Diagnosing Infantile-Onset Pompe Disease

The diagnosis of infantile-onset Pompe disease (IOPD) is often challenging, and its progression variable. IOPD can be rapidly progressive and lead to poorer outcomes in those patients with delayed diagnosis.

 Advances in understanding of disease progression and outcomes, in addition to the use of molecular genetic profiles, help inform infant care decisions.

Incidence of IOPD is believed to vary across ethnic groups, and African Americans may have the highest incidence of IOPD, as Pompe disease has been projected to affect 1 in 14,000 African Americans. Estimates of IOPD incidence in those of European origin, however, are lower and range from 1 in 100,000 to 1 in 200,000.

IOPD presents with the cardinal sign of severe hypertrophic cardiomyopathy in the first few months of life. IOPD patients also present with hypotonia, hepatomegaly, failure to thrive, feeding difficulties, respiratory distress, and respiratory infections. According to natural history data, those with IOPD are expected to die from heart and/or respiratory failure prior to their first birthday.


Although the clinical paths to diagnosis are variable, the process could generally involve:


Clinical evaluation of presenting symptoms by a gateway physician

  • An infant may present to a pediatrician with signs of hypotonia, developmental delays, and/or feeding difficulties
  • An infant may be seen by an emergency room physician for cardiac and/or respiratory distress


Specialist referral for further clinical investigation

  • As cardiac involvement is predominant, the initial referral is often to a pediatric cardiologist. Chest x-rays, ECHO, and ECG usually reveal cardiomegaly and other cardiac complications such as arrhythmias. If present, an abnormal ECG finding in IOPD is often shortened PR interval, which can present as Wolff-Parkinson-White syndrome
  • Respiratory insufficiency may be indicated by physical signs and elevated serum bicarbonate levels
  • Elevated creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and urine hexose tetrasaccharide (Hex4) levels are also signs


Lysosomal enzyme acid alpha-glucosidase (GAA) activity and confirmatory testing

  • Pompe can be identified with a GAA enzyme assay; confirmatory testing such as molecular genetic testing for GAA gene mutations should follow
  • Upon a conclusive diagnosis, family genetic testing is recommended


Molecular genetic profile

  • Molecular genetic testing (if not done so already) can be used to identify common variants associated with IOPD and assist with the characterization of IOPD. Please read more about the role of genetics in Pompe

Identifying a decrease in the levels of GAA enzyme activity remains the standard for diagnosis of IOPD. Variant analysis of the GAA gene, however, may be part of clinical decision-making at various points in an IOPD diagnostic pathway.

Low GAA levels in the presence of clinical findings of IOPD confirms an IOPD diagnosis. Generally, GAA levels <1% of those observed in infant controls are observed in IOPD. This can be identified with tests such as blood assays, skin fibroblasts, and biopsy of muscle tissue. Ideally, this measure of GAA enzyme activity is immediately followed by GAA gene mutation analysis for diagnostic confirmation.

Blood assays

Dried blood spot samples are the typical blood-based assay for measure of GAA enzyme activity in the infant. They are minimally invasive, have rapid turnaround time, and can be used for screening extensive numbers of samples in cases such as newborn screening.

The majority of testing labs performing blood assays for GAA enzyme activity can also use samples to perform immediate variant analysis of the GAA gene for diagnostic confirmation.

Learn more about the genetics of Pompe and diagnostic role of various GAA gene mutations in IOPD Diagnosis.

Skin fibroblasts

Skin fibroblasts have long been the gold standard for definitive measure of GAA enzymatic activity, but a long turnaround time limits their usefulness in infants. Samples are obtained by skin biopsy and require 4 to 6 weeks of cell culture to generate adequate material for the GAA enzyme assay.

Muscle biopsy

Although an option, muscle biopsies are generally not preferred for GAA enzyme assay in the infantile setting because they are invasive and can require general anesthesia. Muscle biopsy, however, can be quite useful to confirm diagnosis of Pompe in the identification of glycogen buildup in muscle tissues. It is important to remember that absence of glycogen accumulation in any particular biopsy sample does not rule out Pompe disease since glycogen buildup can vary across different muscles and by stage of the disease progression.

Analysis of Pompe Registry data has shown a median delay of 1.4 months from time of initial symptoms to diagnosis in IOPD patients. Additionally, a median diagnostic delay of 12.6 years has been observed in the combination of IOPD patients and late-onset Pompe disease (LOPD) patients younger than 12 years. Clinical decline during delay periods can be profound, especially in the case of IOPD, with irreversible disease progression occurring.

IOPD shares signs and symptoms with many other disease states, and a differential diagnosis can delay initiation of critical disease management. Consult the infographic below, which demonstrates how IOPD could easily be misdiagnosed.

Shared Symptoms Between IOPD Other Disorders


  • Shared symptoms with IOPD

Spinal muscular atrophy | acute Werdnig-Hoffman disease)

  • Hypotonia
  • Progressive proximal muscle weakness
  • Absent reflexes
  • Feeding difficulties
  • Elevated CK


  • Hypotonia
  • Macroglossia

Congenital muscular dystrophy

  • Severe Hypotonia
  • Severe muscle weakness

Danon disease

  • Hypertrophic cardiomyopathy
  • Skeletal muscle myopathy
  • Vacuolar glycogen storage
  • Elevated CK

Endocardial fibroelastosis

  • Breathlessness
  • Feeding difficulties
  • Cardiomegaly
  • Heart failure

Carnitine deficiency

  • Cardiomyopathy
  • Muscle weakness

Glycogen storage diseases III and IV

  • Cardiomegaly
  • Muscle weakness
  • Elevated CK
  • Hepatomegaly
  • Hypotonia

Idiopathic hypertrophic cardiomyopathy

  • Biventricular hypertrophy


  • Cardiomegaly

Mitochondrial/respiratory chain disorders

  • Hepatomegaly
  • Cardiomyopathy
  • Myopathy
  • Elevated CK

Peroxisomal disorders

  • Hypotonia
  • Hepatomegaly