Diagnosis and testing

Differential diagnosis

The ability to correctly differentiate Pompe disease from other disorders is crucial for minimizing diagnostic delays and optimizing patient outcomes. However, because Pompe disease is rare and many of its signs and symptoms are shared with other conditions, the differential diagnosis can be challenging.

Pompe disease should be considered when signs and symptoms suggest progressive muscular degeneration in infants, children and adults:

  • Infantile onset: cardiomegaly/cardiomyopathy, hypotonia, rapidly progressive skeletal, smooth, and ventilatory muscle weakness, feeding difficulties and failure to thrive.1–4
  • Children and adults: proximal limb-girdle and/or respiratory muscle weakness and elevated creatine kinase (CK) levels.5,6

Once a clinical suspicion is raised, Pompe disease can be tested for by measuring acid alpha glucosidase (GAA) enzyme activity.

Populations at risk of late-onset Pompe disease

As shown in the following tables, there is compelling evidence to support routinely testing for Pompe disease (using a GAA enzyme assay) in patient populations presenting with certain symptoms suggestive of Pompe disease, such as limb-girdle muscle weakness and/or persistent and unexplained moderately elevated creatine kinase (CK), with or without respiratory muscle weakness:


Pompe diagnosis in patients with limb-girdle muscle weakness8,9, 19


Pompe diagnosis in patients with elevated creatine kinase (CK)8,10, 12, 19


Diagnostic and confirmatory testing


Pompe disease is a rare condition with signs and symptoms that mimic many other conditions. This means that Pompe disease tends to be overlooked, at least at first, until more common diseases have been excluded. The result can be damaging diagnostic delays. In infants, early diagnosis is particularly important, as without treatment death typically occurs within the first year of life. A retrospective analysis of infants with Pompe disease reported a difference of 2.7 months between the median age of onset of symptoms and diagnosis.13

Another analysis of data from the Pompe Registry found diagnostic delays in infants, children and adolescents/adults. In infants who had symptom onset during the first 12 months of life, and presented with cardiomyopathy (i.e. classic infantile Pompe disease), the median diagnostic delay was 1.4 months. For patients with onset over the age of 12 years, the median diagnostic delay was 6.0 years. The longest delay in diagnosis was a median of 12.6 years, found in patients who had symptom onset during the first 12 months of life but did not have cardiomyopathy, or had symptom onset between 12 months and 12 years of age.14
There is therefore a need for earlier diagnosis across the whole spectrum of Pompe disease, to help optimize patient outcomes.


Diagnostic delay in infants, children and adolescents/adults with Pompe disease14

Adapted from Kishnani et al, 201314


Diagnostic pathway
Although the clinical paths to diagnosis of Pompe disease are variable, the process generally involves:

  • Clinical evaluation of presenting symptoms by a gateway physician
  • Referral to a specialist for further clinical investigation, including additional lab or clinical tests
  • Confirmatory testing


Definitive diagnosis
Pompe disease is confirmed by a complete absence or marked reduction of acid alpha-glucosidase (GAA) activity.15,16 Residual GAA activity in Pompe patients can be anywhere from less than 1% (generally in infants) to 30% of average normal levels.17 Pompe disease should also be confirmed by mutation analysis to confirm the presence of two mutated alleles (See Genetics section). 18


Dried Blood Spot


Historically, the GAA enzyme assay was performed using cultured skin fibroblasts.15, 16 However, sample collection is relatively invasive and results take approximately 6 weeks to obtain. This long turnaround time is clearly undesirable, especially in infants with rapidly progressive disease. The use of blood samples, including dried blood spots, is now standard practice. Blood sampling for testing for Pompe disease is minimally invasive, accurate, and can usually provide results within just a few days.15, 16 If a reduced GAA enzyme activity is found, this should be confirmed in a second sample and/or by GAA gene sequencing.5


Although muscle biopsies are an option for GAA activity testing, they are generally not preferred. This is because they are invasive and have a high risk of false positives due to sample mishandling. Muscle biopsies may be useful for histological evaluation, but it is important to note that glycogen content can vary widely among muscles, so seemingly normal biopsies do not rule out Pompe disease.16 Thus, a diagnosis of Pompe disease should always be confirmed by absence or reduction of GAA activity, and/or by genetic analysis18.



DBS Video included here - GZEMEA.PD.19.01.0001 (just approved)



  1. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med 2006; 8:267-88.

  2. Gilbert-Barness E. Review: Metabolic cardiomyopathy and conduction system defects in children. Ann Clin Lab Sci 2004; 34:15-34.

  3. Howell RR, Byrne B, Darras BT, Kishnani P, Nicolino M, van der Ploeg A. Diagnostic challenges for Pompe disease: An under-recognized cause of floppy baby syndrome. Genet Med 2006:8;1-8.

  4. Gilchrist JM. Overview of neuromuscular disorders affecting respiratory function. Semin Respir Crit Care Med 2002; 23:191-200.

  5. American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve. 2009;40:149-60.

  6. Ausems MG, Lochman P, van Diggelen OP, Ploos van Amstel HK, Reuser AJ, Wokke JH. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology. 1999 Mar 10;52(4):851-3.

  7. Goldstein JL, Young SP, Changela M, Dickerson GH, Zhang H, Dai J, Peterson D, Millington DS, Kishnani PS, Bali DS (2009). Screening for Pompe disease using a rapid dried blood spot method: experience of a clinical diagnostic laboratory. Muscle Nerve 40:32-36.

  8. Lukacs Z, et al. Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness. American Academy of Neurology 2016;87:295-298
  9. Willis T, Roberts M, Hilton-Jones D, Quinlivan R,5 Hanna M, Straub V (2012). Detection rate of Pompe disease in undiagnosed neuromuscular patients from four major centre’s in the UK- Results of a 12 month prospective audit. BMC Musculoskelet Disord 14(Suppl 2):P20.

  10. Bautista Lorite J (2013) Detección de la enfermedad de Pompe en pacientes con distrofia de cinturas indefinidas o hiperCKemias asintomáticas. Expert Rev Neur Ed especial Octubre 2013:17-19. [Article in Spanish]

  11. Fernandez C, de Paula AM, Figarella-Branger D, Krahn M, Giorgi R, Chabrol B, et al. (2006). Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 66:1585-7.

  12. Spada M, Porta F, Vercelli L, Pagliardini V, Chiadò-Piat L, Boffi P, Pagliardini S, Remiche G, Ronchi D, Comi G, Mongini T (2013). Screening for later-onset Pompe's disease in patients with paucisymptomatic hyperCKemia. Mol Genet Metab 109:171-173.

  13. Kishnani PS, Hwu W-L, Mandel H, Nicolino M, Yong F, Corzo D. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr 2006; 148:671-676.

  14. Kishnani PS, Amartino HM, Lindberg C, Miller TM, Wilson A, Keutzer J; Pompe Registry Boards of Advisors. Timing of diagnosis of patients with Pompe disease: data from the Pompe registry. Am J Med Genet A. 2013;161A(10):2431-43.

  15. Zhang H, Kallwass H, Young SP, et al. Comparison of maltose and acarbose as inhibitors of maltase-glucoamylase activity in assaying acid alpha-glucosidase activity in dried blood spots for the diagnosis of infantile Pompe disease. Genet med 2006; 8:302-306.

  16. Winchester B, Bali D, Bodamer OA, et al for The Pompe Disease Diagnostic Working Group. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008;93(3):275-281.

  17. van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. 2008;372(9646):1342-53.

  18. van der Ploeg AT et al. European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience. Eur. J. Neurol 2017; 24(6):768-e31

  19. *Musumeci O. et al. LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population. J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):5-11.

GZEMEA.PD.14.11.0313d (1) - March 2019