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Pompe Disease

Quick Summary

Definition: An autosomal recessive lysosomal storage disorder caused by acid α-glucosidase (GAA) deficiency, with glycogen accumulation causing skeletal myopathy and (in infantile-onset disease) a hypertrophic cardiomyopathy phenotype.[1][2]

  • Prevalence: 1 in 40,000 (infantile-onset severe, late-onset milder)[1]
  • Key gene: GAA (acid α-glucosidase), autosomal recessive - glycogen accumulates in lysosomes
  • Hallmark: Infantile: massive LVH + short PR + muscle weakness + fatal by 1yr without ERT; Late-onset: skeletal myopathy ± mild cardiac
  • High-risk markers: Infantile presentation, severe LVH, respiratory failure, CK elevation
  • First-line Mx: Enzyme replacement therapy according to phenotype, licence and specialist pathway; start early, especially in infantile-onset disease, with supportive respiratory/cardiac care

Aetiology

Monogenic (Mendelian): 100%, GAA mutations causing acid α-glucosidase deficiency[1]

Genetics

Inheritance: Autosomal recessive (GAA gene)

Enzyme deficiency: Acid α-glucosidase → glycogen accumulation in lysosomes

Prevalence

1 in 40,000 (all forms combined)[1]

Infantile-onset: Most severe, presents <1 year

Late-onset: Childhood to adulthood, slower progression

Diagnosis

Confirming the diagnosis: screen with acid α-glucosidase (GAA) enzyme activity on a dried blood spot; a low result must be confirmed by a second method (enzyme assay on alternative tissue or GAA gene sequencing). Determine CRIM (cross-reactive immunologic material) status before ERT in infantile-onset disease, as it predicts the immune response.[3][5]

Infantile-onset (classic):

  • Severe cardiomyopathy (massive LVH, short PR)
  • Muscle weakness, respiratory failure
  • Fatal in first year without treatment

Late-onset (juvenile/adult):

  • Skeletal myopathy predominant (proximal weakness)
  • Respiratory muscle involvement
  • Cardiac involvement less common, milder

Investigations

Enzyme assay: Low acid α-glucosidase activity (diagnostic)[3]

Genetic testing: GAA gene sequencing

CK: Elevated

ECG (infantile): Short PR, massive LVH

Echo: Concentric LVH (infantile form)

Treatments

1. General measures:

  • Respiratory support (NIV as needed), physiotherapy, nutritional support
  • Genetic counselling and family cascade testing, see the Genetic Testing page

In infantile-onset disease ERT is time-critical, start as soon as the diagnosis is confirmed; outcomes depend on early treatment and CRIM status.[3]

2. Medical therapy:

  • Enzyme Replacement Therapy (ERT):
    • Avalglucosidase alfa (Nexviazyme): next-generation ERT, FDA/EMA approved 2021; in COMET it met non-inferiority versus alglucosidase alfa for respiratory function with favourable secondary outcomes[4]; choice of ERT should follow licence, NICE and local specialist guidance
    • Alglucosidase alfa (Myozyme/Lumizyme): original ERT; IV every 2 weeks; dramatically improves survival in infantile form
    • Cipaglucosidase alfa + miglustat (Pombiliti + Opfolda): novel ERT + substrate reduction combination, FDA/EMA approved 2023; for patients ≥1 year not previously treated with ERT or switching

3. Device therapy:

  • Managed per standard indications if arrhythmia or conduction disease develops

4. Advanced heart failure and/or transplant referral:

  • Standard advanced-heart-failure pathways apply for refractory cardiomyopathy; respiratory failure is managed jointly with respiratory medicine

Complications

  • Infantile form: massive HCM phenotype leading to heart failure and death in the first year without enzyme replacement therapy[1]
  • Late-onset form: respiratory failure (diaphragmatic weakness) and progressive limb-girdle weakness dominate, with lesser cardiac involvement
  • Arrhythmia and short PR interval.

Risk Stratification

Infantile without ERT: Death <1 year

With ERT: Improved survival, but monitoring essential

Key Points

  • Suspect in infant with massive LVH + short PR + hypotonia[1]
  • Late-onset: mainly skeletal/respiratory - cardiac less prominent
  • ERT available and effective - early diagnosis saves lives[1]

References & Review Date

Last reviewed: May 2026

  1. van der Ploeg AT, Reuser AJJ. Pompe's disease. Lancet. 2008;372(9646):1342–1353. doi:10.1016/S0140-6736(08)61555-X
  2. Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. doi:10.1093/eurheartj/ehad194
  3. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline (ACMG). Genet Med. 2006;8(5):267–288. doi:10.1097/01.gim.0000218152.87434.f3
  4. Diaz-Manera J, Kishnani PS, Kushlaf H, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol. 2021;20(12):1012–1026. doi:10.1016/S1474-4422(21)00241-6
  5. Leslie N, Bailey L. Pompe Disease. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews (updated periodically). University of Washington, Seattle. ncbi.nlm.nih.gov/books/NBK1261