What is Pompe disease (Glycogen storage disease type II)?

From the Guidelines

Pompe disease should be managed with enzyme replacement therapy (ERT) and supportive care to slow disease progression and improve quality of life, as evidenced by the 2006 guideline for the management of Pompe disease 1. The disease is a rare, progressive, and often fatal muscular disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), leading to glycogen accumulation in various tissues.

Key Considerations

• The disease presents in two main forms: infantile-onset (more severe) and late-onset, with the former characterized by hypertrophic cardiomyopathy, generalized muscle weakness, and hypotonia, and the latter by progressive skeletal muscle dysfunction 1.
• Treatment with ERT, such as alglucosidase alfa (Myozyme or Lumizyme), administered intravenously at 20 mg/kg every two weeks, can help slow disease progression but cannot reverse existing damage.
• Supportive care, including respiratory support, physical therapy, and dietary management, is essential to manage complications and improve quality of life.
• Early diagnosis and treatment are crucial for better outcomes, and regular monitoring by a multidisciplinary team is necessary to adjust treatment as needed.

Disease Management

• The natural history of infantile Pompe disease is characterized by a rapidly progressive course, with death from cardiorespiratory failure usually occurring by 1 year of age 1.
• Late-onset Pompe disease can present at any age and is characterized by a lack of severe cardiac involvement and a less dismal short-term prognosis, with symptoms related to progressive skeletal muscle dysfunction.
• The age of death varies from early childhood to late adulthood, depending on the rate of disease progression, extent of respiratory muscle involvement, and other comorbidities.

Treatment Recommendations

• Enzyme replacement therapy (ERT) should be initiated as soon as possible after diagnosis to slow disease progression and improve quality of life.
• Supportive care, including respiratory support, physical therapy, and dietary management, should be provided to manage complications and improve quality of life.
• Regular monitoring by a multidisciplinary team is necessary to adjust treatment as needed and manage complications.

From the FDA Drug Label

Pompe disease (acid maltase deficiency, glycogen storage disease type II, GSD II, glycogenosis type II) is an inherited disorder of glycogen metabolism caused by the absence or marked deficiency of the lysosomal enzyme GAA. Alglucosidase alfa provides an exogenous source of GAA Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen.

Pompe disease is an inherited disorder caused by the deficiency of the lysosomal enzyme GAA. Alglucosidase alfa is a treatment that provides an exogenous source of GAA, helping to cleave glycogen.

• The mechanism of action involves binding to mannose-6-phosphate receptors, internalization, and proteolytic cleavage, resulting in increased enzymatic activity.
• Alglucosidase alfa is used to treat Pompe disease by replacing the deficient GAA enzyme. 2 2 2

From the Research

Overview of Pompe Disease

• Pompe disease is a rare progressive autosomal recessive disorder resulting from the deficiency of acid alpha-glucosidase (GAA) enzyme activity 3.
• It is caused by mutations in the GAA gene, localized on chromosome 17, and leads to lysosomal storage of glycogen in several tissues, particularly in muscle 4.
• The disease manifests with a broad spectrum of disease severity, ranging from severe infantile-onset diseases to late-onset diseases 5.

Clinical Manifestations

• Hypotonia and hypertrophic cardiomyopathy are the most documented clinical manifestations for infantile-onset Pompe disease (IOPD) 3.
• Progressive muscle weakness and dyspnea are the most prevalent clinical manifestations for late-onset Pompe disease (LOPD) 3.
• PD patients exhibit a multisystemic manifestation that depends on age of onset, including limb-girdle muscle weakness and respiratory failure 4.

Diagnosis and Screening

• The diagnosis of Pompe disease requires demonstration of deficiency of the lysosomal acid alpha-glucosidase enzyme, which can be assayed in dried blood spot or liquid blood samples 5.
• Targeted screening of at-risk populations and universal newborn screening can result in earlier diagnosis and enable earlier treatment initiation 5, 6.
• Newborn screening programs have the potential to improve PD prevalence estimations, but their availability is still limited among countries 3.

Treatment and Management

• Disease-modifying treatment with enzyme replacement therapy (ERT) has partially altered the natural history of the disease 5.
• ERT with recombinant human GAA (rhGAA) supplies exogenous GAA to reduce glycogen deposits, thereby improving motor and respiratory functioning 7.
• Newer forms of ERT, such as avalglucosidase alfa and cipaglucosidase alfa, are being developed to overcome the limitations of existing treatments 7.
• Gene therapy and substrate reduction therapy are also being explored as potential therapeutic approaches for Pompe disease 6, 7.