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The Diagnostic Path to Pompe Disease

US Neurology, 2014;10(1):44–7 DOI:


Pompe disease (PD) is a lysosomal disease that primarily affects skeletal and smooth muscles due to a deficiency of acid alpha glucosidase. The resulting clinical phenotype reflects a continuum ranging from severe infantile to later onset forms of PD. Early diagnosis is essential to prevent long-term complications and/or disease progression through initiation of enzyme-replacement therapy. The diagnostic path to PD starts with the ascertainment of medical and family history as well as an in-depth clinical and neurologic evaluation. The involvement of proximal muscle groups including hip and thigh muscles as well as the diaphragm is characteristic for later onset PD. Once PD is considered creatine kinase (CK) should be measured, realizing that levels may be within normal limits in end stage disease. Ultimately, diagnostic confirmation is readily achieved by enzyme analysis in dried blood spots and/or leukocytes followed by molecular analysis. Muscle biopsy is not sensitive enough for diagnostic testing of PD but may be an important diagnostic test for the differential diagnosis of myopathies. Future diagnostic approaches include whole exome and genome sequencing, which may contribute to our understanding of genotype–phenotype correlation and phenotype prediction.

Keywords: Pompe disease, alpha glucosidase, glycogen storage disease II, diagnosis, laboratory testing, dried blood spot
Disclosure: Olaf A Bodamer, MD, PhD, is a member of Genzyme speaker’s bureau and has also received research funding. Christina Y Hung, MD, has no conflicts of interest to declare.
Received: September 02, 2013 Accepted: February 24, 2013
Correspondence: Olaf A Bodamer, MD, PhD, Professor of Human Genetics, Biochemistry and Molecular Biology, Director, Division of Clinical and Translational Genetics, Dr John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Biochemical Research Building Room 608 (M-860), 1501 NW 10th Ave, Miami, FL 33136, US. E:
An erratum to this article can be found below.

Pompe disease (PD, glycogen storage disease type II, OMIM # 232300) is an autosomal recessive lysosomal storage disease caused by deficiency of acid alpha-glucosidase (GAA) (acid maltase, EC due to mutations in the GAA gene.1 Progressive storage of intra-lysosomal glycogen in skeletal, cardiac, and smooth muscle cells leads to impairment of cellular integrity and function with eventual apoptosis of affected muscle fibers, inflammatory processes, and subsequent replacement through connective tissue.2 Additional systemic metabolic abnormalities may be observed although their clinical relevance is unknown.3

PD represents a continuous clinical spectrum with about one-third of patients presenting during the first months of life or prenatally with hypertrophic cardiomyopathy, muscle hypotonia, and secondary complications, such as respiratory insufficiency, feeding difficulties, and failure to thrive.1,4,5 The remaining two-thirds of patients present as clinical continuum resembling the clinical picture of a limb girdle muscular dystrophy (LGMD) without cardiomyopathy and with variable age of onset ranging from late infancy to adulthood.6 The proximal muscle groups including thigh, pelvic, and shoulder muscles are affected while the distal muscle groups are typically spared.7 The diaphragm in contrast to other genetic causes of LGMD is typically affected in PD contributing to the respiratory insufficiency and CO2 retention in later onset patients.6,8 Importantly, asymptomatic patients with PD have been reported.9 Residual GAA activity correlates with severity of PD, such that infantile onset patients show complete absence of enzyme activity whereas later onset patients retain up to 30 % residual enzyme activity.8

PD is a pan-ethnic disease with an estimated frequency of 1:40,000, although recent reports from newborn screening studies suggest that PD may be more frequent.1,8,10,11 The advent of recombinant human enzyme replacement therapy (ERT) has improved quality of life and reduced morbidity and mortality in the majority of patients with both infantile-onset PD11,12 and later-onset PD.13 Recombinant human GAA (rhGAA) is harvested from Chinese hamster ovary (CHO) cells and exerts its activity after proteolytic cleavage in the lysosomes. The uptake of rhGAA is readily achieved via mannose receptors on macrophages of the liver and spleen.8

Diagnostic Approaches
The diagnostic path to late-onset PD may be long and extensive for adult patients presenting with muscular symptoms due to the phenotypic overlap with LGMD. Although the presence of clinical clues have been reported in the medical literature, the predominant and first-presenting symptoms are typically muscular in nature.14 Early involvement of the diaphragm causing respiratory insufficiency15–17 as well as cardiac arrythmias18 or vascular involvement19 may increase the clinician’s suspicion for PD. Since late-onset PD lacks a definite clinical phenotype that allows clinicians to clearly differentiate PD from other LGMDs, it is important for physicians to include PD in the differential diagnosis for LGMD considering the availability of ERT.

A diagnosis of infantile-onset PD is readily suspected in any infant with hypertrophic cardiomyopathy, muscular hypotonia, and moderate elevation of creatine kinase (CK) levels.1,4,5 Any delay in diagnosis is not acceptable since it is now well established that an early diagnosis and timely initiation of ERT will have a drastic impact on the natural disease course.12 The delayed start of ERT, even by only a few weeks increases the morbidity in affected infants significantly.11

Laboratory Abnormalities
CK levels are a sensitive marker for PD as CK is moderately elevated in all infants with PD and in more than 95 % of adults with PD.7,8, The remaining 5 % of adults with PD have either very mild disease or, which is more likely, are in the terminal stage of PD with little or no residual skeletal muscle mass. Muscle injury in PD will not only lead to elevations of CK, but also to a release of other muscle enzymes including aldolase, lactate dehydrogenase (LDH), and amino transaminases (AST, ALT). The ratio of AST to ALT in PD is typically close to 1 in contrast to acute rhabdomyolysis where AST/ALT is greater than 3.20 However, elevated transaminases should not be misinterpreted in the context of PD or other myopathies as being secondary to liver disease.20,21

Muscle Biopsy
Muscle biopsies have an important place in the diagnostic workup of myopathies where the differential diagnosis may be extensive. However, if PD is considered in a patient based on the clinical phenotype, family history, and/or elevated CK levels, a muscle biopsy may not be used as the first-line diagnostic test. Instead, analysis of GAA activity is preferred for initial screening due to its short turnaround time and non-invasiveness.22 In cases of uncertain or conflicting laboratory test results (enzyme and molecular), muscle biopsies as a second-tier test may guide the physician and provide additional valuable information for the differential diagnosis. Physicians need to be aware that up to 25 % of adult patients with PD may have normal muscle biopsies without pathologic storage of glycogen on periodic acid–Schiff (PAS) staining.22,23

  1. Hirschhorn R, Reuser AJJ, Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (Eds.), The Metabolic & Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001:3389–420.
  2. Thurberg BL, Lynch Maloney C, Vaccaro C, et al., Characterization of pre- and post-treatment pathology after enzyme replacement therapy for pompe disease, Lab Investig, 2006;86:1208–20.
  3. Pascual JM, Roe CR, Systemic metabolic abnormalities in adult-onset acid maltase deficiency: beyond muscle glycogen accumulation, JAMA Neurol, 2013;70:756–63.
  4. Kishnani PS, Hwu WL, Mandel H, et al., A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease, J Pediatr, 2006;148:671–6.
  5. Chiang SC, Hwu WL, Lee NC, et al., Algorithm for Pompe disease newborn screening: results from the Taiwan screening program, Mol Genet Metab, 2012;106:281–6.
  6. Hagemanns ML, Winkel LP, van Doorn PA, et al., Clinical manifestation and clinical course of late-onset Pompe’s disease in 54 Dutch patients, Brain, 2005;128:671–7.
  7. Vissing J, Lukacs Z, Straub V, Diagnosis of Pompe disease, JAMA Neurol, 2013; 486:E1–5.
  8. von der Ploeg AT, Reuser AJJ, Pompe disease, Lancet, 2008;372:1342–53.
  9. Ausems MG, ten Berg K, Beemer FA, Wokke JH, Phenotypic expression of late-onset glycogen storage disease type II: identification of asymptomatic adults through family studies and review of reported families, Neuromuscular Disord, 2000;10:467–71.
  10. Mechtler TP, Stary S, Metz TF, et al., Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria, Lancet, 2012;379:335–41.
  11. Chien YH, Lee NC, Thurberg BL, et al., Pompe disease in infants: improving the prognosis by newborn screening and early treatment, Pediatrics, 2009;124: e1116–25.
  12. Nicolino M, Byrne B, Wraith JE, et al., Clinical outcomes after longterm treatment with alglucosidase alfa in infants and children with advanced Pompe disease, Genet Med, 2009;11:210–9.
  13. Gungor D, Kruijshaar ME, Plug I, et al., Impact of enzyme replacement therapy on survival in adults with Pompe disease: results from a prospective international observational study, Orphanet J Rare Dis, 2013;8:49–56.
  14. Laforet P, Nicolino M, Eymard PB, et al., Juvenile and adultonset acid maltase deficiency in France: genotype-phenotype correlation, Neurology, 2000;55:1122–8.
  15. Engel AG, Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies, Brain, 1970;93:599–616.
  16. Sivak ED, Salanga VD, Wilbourn AJ, et al., Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis, Ann Neurol, 1981;9:613–5.
  17. Trend PS, Wiles CM, Spencer GT, et al., Acid maltase deficiency in adults. Diagnosis and management in five cases, Brain, 1985;108:845–60.
  18. Francesconi M, Auff E, Cardiac arrhythmias and the adult form of type II glycogenosis, N Engl J Med, 1982;306:937–8.
  19. Makos MM, McComb RD, Hart MN, Bennett DR, Alphaglucosidase deficiency and basilar artery aneurysm: report of a sibship, Ann Neurol, 1987;22:629–33.
  20. Nathwani RA, Pais S, Reynolds TB, Kaplowitz N, Serum alanine aminotransferase in skeletal muscle disease, Hepatology, 2005;41:380–2.
  21. Hoeksma M, Boon M, Niezen-Koning KE, et al., Isolated elevated serum transaminases leading to the diagnosis of asymptomatic Pompe disease, Eur J Pediatr, 2007;166:871–4.
  22. Ausems MG, Lochman P, van Diggelen OP, et al., A diagnostic protocol for adult-onset glycogen storage disease type II, Neurology, 1999;52:851–3.
  23. Vissing J, Lukacs Z, Straub V, Diagnosis of Pompe disease. Muscle biopsy vs blood-based assays, JAMA Neurol, 2013;70:923–7.
  24. Chamoles NA, Niizawa G, Blanco M, et al., Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper, Clin Chim Acta, 2004;347:97–102.
  25. Gelb MH, Turecek F, Scott CR, Chamoles NA, Direct multiplex assay of enzymes in dried blood spots by tandem mass spectrometry for the newborn screening of lysosomal storage disorders, J Inherit Metab Dis, 2006;29:397–404.
  26. Winchester B, Bali D, Bodamer OA, et al., Pompe Disease Diagnostic Working Group, Methods for a prompt and reliable laboratory diagnosis of Pome disease: report from an international consensus meeting, Mol Genet Metab, 2008;93:275–81.
  27. Dajnoki A, Bodamer OA, Diagnosing lysosomal storage diseases: Pompe Disease, Curr Protoc Hum Genet, 2012;Chapter 17:Unit 17.11.
  28. Reuser AJ, Verheijen FW, Bali D, et al., The use of dried blood spot samples in the diagnosis of lysosomal storage disorders – current status and perspectives, Mol Genet Metab, 2011;104:144–8.
  29. Krishani PS, Steiner RD, Bali D, et al., Pompe disease diagnosis and management guideline, Genet Med, 2006;8:267–88.
  30. Chester MA, Lundblad A, Hager A, et al., Increased urinary excretion of a glycogen-derived tetrasaccharide in heterozygotes with glycogen storage diseases type II and III, Lancet, 1983;1:994–5.
  31. Bali DS, Goldstein JL, Banugaria S, et al., Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience, Am J Med Genet C Semin Med Genet, 2012;160C(1):40–9.B
  32. Kishnani PS, Goldenberg PC, DeArmey SL, et al., Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants, Mol Genet Metab, 2010;99:26–33.
  33. Banugaria SG, Prater SN, Ng YK, et al., The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease, Genet Med, 2011;13:729–36.
  34. Messinger YH, Mendelsohn NJ, Rhead W, et al., Successful immune tolerance induction to enzyme replacement therapy in CRIMnegative infantile Pompe disease, Genet Med, 2012;14:135–42.
  35. Lacaná E, Yao LP, Pariser AR, Rosenberg AS, The role of immune tolerance induction in restoration of the efficacy of ERT in Pompe disease, Am J Med Genet C Semin Med Genet, 2012;160:30–9.
  36. Wang Z, Okamoto P, Kreuzer J, A new assay for fast, reliable CRIM status determination in infantile-onset Pompe disease, Mol Genet Metab, 2014;111:92–100.
  37. Kroos M, Hoogeveen-Westerveld H, Michelakakis H, et al., GAA Database Consortium. Update of the Pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants, Hum Mutat, 2012;33:1161–5.
  38. Tajima Y, Matsuzawa F, Aikawa S, et al., Structural and biochemical studies on Pompe disease and a “pseudodeficiency of acid alpha-glucosidase”, J Hum Genet, 2007;52:898–906.
  39. McCarthy JJ, McLeod HL, Ginsburg GS, Genomic medicine: a decade of successes, challenges, and opportunities, Sci Transl Med, 2013;5:189sr4 [Epub before press].
  40. Lo SM, Choi M, Jain D, et al., Phenotypic diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis, Blood, 2012;119:4731–40.
  41. Chien YH, Chiang SC, Zhang XK, et al., Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program, Pediatrics, 2008;122:e39–45.
  42. Scott CR, Elliott S, Buroker N, et al., Identification of infant at risk for developing fabry, pompe, or mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry, J Pediatr, 2013;163:498–503.
  43. Dajnoki A, Muhl A, Fekete G, et al., Newborn screening for Pompe disease by measuring acid alpha-glucosidase activity using tandem mass spectrometry, Clin Chem, 2008;54:1624–9.
  44. Wittmann J, Karg E, Turi S, et al., Newborn screening for lysosomal storage disorders in Hungary, JIMD Rep, 2012;6:117–25.
Keywords: Pompe disease, alpha glucosidase, glycogen storage disease II, diagnosis, laboratory testing, dried blood spot
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