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 and even potentially life-threatening 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 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. .

A recent 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 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. .

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  disease 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.

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

 

Diagnostic delay in infants, children and adolescents/adults with Pompe disease 2

Adapted from Kishnani et al,  2013 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.

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 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. -- 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. . Residual GAA activity in Pompe patients can be anywhere from less than 1% (generally in infants) to 30% of average normal  levels Van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. 2008;372(9646):1342-53. . Pompe disease can also be confirmed by mutation analysis to confirm the presence of two mutated alleles (See Genetics section).

Historically, the GAA enzyme assay was performed using cultured skin  fibroblasts 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. 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. . 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 thus becoming standard practice. Blood sampling for testing for Pompe disease is minimally invasive, accurate, and can usually provide results within just a few  days 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. -- 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. . If a reduced GAA enzyme activity is found, this should be confirmed in a second sample and/or by GAA gene  sequencing American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM). Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve. 2009;40:149-60. .

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 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. . Thus, a diagnosis of Pompe disease should always be confirmed by absence or reduction of GAA activity, or by genetic analysis.