Genetics of Glycogen-Storage Disease Type II (Pompe Disease) Clinical Presentation

Updated: Oct 12, 2023
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
  • Print


Infantile-onset forms (classic and non-classic) of Pompe disease

Affected infants typically present with muscle weakness, hypotonia, and motor delay within the first 6 months of life (20-63% of patients).

Feeding difficulties and failure to thrive are described in 44% to 97% of patients.

Early cardiac failure results from LV enlargement and outflow obstruction (50-92% of patients), along with respiratory concerns (27-78% of patients). ​Electrocardiography (ECG) findings show a shortened PR interval with a broad and wide QRS complex. In one infant described, the presenting sign was Wolff-Parkinson-White syndrome. [12]

Family histories are usually noncontributory. Families with a history of consanguinity should raise concern.

Late-onset form of Pompe disease

TThe history of childhood and juvenile-onset glycogen-storage disease type II (GSD II) is as follows:

  • Patients present with delayed motor milestones, muscle weakness, and hypotonia.
  • Intelligence is normal.

The history of adult-onset GSD II is as follows:

  • Patients present with physical challenges related to proximal muscle weakness, such as difficulty climbing stairs.
  • Respiratory symptoms are present in about 33% of cases.
  • Other symptoms may include exercise intolerance, orthopnea, somnolence, and headaches.
  • Cardiac involvement is not a significant component.


Infantile-onset form of GSD II

Abnormal glycogen storage (eg, macroglossia, hepatomegaly, normal or increased muscle bulk) is clinically evident.

Involvement of respiratory muscles manifests as respiratory distress (eg, tachypnea).

Cardiomegaly or cardiomyopathy leads to murmur and signs of cardiac failure, such as feeding difficulties.

Profound diffuse hypotonia and muscle weakness occurs.

Cognitive development is normal.

Late-onset form of GSD II

The juvenile form is characterized by the following:

  • Respiratory distress
  • Hypotonia (typically more proximal than distal)
  • Macroglossia and hepatomegaly (not common)
  • No associated cardiomegaly or cardiomyopathy

The adult form is characterized by the following:

  • Proximal muscle weakness
  • Decreased bulk of involved muscles
  • Diminished deep tendon reflexes


Pompe disease, or glycogen-storage disease type II (GSD II), is inherited in an autosomal-recessive manner. Clinical presentation requires 2 copies of pathogenic variants of the gene, GAA. GAA codes for the enzymatic activity of acid alpha-glucosidase and is the only human gene mutation known to cause GSD II. GAA has been localized in the human karyotype to the long arm of chromosome 17 at band q25.2 - q25.3. Heterozygotes, or carriers (persons with one normal copy and one pathogenic variant copy of the gene), are asymptomatic and hence have no clinical manifestations of the disease. Two copies of the mutated variant are needed to express the clinical disease, GSD II.

Allelic variants have been identified within GAA and include missense, nonsense, intragenic deletions/insertions, and splice-site mutations. [13, 14] The spectrum of mutations can result in the following:

  • No detectable messenger RNA (mRNA) and complete absence of enzymatic protein
  • A normal amount of enzyme with reduced activity (eg, reduced affinity for glycogen)
  • A reduced amount of enzyme with normal activity
  • No detectable enzyme activity in infantile form; varying amounts of residual enzyme activity in late-onset forms

Molecular genetic testing enables for the identification of the more common allelic variants within the GAA gene. Ethnicity and phenotype can help identify the more likely pathogenic variants, such as p.Arg854Ter, p.Asp645Glu, and c.336-13T>G.

  • p.Arg854Ter is present in 50-60% of African Americans with infantile-onset GSD II. [4]
  • p.Asp645Glu is identified in 40-80% of patients of Chinese ancestry with infantile-onset GSD II. [4]
  • The c.336-13T>G mutation is most commonly found in late-onset adult patients with GSD II. [15] This mutation is present in 50-85% of affected persons. [4, 16] No individuals with this mutation have the classic infantile-onset form. Cardiac involvement is rare among patients with this genotype. [17]