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, adolescents and adults: 

  • Infantile onset: cardiomegaly/cardiomyopathy, hypotonia, rapidly progressive skeletal, smooth, and ventilatory muscle weakness, feeding difficulties and failure to  thrive Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med 2006; 8:267-88. -- Gilbert-Barness E. Review: Metabolic cardiomyopathy and conduction system defects in children. Ann Clin Lab Sci 2004; 34:15-34. -- 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. -- Gilchrist JM. Overview of neuromuscular disorders affecting respiratory function. Semin Respir Crit Care Med 2002; 23:191-200. .
  • Children, adolescents and adults: proximal limb-girdle and/or respiratory muscle weakness and/or elevated creatine kinase (CK)  levels American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve. 2009;40:149-60. -- 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. .

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 elevated creatine kinase (CK), with or without respiratory muscle weakness:

Pompe diagnosis in patients with unexplained limb-girdle muscle weakness *Lukacs Z. et al. Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness. Neurology. 2016 Jul 19;87(3):295-8.
*Mucumesi 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.
*Gutiérrez-Rivas E. et al. Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: A Spanish cohort. Neuromuscul Disord. 2015 Jul;25(7):548-53. doi: 10.1016/j.nmd.2015.04.008. Epub 2015 Apr 23.
*Willis T, et al. 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.

Pompe diagnosis in patients with unexplained and sustained HyperCKaemia *Lukacs Z. et al. Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness. Neurology. 2016 Jul 19;87(3):295-8.
*Mucumesi 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.
*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.
* 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.