Pompe disease, also known as acid maltase deficiency or glycogen storage disease type II, is a rare genetic disorder characterized by a deficiency or absence of the lysosomal acid alpha-glucosidase enzyme (GAA). GAA normally cleaves glycogen to form glucose. Abnormalities of the GAA enzyme due to mutations in the GAA gene result in an accumulation of glycogen in tissues, especially cardiac and skeletal myocytes, and subsequent impairment.1
Pompe disease was first described in 1932 in several case studies, most notably one by the Dutch pathologist Johannes Cassianus Pompe.1,2 He reported the case of a 7-month-old infant with generalized muscle weakness who died of idiopathic cardiac hypertrophy. Pompe noted massive amounts of vacuolar glycogen stored in tissues throughout the infant’s body.2,3
In 1954, G.T. Cori classified Pompe disease as glycogen storage disease type II because of the associated abnormal glycogen metabolism.1,4,5 In 1963, the Belgian biochemist Henri-Gery Hers discovered the maltase (GAA) enzyme, a catalyst for the hydrolysis of glycogen to glucose at an acidic pH, and noted that it is normally the only glycogen-degrading enzyme present in lysosomes.1,6 Cori also demonstrated that the enzyme is absent in patients with Pompe disease.1
Milder forms of Pompe disease that manifest later than infancy were described by Engel and others in the 1960s and 1970s.3,7
Phenotypes and Symptoms
Pompe disease comprises a continuum of phenotypes and related symptoms. The 2 main categories generally used to describe the condition, however, are based on age at onset and on the presence or absence of cardiomyopathy.3 The most severe form, which affects children younger than 12 months of age, usually manifests as hypotonia and feeding difficulties and is referred to as classic or infantile-onset Pompe disease (IOPD).3,4 Other symptoms include cardiomegaly, macroglossia, mild hepatomegaly, left ventricular outflow obstruction, respiratory distress, and progressive loss of ventilation.1,3 Untreated patients generally do not survive past 1 year of age, with cardiac and respiratory failure the primary cause of dealth.3
Read more about Pompe disease symptoms
The second main category, late-onset Pompe disease (LOPD), is less severe, with an onset of symptoms after the age of 12 months and usually without cardiac involvement.3 Symptoms generally progress more slowly in this form, with paraspinal and lower-limb muscles affected by weakness first.1 As the disease advances, scoliosis, lumbar hyperlordosis, and loss of mobility develop.1 The disease eventually progresses to affect the respiratory muscles, so that assisted ventilation becomes necessary.1 More recently, several other multisystem conditions have been identified in patients with LOPD, including osteoporosis, sleep apnea, neuropathy of small nerve fibers, dysarthria, dysphagia, hearing loss, gastric dysfunction, involvement of the urinary tract and anal sphincter, cardiac arrhythmia, and intracranial or cerebral aneurysms.3
Pathophysiology and Diagnosis
The GAA protein is synthesized by the GAA gene, located on chromosome 17q25.3.8 The GAA enzyme normally cleaves the α-1,4- and α-1,6-glycosidic bonds of glycogen to form glucose, and when the enzyme is absent or deficient, glycogen builds up in tissues.1 Hundreds of mutations have been described in the literature that affect one or more steps related to the synthesis, post-translational modification, trafficking, or proteolytic processing of the GAA enzyme.1,3 Most mutations are compound heterozygotes and are isolated to single families or small populations.3
Read more about Pompe disease diagnosis
Pompe disease is usually diagnosed through enzymatic assay to investigate GAA activity.9 It is confirmed through sequencing of the GAA gene to detect mutations. Other tests that may be beneficial in the diagnosis of Pompe disease include measurement of the serological levels of creatine kinase, aspartate and alanine aminotransferases, and lactate dehydrogenase, which may be elevated in some patients. The detection of tetrasaccharide 6-α-D-glucopyranosyl-maltotriose (Glc4) in urine can signify that the patient has a glycogen storage disease but cannot differentiate Pompe disease from other glycogen storage diseases. The presence of electrical myotonia on electromyography is not limited to patients with Pompe disease but can further support the diagnosis.
Treatment and Management
The only currently approved disease-modifying therapy for Pompe disease is enzyme replacement therapy (ERT). A recombinant human GAA (rhGAA) enzyme, known as alglucosidase alfa, is available as Myozyme® or Lumizyme®, depending on the batch size and the country in which it is being prescribed.10
Read more about Pompe disease treatment
Except for ERT, the management of Pompe disease is largely symptom-based, with cardiac and respiratory monitoring potentially becoming necessary, especially in patients with IOPD. Patients with LOPD may require occupational, physical, and speech therapy to improve quality of life. As the disease progresses, palliative care may also become necessary.10
Research continues into new treatments for Pompe disease. Over time, neutralizing humoral immune responses to rhGAA tend to develop, reducing its effectiveness. New generations of rhGAA are under investigation in clinical trials to increase its efficacy. Possible gene therapies are also in various levels of investigation.9
- Lim J-A, Li L, Raben N. Pompe disease: from pathophysiology to therapy and back again. Front Aging Neurosci. 2014;6:177. doi:10.3389/fnagi.2014.00177
- Pompe JC. Over idiopatische hypertrophie van het hart. Ned Tijdschr Geneeskd. 1932;76:304
- Kohler L, Puertollano R, Raben N. Pompe disease: from basic science to therapy. Neurotherapeutics. 2018;15(4):928-942. doi:10.1007/s13311-018-0655-y
- Cupler EJ, Berger KI, Leshner RT, et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45(3):319-333. doi:10.1002/mus.22329
- Cori GT. Enzymes and glycogen structure in glycogenosis. Osterreichische Zeitschrift fur Kinderheilkunde und Kinderfursorge. 1954;10(1-2):38-42.
- Hers HG. ⍶-Glucosidase deficiency in generalized glycogen storage disease (Pompe’s disease). Biochem J. 1963;86:11-16. doi:10.1042/bj0860011
- Engel AG, Seybold ME, Lambert EH, Gomez MR. Acid maltase deficiency: comparison of infantile, childhood, and adult types. Neurology. 1970;20:382.
- Morales JA, Anilkumar AC. Glycogen storage disease type II. StatPearls. Updated May 4, 2021. Accessed July 25, 2021.
- Taverna S, Cammarata G, Colomba P, et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). 2020;12(15):15856-15874. doi:10.18632/aging.103794
- Tarnopolsky M, Katzberg H, Petrof BJ, et al. Pompe disease: diagnosis and management. Evidence-based guidelines from a Canadian expert panel. Can J Neurol Sci. 2016;43(4):472-485. doi:10.1017/cjn.2016.37
Reviewed by Debjyoti Talukdar, MD, on 7/27/2021.