Pompe Disease

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Written by: Dr Jeremy Steinberg – created: 5 March 2023; last modified: 2 April 2023

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Pompe clinical features.jpg
Clinical features in Pompe disease. Atrophy of the quadriceps muscle (A), scapular winging (B), and ptosis (C) as notable clinical features in adults with Pompe disease.[1]
Pompe Disease
Synonym GSD II, acid maltase deficiency
Inheritance Autosomal recessive
Genetics Biallelic pathogenic variant in the GAA gene
Pathophysiology GAA deficiency causes glycogen to accumulate in lysosomes and cytoplasm, resulting in tissue damage and various clinical features depending on the form of the disease.
Classification Pompe disease presents in two forms: infantile-onset, characterized by hypertrophic cardiomyopathy and hypotonia, and late-onset, characterized by limb girdle and axial weakness and respiratory insufficiency in late disease.
Clinical Features Limb girdle weakness, exercise intolerance, chronic pain
Tests Blood test for enzyme activity, genetic testing for GAA gene mutations, and muscle biopsy in some cases
DDX Other glycogen storage diseases, muscular dystrophies, and metabolic myopathies
Treatment Enzyme replacement therapy with intravenous alglucosidase alfa and supported by multidisciplinary care

Pompe disease is a Lysosomal Storage Disease (LSD), also a type of Glycogen Storage Disease (GSD II), that is caused by a deficiency in acid alpha-glucosidase (GAA), also known as acid maltase. GAA deficiency results in the accumulation of glycogen in lysosomes in all tissues. Unlike other GSDs, which affect glycogen synthesis or regulation of energy production, GAA deficiency affects lysosomal-mediated degradation of glycogen. GAA deficiency can present in two forms: an infantile-onset form, which typically involves hypertrophic cardiomyopathy and hypotonia, and a late-onset form, which is characterised by limb girdle and axial weakness and respiratory insufficiency in late disease.


According to a study in the Netherlands that screened newborn blood spots for the three common variant alleles in that population, the estimated incidence of GAA deficiency was 1 in 40,000. Based on carrier frequencies, the predicted incidence was 1 in 138,000 for classic infantile disease and 1 in 57,000 for late-onset disease. However, studies in Austria and the United States investigating strategies for newborn screening found a higher incidence (1 in 8686 and 1 in 21,979, respectively) for the combined early- and late-onset forms.[2][3]


Lysosomal GAA plays a crucial role in breaking down both alpha-1,4- and alpha-1,6-glucosidic linkages in the acidic environment of the lysosome. When the enzyme is deficient, glycogen accumulates in lysosomes and cytoplasm, leading to tissue damage. This deficiency may also affect vesicle systems linked to lysosomes and receptors, including glucose transporter 4, that move through these organelles.

The activity of the enzyme is linked to genotype and is either absent or very low in individuals with infantile-onset phenotype. In those with the late-onset phenotype, the enzyme activity is reduced to varying degrees.


GAA deficiency is an autosomal-recessive disorder with significant genetic diversity. The disease is caused by mutations in the gene that encodes lysosomal acid alpha-1,4-glucosidase (GAA), which is located at 17q25.2-q25.3. It has high allelic heterogeneity with hundreds of different mutations having been identified as the cause of the disorder. There are also some pseudodeficiency alleles which don't cause the disease but result in lower GAA enzyme activity leading to a false-positive diagnosis.

Clinical Features

Muscle weakness in adults with Pompe disease. Distribution of skeletal muscle weakness (A), severity of muscle weakness of the individual muscle groups (B), and involvement of the individual muscles over time (C) in 94 adults with Pompe disease.[1]

Infantile Form

Infants with infantile-onset GAA deficiency typically present in the first few months of life with cardiomyopathy and severe muscular hypotonia.

Late Onset Form

Patients with late-onset GAA deficiency present at any age and have variable age of onset and clinical and histologic features. They do not experience cardiomyopathy. The primary clinical finding in late-onset GAA deficiency is a limb girdle and axial pattern of skeletal muscle myopathy, which can range from asymptomatic to severe. The myopathy is typically progressive over time. Chronic pain and exercise intolerance are common. Ptosis (often unilateral) and bulbar weakness occur in around a quarter of patients, and scapular winging in around a third.[1]

Patients typically experience delayed gross-motor development and progressive weakness in a limb-girdle distribution. Involvement of the diaphragm is common, leading to respiratory insufficiency early in the course of the disease. Camptocormia can occur.

Other symptoms, including gastrointestinal symptoms, dilative arteriopathy, carotid artery dissection, and basilar artery dolichoectasia, may also occur in some patients.


Affective individuals typically have moderately elevated serum creatine kinase levels (around +/- 500) and decreased leukocyte GAA activity. However normal CK does not rule out the disease, especially in later stages. GAA activity is typically less than 10 percent of normal in tissues such as fibroblasts and muscle.

Muscle biopsy reveals vacuolar myopathy with glycogen storage in lysosomes and free glycogen in the cytoplasm seen by electron microscopy.


Infantile-onset GAA deficiency should be suspected in infants presenting with severe hypotonia and cardiac insufficiency. Commonly seen laboratory abnormalities include elevated levels of creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST). The electrocardiogram typically shows a short PR interval with giant QRS complexes in all leads, which may suggest biventricular hypertrophy, but this is not unique to GAA deficiency.

Late-onset GAA deficiency should be suspected in individuals with progressive proximal weakness in a limb-girdle distribution. The electromyogram may show characteristic myopathic discharges that are sometimes associated with abundant myotonic and complex repetitive discharges, especially in the paraspinal muscles. Pulmonary function testing typically reveals a substantially reduced forced vital capacity (FVC) in adults. The forearm ischaemic lactate test is normal in patients with GAA deficiency.

GAA enzyme activity can be measured in white blood cells or dried blood spots, and the addition of acarbose is recommended to improve the sensitivity of the assay. Gene sequencing is the preferred test for confirming the diagnosis. Confirmation of the diagnosis requires the identification of two pathogenic variants in the GAA gene. GAA enzyme activity measurement in fibroblasts or muscle biopsy can be performed if blood tests are inconclusive. However, muscle biopsy is more invasive and has a higher risk of false positives due to poor sample processing.

At the time of writing the New Zealand Newborn Metabolic Screening Programme does not include testing for Pompe disease.[4]

Natural History

In the absence of treatment, most patients with the classic infantile form of GAA deficiency experience unremitting deterioration and die within the first two years of life from cardiac insufficiency, although prolonged survival has been reported in infants with less severe cardiomyopathy. Early diagnosis and prompt initiation of enzyme replacement therapy (ERT) are essential for improving outcomes.

The rate of progression and sequence of respiratory and skeletal involvement vary significantly among patients with late-onset disease. Disease severity is related to disease duration rather than age, with the odds for wheelchair use and respiratory support increasing by 13 and 8 percent, respectively, for every additional year since diagnosis.[5] A two-year follow-up of 52 Dutch patients with untreated late-onset GAA deficiency indicated a progressive decline in functional activities, respiratory function, handicap, and survival at the group level.[6]


The main treatment for GAA deficiency is intravenous alglucosidase alfa enzyme replacement therapy (ERT). A randomised controlled trial has been conducted proving efficacy.[7] ERT enhances survival. However many patients still develop progressive pelvic girdle weakness.

A multidisciplinary team is necessary for the coordination of care. Many patients require some level of respiratory support, with some patients progressing to require mechanical ventilation.


Gene Reviews - Pompe Disease

https://www.nzpompe.network/ - New Zealand charity.


  1. 1.0 1.1 1.2 van der Beek, Nadine A. M. E.; de Vries, Juna M.; Hagemans, Marloes L. C.; Hop, Wim C. J.; Kroos, Marian A.; Wokke, John H. J.; de Visser, Marianne; van Engelen, Baziel G. M.; Kuks, Jan B. M.; van der Kooi, Anneke J.; Notermans, Nicolette C. (2012-11-12). "Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study". Orphanet Journal of Rare Diseases. 7: 88. doi:10.1186/1750-1172-7-88. ISSN 1750-1172. PMC 3551719. PMID 23147228.
  2. Mechtler, Thomas P.; Stary, Susanne; Metz, Thomas F.; De Jesús, Víctor R.; Greber-Platzer, Susanne; Pollak, Arnold; Herkner, Kurt R.; Streubel, Berthold; Kasper, David C. (2012-01-28). "Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria". Lancet (London, England). 379 (9813): 335–341. doi:10.1016/S0140-6736(11)61266-X. ISSN 1474-547X. PMID 22133539.
  3. Burton, Barbara K.; Charrow, Joel; Hoganson, George E.; Waggoner, Darrell; Tinkle, Brad; Braddock, Stephen R.; Schneider, Michael; Grange, Dorothy K.; Nash, Claudia; Shryock, Heather; Barnett, Rebecca (2017-11). "Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience". The Journal of Pediatrics. 190: 130–135. doi:10.1016/j.jpeds.2017.06.048. ISSN 1097-6833. PMID 28728811. Check date values in: |date= (help)
  4. "About the test | National Screening Unit". www.nsu.govt.nz. Retrieved 2023-03-05.
  5. Hagemans, M. L. C.; Winkel, L. P. F.; Hop, W. C. J.; Reuser, A. J. J.; Van Doorn, P. A.; Van der Ploeg, A. T. (2005-06-28). "Disease severity in children and adults with Pompe disease related to age and disease duration". Neurology. 64 (12): 2139–2141. doi:10.1212/01.WNL.0000165979.46537.56. ISSN 1526-632X. PMID 15985590.
  6. Hagemans, M. L. C.; Hop, W. J. C.; Van Doorn, P. A.; Reuser, A. J. J.; Van der Ploeg, A. T. (2006-02-28). "Course of disability and respiratory function in untreated late-onset Pompe disease". Neurology. 66 (4): 581–583. doi:10.1212/01.wnl.0000198776.53007.2c. ISSN 1526-632X. PMID 16505317.
  7. van der Ploeg, Ans T.; Clemens, Paula R.; Corzo, Deyanira; Escolar, Diana M.; Florence, Julaine; Groeneveld, Geert Jan; Herson, Serge; Kishnani, Priya S.; Laforet, Pascal; Lake, Stephen L.; Lange, Dale J. (2010-04-15). "A randomized study of alglucosidase alfa in late-onset Pompe's disease". The New England Journal of Medicine. 362 (15): 1396–1406. doi:10.1056/NEJMoa0909859. ISSN 1533-4406. PMID 20393176.

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