Pulmonary rehabilitation may also be a treatment option to assist in strengthening the respiratory muscles and to delay or reduce the need for mechanical ventilation.31

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

A major consideration often ignored is the mental health aspect of this progressive disorder. Studies have shown increased prevalence of anxiety and depression in patients and families of patients affected by PD.28 The knowledge of the diagnosis in individuals without symptoms or functional loss can also cause anxiety and depression. Patients and their families often experience significant stress due the uncertainty of the prognosis, the drastic modifications to lifestyle due to the disease and concern for unnecessary treatments that parents may want their children to undergo in an effort to slow down the disease.29 As such, involving mental health specialists in the multidisciplinary team approach is an important consideration.

Cutting Edge/Emerging and Unique Concepts and Practice

An alternative to ERT is gene therapy, which involves delivery of a functional copy of a gene into a genome without removing the mutated copy. Delivery relies on using viral vector for delivery, such as adenoviruses or retroviruses, and could offer several benefits, including cost effectiveness and time effectiveness with less lengthy treatment sessions compared to ERT.1,4 Furthermore, gene therapy has the potential to be more efficacious, with some research suggesting that certain viral vectors have the ability to cross the blood brain barrier and thus theoretically may help to improve neurological symptoms. 17 However, several obstacles have also come to light, including the safety of retroviral vectors (concerns for random integration causing unintended mutations), and activation of nearby oncogenes due to the long terminal repeats that flank each end of the virus endogenous genome.1,4

Another promising treatment is genome editing via CRISPR/Cas. This system relies on delivery of Cas9 protein and an RNA guide sequence to target and edit existing mutations in the genome, either by nonhomologous end joining (NHEJ) or homology-directed repair (HDR).1,4 Preclinical trials have been promising – animal studies using an NHEJ-based process have successfully improved pathology in mdx mice (model for Duchenne’s muscular dystrophy),(18) and in dy2J/dy2J mice (model for congenital muscular dystrophy type 1A).(19) A major barrier to this therapy is implementation – if the target tissue (e.g. myocytes) do not express the DNA repair proteins necessary for NHEJ or HDR at high levels, this treatment course may not be viable.1,4

Disrupting glycogen metabolism is also a potential target. Several treatments are being studied, including those that inhibit glycogen synthesis and those that stimulate lysosomal exocytosis of deposits outside of the cell. Substrate reduction therapy is one such approach, which is designed to prevent accumulation of glycogen by inhibition of enzymes involved in its synthesis, such as glycogen synthase.1,4 Preclinical studies that were able to inhibit glycogen synthase in mice have reported decreased glycogen build-up, leading to improved cardiac function and preserved motor ability in the mice due to muscle health.20 Of note, genetic suppression of autophagic genes in skeletal muscles, which also works along this pathway, is currently being studied in the preclinical stage as a potential post-ERT adjunctive treatment to promote further clearance of glycogen accumulation compared to ERT alone.21 The major utility of therapies that target the metabolism pathway lies in their potential ability to circumvent a common obstacle of other treatments – inefficient delivery to skeletal muscle cells.1,4  

Gaps in the Evidence-Based Knowledge

Little literature exists on how different training regimens many influence disease severity.22 A few studies have been conducted on the effects of resistance training with concomitant ERT, and all three agreed there is a positive effect on strength and endurance of various muscle groups, such as the muscles of respiration and core stability muscles.23-25 However, these studies were limited by small sample size (n<25), thus could benefit from future study on a larger scale. The findings of such studies bolster the recommendation to start patients on aerobic therapies and avoiding overly stimulating or exhaustive exercise.

One study specifically focusing on respiratory therapy suggests that in earlier stages, aerobic rehabilitation should be performed to maximize respiratory function and core strength (e.g. forced vital capacity, muscle strength tests like MIP/MEP).  With continual progression, aerobic rehabilitation should shift towards general reduction of dyspnea and improved life quality while maintaining some independence and function. In more severe cases, rehabilitation should instead focus on therapies that help to reduce aspirations, ventilator hours, and to maximize functional independence to perform activities of daily living in the latter stages of life.27

References

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  17. Fu H, DiRosario J, Killedar S, Zaraspe K, McCarty DM. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood–brain barrier gene delivery. Molecular Therapy. 2011;19(6):1025-33.
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  29. Pruniski B, Lisi E, Ali N. Newborn screening for Pompe disease: Impact on families. Journal of inherited metabolic disease. 2018;41:1189-203.
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  32. Reuser, A & Dick, J (January 18, 2024). Pompe Disease. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/pompedisease. Accessed October 30, 2024.

Author Disclosure

Sara Flores, MD
Nothing to Disclose

Kristen Clark, MD
Nothing to Disclose

Sneh Patel, MD
Nothing to Disclose