For a child, adolescent, or adult with slowly progressive proximal limb‑girdle weakness, early nocturnal hypoventilation, modestly elevated creatine kinase, and minimal cardiac involvement, how should I suspect, confirm, and treat late‑onset Pompe disease?

Late-Onset Pompe Disease: Diagnostic and Treatment Approach

When to Suspect Late-Onset Pompe Disease

Suspect late-onset Pompe disease in any patient presenting with the triad of slowly progressive proximal limb-girdle weakness, early respiratory symptoms (particularly nocturnal hypoventilation or unexplained dyspnea), and modestly elevated creatine kinase—especially when cardiac involvement is minimal or absent. 1

Key Clinical Features That Should Trigger Suspicion

• Proximal muscle weakness pattern: Progressive weakness affecting pelvis, legs, and shoulders, with particular involvement of paraspinal trunk muscles 1
• Early diaphragmatic involvement: Diaphragmatic weakness may be evident before other significant weakness is noted, presenting as nocturnal hypoventilation, orthopnea, or unexplained dyspnea 1, 2
• Elevated CK with minimal cardiac involvement: Approximately 95% of late-onset patients have elevated CK (though some adults may have normal levels), but unlike infantile Pompe disease, late-onset cases rarely display cardiomegaly on chest x-ray or ECG 1
• Progressive respiratory insufficiency: Involvement of diaphragm and accessory muscles of respiration often leads to ventilatory dependence 1

Critical Differential Diagnoses to Consider

The presentation overlaps significantly with other neuromuscular disorders 1:

• Limb-girdle muscular dystrophy (LGMD): Progressive muscle weakness in pelvis, legs, and shoulders
• Becker muscular dystrophy: Progressive proximal weakness with respiratory impairment and elevated CK
• Other glycogen storage diseases: Types IIIa, IV, V, and VII can present with hypotonia, muscle weakness, and elevated CK
• Polymyositis and inflammatory myopathies: Unexplained muscle weakness
• Danon disease: Hypertrophic cardiomyopathy with skeletal myopathy and vacuolar glycogen storage

How to Confirm the Diagnosis

Step 1: Initial Screening Tests

Order a blood-based acid α-glucosidase (GAA) enzyme activity assay as the primary screening tool—this is the optimal initial test for confirming or excluding Pompe disease. 2, 3

• CK measurement: Check serum CK, though recognize it may be normal or only mildly elevated in late-onset disease 3
• Additional muscle enzymes: Measure AST, ALT, and LDH, which may be elevated reflecting enzymes released from muscle 1, 4
• Urinary glucose tetrasaccharide (Glc4): This is a sensitive though nonspecific marker that can support the diagnosis 1

Step 2: Confirmatory Testing

The diagnosis must be confirmed by a second test after a positive GAA enzyme activity assay: either a second GAA enzyme activity assay in another tissue (such as muscle biopsy or fibroblasts) or GAA gene sequencing. 2, 5

• Dried blood spot (DBS) testing: This is a safe and reliable screening method using tandem mass spectrometry, but must be confirmed by genetic analysis 5
• Genetic analysis: GAA gene sequencing confirms the diagnosis and identifies specific mutations 5
• Muscle biopsy limitations: Relying solely on visualizing periodic acid-Schiff-positive vacuolar myopathy often leads to false-negative results and delays in diagnosis 3

Step 3: Functional Assessment

Once diagnosis is suspected or confirmed 2:

• Muscle strength evaluation: Formal assessment of proximal and axial muscle strength
• Motor function testing: Standardized motor function assessments
• Pulmonary function testing: Critical for assessing diaphragmatic involvement and respiratory muscle weakness

Common Diagnostic Pitfalls to Avoid

• Do not rely on muscle biopsy alone: Experience shows this frequently leads to false-negative results in late-onset Pompe disease 3
• Do not dismiss normal CK: Some adults with Pompe disease have CK levels within normal reference range 1
• Do not overlook isolated respiratory symptoms: Diaphragmatic weakness may precede limb weakness 1, 2
• Do not stop at positive DBS test: In patients with positive DBS test but negative genetic analysis, tissue assay of GAA should be considered 5

Treatment Approach

Enzyme Replacement Therapy (ERT)

Initiate enzyme replacement therapy promptly after diagnosis confirmation, as timely treatment improves patient outcomes and allows application of care standards while anticipating complications. 3, 6

• ERT has been universally accepted since 2006 as the first treatment for Pompe disease 6
• Early diagnosis and treatment likely improve patient outcomes 3

Multisystem Monitoring and Management

Recognize that Pompe disease is now understood as a multisystem disorder requiring comprehensive monitoring beyond muscle involvement. 6

Monitor for involvement of 6:

• Central, peripheral, and autonomic nervous systems
• Vascular malformations and cardiac complications
• Musculoskeletal and bone changes
• Oro-gastrointestinal and urinary tract alterations

Follow-Up Schedule

Follow patients with late-onset Pompe disease every six months after diagnosis. 1

This interval allows for:

• Monitoring disease progression
• Assessing treatment response
• Adjusting supportive care measures
• Anticipating respiratory complications

Supportive Care Considerations

While ERT is the primary treatment, patients may require 1, 6:

• Respiratory support including assisted ventilation as disease progresses
• Physical therapy and mobility aids
• Management of multisystem complications
• Quality of life interventions