What is Pompe disease?

Pompe Disease: Overview and Management

Pompe disease is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid α-glucosidase (GAA), resulting in glycogen accumulation in multiple tissues, particularly skeletal, cardiac, and smooth muscle, leading to progressive debilitation, organ failure and potentially death. 1

Disease Characteristics

• Pompe disease is also known as acid maltase deficiency (AMD) or glycogen storage disease type II (GSDII) 1
• It was the first recognized lysosomal storage disease and is the only glycogen storage disease that is also a lysosomal storage disease 1
• The pathophysiology involves accumulation of lysosomal glycogen in tissues, with skeletal, cardiac, and smooth muscle most prominently affected 1
• The disease follows a progressive course with steady accumulation of glycogen substrate in target tissues 1

Disease Classification

Pompe disease presents as a spectrum with varying severity based on:

Infantile Form

• Classic infantile Pompe disease: Rapidly progressive disease with prominent cardiomegaly, hepatomegaly, weakness, hypotonia, and death due to cardiorespiratory failure typically in the first year without treatment 1
• Nonclassic infantile Pompe disease: Presents in the first year of life with slower progression and less severe cardiomyopathy 1

Late-Onset Form

• Childhood/juvenile variant: Heterogeneous group usually presenting after infancy, typically without severe cardiomyopathy 1
• Adult-onset form: Characterized by slowly progressive myopathy predominantly involving skeletal muscle, can present as late as the second to sixth decade of life 1

Epidemiology

• Incidence ranges from 1 in 14,000 to 1 in 300,000 depending on ethnicity and geographic area 1
• The infantile form has a higher incidence among African-Americans and Chinese populations 1
• The late-onset adult form has a higher incidence in the Netherlands 1
• The combined incidence of all forms of Pompe disease is estimated to be 1:40,000 1

Clinical Presentation

Infantile Form

• Presents with cardiomegaly, hepatomegaly, weakness, and hypotonia 1
• Hypertrophic cardiomyopathy typically revealed by echocardiogram 1
• In late stages, may develop impaired cardiac function and dilated cardiomyopathy 1

Late-Onset Form

• Progressive proximal muscle weakness 1
• Respiratory muscle involvement leading to respiratory insufficiency 1
• Elevated serum creatine kinase (CK) in approximately 95% of patients 1

Diagnostic Testing

• Gold standard: Measurement of GAA activity in skin fibroblasts 1
• Laboratory tests: Serum creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) 1
• Urinary biomarker: Glucose tetrasaccharide (Glc4) can be a sensitive though nonspecific marker 1
• Muscle testing: EMG, nerve conduction studies, and/or muscle biopsy 1
• Pulmonary function testing: To identify respiratory compromise 1

Treatment

Enzyme Replacement Therapy (ERT)

• Alglucosidase alfa provides an exogenous source of GAA 2
• Mechanism: Binds to mannose-6-phosphate receptors on the cell surface, is internalized and transported into lysosomes, where it undergoes proteolytic cleavage resulting in increased enzymatic activity to cleave glycogen 2
• ERT has been available since 2006 and offers clinical benefits but is not a cure 3
• Second-generation ERTs (avalglucosidase alfa and cipaglucosidase alfa) have been developed to address limitations of alglucosidase alfa 4, 5

Emerging Therapies

• Gene therapy using intravenous delivery of adeno-associated virus (AAV) vectors is in clinical trials 3
• Substrate reduction therapy is being developed to reduce intracellular glycogen concentrations 5
• Tissue-targeted enzyme replacement therapy aims to enhance enzyme concentration in specific tissues 5

Management Considerations

• Physical therapy is important for maximizing motor function 6
• Respiratory support may be needed, particularly in late-onset disease 1
• Cardiac monitoring is essential, especially in infantile-onset disease 1
• Multidisciplinary care involving specialists in cardiology, pulmonology, neurology, and genetics 1

Differential Diagnosis

For late-onset Pompe disease, consider:

• Limb girdle muscular dystrophy
• Becker muscular dystrophy
• Myasthenia gravis
• Spinal muscular atrophy
• Other glycogen storage diseases 1

Prognosis

• Without treatment, classic infantile-onset Pompe disease leads to death by age 2 years 3
• With ERT, children with infantile-onset disease are living longer, with some achieving independent sitting, creeping, and walking 6
• Late-onset disease has a variable but generally slower progression 7