What are the clinical features of Pompe disease?

Clinical Features of Pompe Disease

Pompe disease presents as a progressive muscular disorder with a clinical spectrum ranging from severe infantile cardiomyopathy with early death to adult-onset proximal muscle weakness with respiratory failure. 1, 2

Underlying Pathophysiology

• Pompe disease results from deficiency of the lysosomal enzyme acid α-glucosidase (GAA), causing glycogen accumulation predominantly in skeletal, cardiac, and smooth muscle tissues. 1, 2
• The disease follows an autosomal recessive inheritance pattern with an estimated combined incidence of 1:40,000. 2
• Progressive glycogen substrate accumulation in target tissues leads to steady debilitation, organ failure, and potentially death. 1, 2

Clinical Subtypes and Presentations

Classic Infantile-Onset Pompe Disease (IOPD)

• Presents shortly after birth with generalized hypotonia ("floppy baby"), failure to thrive, and rapidly progressive cardiorespiratory failure. 2, 3
• Prominent cardiomegaly and hepatomegaly are hallmark features. 2
• Hypertrophic cardiomyopathy revealed by echocardiogram, which may progress to impaired cardiac function and dilated cardiomyopathy in late stages. 2
• Death typically occurs within the first year of life without treatment. 2, 3
• Higher incidence among African-American and Chinese populations. 2

Nonclassic Infantile Pompe Disease

• Presents within the first year of life but with slower disease progression. 2
• Less severe cardiomyopathy compared to classic infantile form. 2
• Represents an intermediate phenotype between classic infantile and late-onset forms. 2

Childhood/Juvenile Variant

• Heterogeneous presentation typically occurring after infancy. 2
• Usually without severe cardiomyopathy, distinguishing it from infantile forms. 2
• Progressive proximal muscle weakness becomes the predominant feature. 2

Adult-Onset (Late-Onset) Pompe Disease

• Characterized by slowly progressive proximal myopathy predominantly involving skeletal muscle, presenting anywhere from the second to sixth decade of life. 2, 3
• Progressive proximal muscle weakness with decreased muscle volume. 4
• Respiratory muscle involvement leading to respiratory insufficiency, often complicated by obstructive sleep apnea. 2, 4
• Cardiac involvement is typically absent or minimal. 2
• Higher incidence in the Netherlands. 2
• Death usually results from respiratory failure. 4

Key Clinical Features Across the Spectrum

Musculoskeletal Manifestations

• Progressive proximal muscle weakness affecting limb-girdle muscles. 2, 3
• Generalized hypotonia, particularly prominent in infantile forms. 2
• Muscle weakness may interfere with normal daily activities in late-onset disease. 4

Cardiac Manifestations

• Hypertrophic cardiomyopathy (primarily in infantile forms). 2
• Cardiomegaly detectable on physical examination and imaging. 2
• Potential progression to dilated cardiomyopathy in advanced stages. 2

Respiratory Manifestations

• Respiratory muscle involvement leading to progressive respiratory insufficiency. 2, 3
• Increased daytime sleepiness due to nocturnal hypoventilation. 4
• Obstructive sleep apnea may complicate respiratory insufficiency. 4

Laboratory Abnormalities

• Elevated serum creatine kinase (CK) in approximately 95% of patients, though some adults may have normal CK levels. 1, 2
• CK levels can be markedly elevated (as high as 2000 IU/L). 1
• Elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) reflecting muscle enzyme release. 1, 2
• Urinary glucose tetrasaccharide (Glc4) serves as a sensitive though nonspecific biomarker. 1, 2

Important Clinical Pitfalls

• Approximately 5% of late-onset patients may have normal CK levels, which can delay diagnosis if clinicians rely solely on this marker. 1
• The site of muscle biopsy in late-onset disease can impact results due to variable glycogen accumulation between different muscles and fiber types. 1
• Anesthesia carries significant risk in infantile Pompe disease patients with severe cardiomyopathy and skeletal myopathy. 1
• The heterogeneous presentation across the disease spectrum can lead to misdiagnosis as other neuromuscular disorders. 1, 2

Differential Diagnosis Considerations

For late-onset Pompe disease, consider: 2

• Limb girdle muscular dystrophy
• Becker muscular dystrophy
• Myasthenia gravis
• Spinal muscular atrophy
• Other glycogen storage diseases (types IIIa, IV, V, VII)
• Danon disease
• Mitochondrial myopathies