Pompe disease is a rare autosomal recessive disorder caused due to mutation of the gene that encodes alpha-glucosidase (GAA). GAA cleaves alpha 1,4 and 1,6 linkages in the glycogen, which releases glucose. Deficiency of the enzyme can lead to accumulation of the glycogen in various tissues. The clinical features can vary depending upon the enzyme functioning in the body. The combined incidence of Pompe disease is estimated to be 1/40,000. Severe cases of Pompe disease are seen in infants with less than 1% functioning enzymes. It is the limit of the assay sensitivity as well. The clinical features of Pompe disease generally appear between 8 and 12 weeks of age for infants within a range from 0 to 12 months.

Clinical Presentation In Infancy

Infants may present with severe cardiac manifestations, such as cardiomyopathy and cardiomegaly. They may manifest with failure to thrive, and difficulty feeding, also known as ‘floppy babies’ leading to arrhythmias and cardiac failure. Hepatomegaly, weakness, hypotonia, and respiratory difficulty are other manifestations of Pompe disease. They may require assisted ventilation by the age of 6 months with a median age of death of 8.7 months. Respiratory insufficiency is a well associated feature of Pompe disease reported by almost half of the adult patients along with exertional dyspnea. As per studies conducted, it is seen that there is a correlation between respiratory symptoms and age of onset for skeletal muscle weakness. The differential diagnosis of Pompe disease in infants includes other diseases causing cardiomyopathy or hypotonia.¹

Differential Diagnosis For Classic And Non-Classic Infantile Onset 

Infants may present common signs and symptoms for the classic infantile onset form of Pompe disease, which may be similar to other disease modalities as well. For example, common signs and symptoms like hypotonia, respiratory insufficiency, areflexia, progressive proximal muscle weakness may represent congenital neuropathy, infantile onset spinal muscular atrophy type 1, and congenital myopathy (+/-MR). Similarly, for non-classic infantile onset, symptoms like muscle weakness and respiratory distress may represent Duchenne and Becker Muscular Dystrophy. Infants suffering from Pompe disease may manifest gastrointestinal and nutritional manifestations like difficulty sucking due to oral motor weakness, macroglossia, and facial hypotonia. They may suffer from splenomegaly and hepatomegaly as well. Muscle weakness might lead to gastroparesis, gastroesophageal reflux, and constipation.²

Clinical Evaluation Of Symptoms

Infantile Pompe disease may present with subtle impairment related to cognitive function, which can be modified by emerging treatments like enzyme replacement therapy (ERT). Adult onset form may be characterized by a slowly progressive myopathy involving skeletal muscle which may present in the second or sixth decade of life. The late onset of Pompe disease can present at any age, which is characterized by lack or absence of cardiac involvement leading to relatively less morbid short-term prognosis. Symptoms can lead to progressive muscle weakness involving the paraspinal trunk muscle and proximal lower limb. It also involves the accessory muscle of respiration along with the diaphragm. In certain cases, diaphragmatic weakness appears before any other weakness. Patients may require a wheelchair along with assisted ventilation if the muscle weakness progresses further. Significant mortality and morbidity is reported due to respiratory failure.³

Suggestive Findings In Clinical Diagnosis

Pompe disease can be classified based on severity, organ involvement, rate of progression, and age. Infantile onset Pompe disease (IOPD) manifests before the age of 12 months with cardiomyopathy. Clinical findings involve muscle weakness/motor delay (20% to 63%), poor feeding/failure to thrive (44% to 97%), respiratory infections/difficulty (27% to 78%), and cardiac problems related to cardiomegaly, left ventricular outflow obstruction, wide QRS complex with shortened PR interval, cardiomyopathy (50% to 92%). 

Late-onset Pompe disease (LOPD) may present before the age of 12 months without cardiomyopathy and all other individuals with the onset after 12 months. It is characterized by respiratory insufficiency and proximal muscle weakness. Cardiac involvement is uncommon. LOPD is suspected among children, adults, and infants with respiratory insufficiency and proximal muscle weakness. Patients suffering from IOPD require ventilatory support which improves their survival, acquisition of motor skills, ventilation independent survival, and decreased cardiac mass in comparison to untreated controls.⁴

Retrospective View On Diagnosis Of Pompe Disease

Studies show patients with Pompe disease present with a heterogeneous clinical presentation that overlaps with various other muscle diseases making it difficult for physicians to reach a timely diagnosis causing increasing patient morbidity. It is recommended that a creatinine kinase (CK) test should be conducted to exclude Limb-girdle muscular dystrophy (LGMD). Muscle biopsy is recommended for individuals presenting with proximal muscle weakness. 

The current criterion standard for diagnosis of Pompe disease involves measurement of GAA in dried blood using a minimally invasive, cost-effective reliable assay. The assay is considered a first-tier diagnostic test when a patient presents with unexplained increase in CK levels, limb-girdle muscle weakness (LGMW), or respiratory insufficiency. If the GAA enzyme activity within a blood-based assay indicates Pompe disease, a second test is recommended to confirm its diagnosis. Patients with nonspecific, chronically raised CK levels and inconclusive LGMW, should be subjected to a blood-based assay for GAA enzyme activity, to confirm or rule out the diagnosis of Pompe disease.⁵


  1. Katzin LW, Amato AA. Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy. J Clin Neuromuscul Dis. 2008 Jun;9(4):421-31. doi: 10.1097/CND.0b013e318176dbe4
  2. Bay LB, Denzler I, Durand C, et al Infantile-onset pompe disease: diagnosis and management. Arch argent pediatr. 2019 Aug 1;117(4):271-278. English, Spanish. doi: 10.5546/aap.2019.eng.271
  3. Kishnani PS, Steiner RD, Bali D, et al Pompe disease diagnosis and management guideline. Genet Med. 2006 May;8(5):267-88. doi: 10.1097/01.gim.0000218152.87434.f3. Erratum in: Genet Med. 2006 Jun;8(6):382. ACMG Work Group on Management of Pompe Disease; Case, Laura [corrected to Case, Laura E].
  4. Leslie N, Bailey L. Pompe disease. 2007 Aug 31 [Updated 2017 May 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1261/
  5. Vissing J, Lukacs Z, Straub V. Diagnosis of pompe disease: muscle biopsy vs blood-based assays. JAMA Neurol. 2013 Jul;70(7):923-7. doi: 10.1001/2013.jamaneurol

Reviewed by Harshi Dhingra, MD, on 7/27/2021.