ICCnotes

Evidence-based clinical reference for inherited cardiac conditions, genetics, risk, treatment & guidelines

Pompe Disease (GSD-II)

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, 17q25.3). Parents of an affected child are obligate carriers, and each sibling has a 25% risk of being affected.[5]

Enzyme deficiency: acid α-glucosidase deficiency leads to glycogen accumulation within lysosomes of cardiac, skeletal and smooth muscle.[1]

Genotype and phenotype:[1][5]

  • Two null variants: little or no residual enzyme activity, producing classic infantile-onset disease with cardiomyopathy
  • c.-32-13T>G (IVS1) splice variant: a "leaky" variant permitting some normal splicing, present on at least one allele in most late-onset patients of European ancestry
  • CRIM status: infants with no cross-reactive immunologic material (CRIM-negative) develop high-titre antibodies to enzyme replacement therapy and have worse outcomes unless immune tolerance induction is given
  • Pseudodeficiency alleles (e.g. c.1726G>A, common in East Asian populations) lower measured enzyme activity without causing disease, so low activity must be confirmed by genotype

Screening: newborn screening programmes exist in some countries but not currently in the UK; siblings of an affected child should be offered testing.[5]

Prevalence

1 in 40,000 (all forms combined), with estimated frequencies of about 1 in 138,000 for classic infantile-onset disease and 1 in 57,000 for adult-onset disease; frequencies vary by ancestry.[1]

Infantile-onset: most severe, presents in the first months of life with cardiomyopathy and hypotonia

Late-onset: childhood to adulthood, slower progression, dominated by skeletal and respiratory muscle weakness

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 on dried blood spot, confirmed by a second method (leukocyte or fibroblast assay, or GAA genotyping).[3]

Genetic testing: GAA sequencing with deletion/duplication analysis; CRIM status in infantile-onset disease.[3][5]

Biochemistry: CK raised in almost all infantile-onset patients but may be normal or only mildly raised in late-onset disease; ALT, AST and LDH often raised; urinary glucose tetrasaccharide (Glc4) supports the diagnosis and is used to monitor treatment.[3][5]

ECG: in infantile-onset disease, a short PR interval and very large QRS voltages; ventricular pre-excitation can occur. In late-onset disease the ECG is usually normal, but conduction disease, pre-excitation and atrial arrhythmias are reported.[1][3][6]

Echocardiography: in infantile-onset disease, massive concentric LVH with markedly raised LV mass, sometimes with LVOT obstruction, and progression to systolic dysfunction if untreated; LV mass regresses with enzyme replacement therapy. In late-onset disease LVH is uncommon and usually mild.[3][6]

Ambulatory ECG monitoring: baseline in late-onset disease and whenever there are palpitations, presyncope or syncope.[6]

Cardiac MRI: not routinely required; in late-onset disease, significant LVH or scar should prompt a search for a second cause.

Vascular imaging: late-onset disease is associated with ascending aortic dilatation and intracranial arterial abnormalities (basilar dolichoectasia, aneurysms); consider brain MRA with neurological symptoms.[6][7]

Respiratory assessment: forced vital capacity sitting and supine (a supine fall of more than 10% indicates diaphragmatic weakness), and sleep studies for nocturnal hypoventilation.[5]

Before anaesthesia or sedation: infants with severe LVH are at high risk of arrhythmia and haemodynamic collapse at induction, so cardiology and cardiac anaesthetic assessment is needed first.[3]

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): ERT given with oral miglustat, which acts in this combination as an enzyme stabiliser (not substrate reduction); EMA/FDA approved 2023; UK licence: adults with late-onset Pompe disease

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]
  • Arrhythmia: short PR, pre-excitation, and ventricular arrhythmia in infants with severe LVH, particularly at anaesthetic induction[3]
  • Late-onset form: respiratory failure (diaphragmatic weakness) and progressive limb-girdle weakness dominate, with lesser cardiac involvement
  • Vascular: ascending aortic dilatation and intracranial arterial abnormalities in late-onset disease, with a risk of aneurysm rupture[6][7]

Risk Stratification

Infantile-onset without ERT: death, usually from cardiorespiratory failure, within the first year of life.[1]

Infantile-onset with ERT: survival and ventilator-free survival are substantially improved and LV mass regresses; outcomes are worse with CRIM-negative status, high sustained antibody titres, and a later start of treatment.[3][5]

Cardiac risk markers in infants: massive LVH, LVOT obstruction and systolic dysfunction, with the highest arrhythmic risk around anaesthesia and invasive procedures.[3]

Late-onset: respiratory failure is the main cause of death; cardiac risk is low but not absent, with arrhythmia and arterial aneurysm rupture reported.[6][7]

Pregnancy Management

mWHO class II–III or above: refer to a Pregnancy Heart Team before conception (see Pregnancy).

Pregnancy in late-onset Pompe disease - individualised risk assessment

Pregnancy concerns women with late-onset disease, in whom the main maternal risk is respiratory rather than cardiac: the growing uterus reduces diaphragmatic excursion, so baseline and serial vital capacity guide planning. Cardiac assessment before pregnancy (ECG, echocardiography including the ascending aorta, and ambulatory monitoring if symptomatic) identifies the minority with cardiac or aortic involvement.[6][8]

Enzyme replacement therapy: decisions about continuing ERT in pregnancy are made with the metabolic team, weighing maternal benefit against limited pregnancy safety data.

Delivery and anaesthesia: plan with obstetric anaesthesia early, given respiratory muscle weakness and sensitivity to respiratory depressants; mode of delivery is individualised.[8]

Genetic considerations: autosomal recessive; the risk to a child depends on the partner's carrier status, so partner carrier testing informs counselling.

Follow-up

Based on ACMG Pompe guidance and GeneReviews[3][5].

Cardiac surveillance is led by phenotype: infantile-onset disease needs close cardiac follow-up while LVH regresses on ERT; late-onset disease needs periodic screening for arrhythmia and vascular complications.

Infantile-onset (on ERT)Late-onset
FrequencyEvery 3–6 months in the first years, then 6–12 monthly once LV mass has normalisedAnnual review
Clinical reviewHeart failure signs, feeding, respiratory status, antibody titresPalpitations, syncope, respiratory symptoms
ECGEach visit (PR, voltages, pre-excitation)Annual
EchocardiographyEach visit until LV mass normalises, then 6–12 monthlyBaseline, including the aortic root and ascending aorta; repeat if abnormal or symptomatic
Holter / ambulatoryAs indicated, and before anaesthesiaBaseline, then if symptoms
RespiratoryEach visitSitting and supine FVC, sleep study as indicated
Neurovascular imaging–Brain MRA if neurological symptoms

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

Key Points

  • Suspect in an infant with massive LVH + short PR + hypotonia[1]
  • ERT is time-critical in infantile-onset disease: start as soon as the diagnosis is confirmed, and determine CRIM status before starting[3]
  • Infants with severe LVH need cardiology and cardiac anaesthetic assessment before any anaesthesia or sedation[3]
  • Late-onset: mainly skeletal and respiratory; screen for arrhythmia, aortic dilatation and, if symptomatic, intracranial arterial abnormalities[6][7]
  • Confirm low enzyme activity with genotyping: pseudodeficiency alleles cause false-positive results[5]
  • ERT available and effective - early diagnosis saves lives[1]

References & Review Date

Last reviewed: October 2026

Key studies in Pompe disease · the landmark studies, drawn to scale with the other inherited cardiac conditions.

  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
  6. Forsha D, Li JS, Smith PB, et al. Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. Genet Med. 2011;13(7):625–631. doi:10.1097/GIM.0b013e3182142966
  7. Montagnese F, Granata F, Musumeci O, et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016;39(3):391–398. doi:10.1007/s10545-015-9913-x
  8. De Backer J, Haugaa KH, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J. 2025;46(43):4462–4568. doi:10.1093/eurheartj/ehaf193