What essential information should a poster on late‑onset Pompe disease include about its autosomal‑recessive inheritance, clinical presentation, diagnostic work‑up, enzyme replacement therapy (alglucosidase alfa), and prognosis?

Late-Onset Pompe Disease Educational Poster

Disease Definition and Genetics

Late-onset Pompe disease (LOPD) is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), leading to progressive skeletal muscle weakness and respiratory insufficiency without significant cardiac involvement. 1

• Inheritance pattern: Autosomal recessive—both parents must be carriers; 25% recurrence risk for each pregnancy 1
• Genetic basis: Biallelic pathogenic variants in the GAA gene result in deficient lysosomal enzyme activity 1
• Pathophysiology: Glycogen accumulates progressively in lysosomes, particularly affecting skeletal and respiratory muscles 1
• Prevalence: Approximately 1 in 28,000 in the United States, with higher incidence in the Netherlands for late-onset forms 1, 2

Clinical Presentation

LOPD presents anytime from late infancy to adulthood with progressive proximal muscle weakness and respiratory insufficiency, but cardiac involvement is rare. 1

Key Clinical Features:

• Progressive proximal muscle weakness affecting hip flexors, shoulder girdle, and paraspinal muscles 2
• Respiratory muscle involvement leading to respiratory insufficiency if untreated—the major cause of mortality 1, 3
• Cardiac muscle is typically spared in LOPD, distinguishing it from infantile-onset disease 1
• Patients retain measurable residual GAA enzyme activity (unlike infantile form) 1
• Presentation can occur as late as the second to sixth decade of life 2

Common Presenting Symptoms:

• Difficulty climbing stairs or rising from chairs 2
• Exercise intolerance and fatigue 2
• Dyspnea, particularly when supine (orthopnea) 2
• Lower back pain 4

Diagnostic Work-Up

The gold standard for diagnosis is measurement of GAA enzyme activity in cultured skin fibroblasts, though dried blood spot testing offers rapid first-tier screening. 1, 2

Laboratory Testing Algorithm:

Initial Screening:

• Serum creatine kinase (CK): Elevated in approximately 95% of LOPD patients (can reach 2000 U/L), though some adults may have normal CK 1, 2
• AST, ALT, LDH: May be elevated, reflecting muscle enzyme release 1, 5
• Aldolase: May be elevated alongside other muscle enzymes 5

Biomarker Testing:

• Urinary glucose tetrasaccharide (Glc4): Typically elevated in untreated juveniles and adults with LOPD; useful for monitoring ERT response 1
• Important caveat: Glc4 can be temporarily elevated in unaffected individuals with malignancies, acute pancreatitis, muscle trauma, pregnancy, or after meat ingestion 1

Confirmatory Enzyme Testing:

• Gold standard: GAA activity in cultured skin fibroblasts (takes 4-6 weeks) 1, 2
• Rapid alternative: GAA activity in dried blood spots (DBS) with acarbose inhibition of interfering maltase-glucoamylase 1
• Muscle biopsy: Shows glycogen-positive vacuoles; allows direct GAA activity measurement but has variable results due to patchy glycogen accumulation in LOPD 1

Genetic Testing:

• Molecular analysis for biallelic GAA pathogenic variants confirms diagnosis 1

Functional Assessment:

• Pulmonary function testing: Upright forced vital capacity (FVC) to identify respiratory compromise 1, 2
• Six-minute walk test (6MWT): Assesses functional endurance 4, 6, 7
• EMG and nerve conduction studies: Evaluate myopathy pattern 1, 2

Enzyme Replacement Therapy

FDA-approved ERT for LOPD includes both alglucosidase alfa and avalglucosidase alfa-ngpt, with avalglucosidase alfa demonstrating superior respiratory and functional outcomes. 1, 7

Available Therapies:

Alglucosidase alfa (Myozyme/Lumizyme):

• First-generation ERT approved for all forms of Pompe disease 1, 3
• Administered intravenously every other week 3
• Has shown effectiveness but many patients plateau or decline despite treatment 4

Avalglucosidase alfa (Nexviazyme):

• Second-generation ERT designed with enhanced mannose-6-phosphate receptor targeting for increased cellular uptake 4, 6, 7
• Demonstrated non-inferiority and clinically meaningful improvements over alglucosidase alfa in respiratory function (FVC% predicted improvement of 2.89% vs 0.46%) and 6MWT distance (30.01 m greater improvement) at 49 weeks 7
• Well tolerated for up to 6.5 years with safety profile consistent with alglucosidase alfa 6
• Fewer high-persistent antibody titers (≥12,800) compared to alglucosidase alfa (20% vs 33%) 7

Treatment Monitoring:

• Urinary Glc4 levels correlate with clinical response to ERT 1
• Caveat: Glc4 excretion may temporarily increase during intercurrent illness (e.g., infection) in ERT-treated patients 1
• Regular assessment of FVC, 6MWT, and motor function tests 4, 6

Switching Therapy:

• Real-world data shows switching from alglucosidase alfa to avalglucosidase alfa may stabilize motor worsening (from -63 m/year to -1 m/year on 6MWT) 8
• Statistically significant improvements in CK, Hex4, and AST post-switch 4
• Most patients show improved or stabilized functional outcomes after switching 4, 8

Prognosis and Management

Without treatment, LOPD progresses to respiratory insufficiency; with ERT, respiratory function can stabilize and functional endurance can improve, though skeletal muscle remains a challenging target. 3, 6, 7

Expected Outcomes with Treatment:

• Respiratory function (FVC) remains stable in most patients on avalglucosidase alfa 6
• Functional endurance (6MWT) stabilizes or improves, particularly in patients <45 years 6
• Younger patients demonstrate better treatment responses 6
• Long-term treatment (up to 6.5 years) shows sustained efficacy and tolerability 6

Multidisciplinary Care Requirements:

• Pulmonary monitoring: Regular FVC testing; respiratory support may be needed 2
• Cardiology: Monitoring essential though cardiac involvement is rare in LOPD 1, 2
• Neurology: Assessment of motor function and disease progression 2
• Genetics: Family counseling and carrier testing for at-risk relatives 2
• Physical therapy: Rehabilitation and functional assessment 2

Differential Diagnosis Considerations:

• Limb girdle muscular dystrophy 2
• Becker muscular dystrophy 2, 9
• Myasthenia gravis 2
• Spinal muscular atrophy 1, 2
• Other glycogen storage diseases (types III, IV, V, VII) 1, 2
• Polymyositis 1

Key Prognostic Factors:

• Age at treatment initiation: Earlier treatment associated with better outcomes 6
• Baseline respiratory function: Degree of FVC impairment affects trajectory 6, 7
• Antibody development: High-persistent titers may affect response, though less common with avalglucosidase alfa 7
• Treatment adherence and monitoring: Regular infusions and functional assessments critical 4, 6