Glycogen storage disease type II (Pompe disease)

Pompe disease is classified into infantile-onset (IOPD) and late-onset (LOPD) forms.

IOPD typically presents within the first months of life with hypotonia, generalised muscle weakness, feeding difficulties, poor growth, and respiratory distress; cardiomegaly with hypertrophic cardiomyopathy is identifiable on echocardiography in the first weeks of life and progresses to left ventricular outflow obstruction. In untreated infants, IOPD commonly leads to death within the first two years of life.

LOPD manifests from the first to the seventh decade of life with progressive proximal muscle weakness affecting predominantly the lower limbs together with progressive respiratory insufficiency. Disease progression is faster when symptoms appear in childhood, and clinical expressivity is highly variable both between and within families. Multisystem involvement may extend beyond cardiac and skeletal muscle to encompass respiratory, neurologic, auditory, and skeletal manifestations. As a general rule, the earlier the onset of clinical manifestations, the faster the rate of progression.

The prevalence of Pompe disease is not well-defined and estimates vary across geographic regions. Estimates for IOPD range from 1:297,387 in Japan to 1:62,186 in Taiwan.

Pompe disease is caused by lysosomal acid alpha-glucosidase deficiency through biallelic germline loss-of-function pathogenic variants in GAA (17q25.3). The resulting reduction or abolition of enzyme activity leads to lysosomal accumulation of glycogen and progressive damage to cardiac, skeletal, and other tissues.

Pompe disease is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygous carrier, and a 25% chance of being unaffected and not a carrier. Carriers are asymptomatic. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis rests on demonstration of acid alpha-glucosidase (GAA) deficiency. GAA enzyme activity is measured in isolated lymphocytes or mixed leukocytes. Identification of biallelic pathogenic variants in GAA establishes the diagnosis. Supportive findings include elevated serum creatine kinase (up to 2,000 IU/L) and elevated urinary glucotetrasaccharide (Hex4); echocardiography demonstrates cardiomegaly and in IOPD.

Main differential diagnoses include:

• Danon disease: hypertrophic cardiomyopathy and lysosomal glycogen storage myopathy, X-linked with more severe disease in males; LAMP2
• Glycogen storage disease type IIIa (debrancher deficiency): hypotonia, cardiomegaly, muscle weakness, and elevated CK with more dramatic liver involvement; AGL

• Establishing the diagnosis: confirming the molecular cause defines the condition precisely and ends diagnostic uncertainty.
• Specific and individualised surveillance: identification of the underlying genetic variants enables tailored surveillance and management across the affected organ systems, which is a prerequisite for targeted medical care delivered by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variants enables targeted testing of at-risk relatives, including reproductive counselling.

• Sperry E, Leslie N, Berry L, Pena L. Pompe Disease. 2025 Aug 21. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: . Available from:
• Giugliani, R., Solomon, F., Kushlaf, H. et al. Global variations in diagnostic methods and epidemiological estimates in Pompe disease: findings from a scoping review. Orphanet J Rare Dis 2025 20:216. doi: 10.1186/s13023-025-03679-3. PMID: . PMCID: PMC12057045