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Diagnosis of Pompe Disease Muscle Biopsy vs Blood-Based Assays

John Vissing, MD, DMSci1; Zoltan Lukacs, PhD2; Volker Straub, MD, PhD3
[+] Author Affiliations
1Neuromuscular Research Unit, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
2Department of Pediatrics and Institute of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England
JAMA Neurol. 2013;70(7):923-927. doi:10.1001/2013.jamaneurol.486.
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The diagnosis of Pompe disease (acid maltase deficiency, glycogen storage disease type II) in children and adults can be challenging because of the heterogeneous clinical presentation and considerable overlap of signs and symptoms found in other neuromuscular diseases. This review evaluates some of the methods used in the diagnosis and differential diagnosis of late-onset Pompe disease. Muscle biopsy is commonly used as an early diagnostic tool in the evaluation of muscle disease. However, experience has shown that relying solely on visualizing a periodic acid–Schiff–positive vacuolar myopathy to identify late-onset Pompe disease often leads to false-negative results and subsequent delays in identification and treatment of the disorder. Serum creatine kinase level can be normal or only mildly elevated in late-onset Pompe disease and is not very helpful alone to suggest the diagnosis, but in combination with proximal and axial weakness it may raise the suspicion for Pompe disease. A simple blood-based assay to measure the level of α-glucosidase activity is the optimal initial test for confirming or excluding Pompe disease. A timely and accurate diagnosis of late-onset Pompe disease likely will improve patient outcomes as care standards including enzyme replacement therapy can be applied and complications can be anticipated. Increased awareness of the clinical phenotype of Pompe disease is therefore warranted to expedite diagnostic screening for this condition with blood-based enzymatic assays.

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Figure 1.
Hematoxylin-eosin Staining of Muscle Biopsy Tissue From Patients With Confirmed Pompe Disease

A and B, Unspecific myopathic changes with relatively preserved muscle structure and no evidence of vacuolar myopathy or glycogen accumulation. C, Vacuolar myopathy (arrows) in a few muscle fibers. D, Severe vacuolar myopathy (arrow) with myofibrillar loss. (Original magnification ×10).

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Figure 2.
Dried Blood Spot Assay Specimens

A, A blood specimen spotted according to the specified guidelines, which recommend that blood be spotted from only 1 side so that the filter paper is fully soaked. The sample should be allowed to dry overnight at room temperature before being put into an envelope. B, Separation of the erythrocytes from the blood plasma, which can occur when samples are inadequately dried, for instance, when placed into plastic wrapping. When tested for α-glucosidase, moist samples may yield false-positive results that indicate normal levels of enzyme activity. C, An example of dried blood spot samples obtained with incorrect filter paper. These samples cannot be evaluated because eluting sample amounts can vary greatly. Generally, Ahlstrom 226 (Ahlstrom Filtration LLC) and Whatman 903 (Whatman/GE Healthcare Life Sciences) filter papers are acceptable and preferred for dried blood spot analyses. D, An example of overspotting, which should be avoided after an initial spot has been created. E and F, Insufficient amounts of blood. Blood spots 3 mm in diameter or smaller yield lower enzyme activity when compared with standard samples and are unsuitable for analysis.

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