Abstract
Background: Primary aim was to investigate the diagnostic value of PAS-positive vacuolated lymphocytes on blood smear in Late Onset Pompe Disease (LOPD) patients and, secondly, to evaluate its potential utility in monitoring treatment effects.Methods: We examined blood smear of 26 LOPD patients. We evaluated 10 treated and 16 untreated LOPD patients. Among the latter group, 7 patients later initiated ERT and were tested again 6 months after start. Blood smear was also sampled from 82 controls and 19 patients with other muscle glycogenoses (MGSDs). PAS staining was used to evaluate: (1) presence of lymphocytes with glycogen-filled vacuoles, (2) quantification of vacuolated lymphocytes.Results: We found that PAS-positive lymphocytes were significantly higher in LOPD patients than in controls or other MGSDs (p < 0.05 and p < 0.001, respectively). ROC curve for discriminating between untreated LOPD patients and controls yielded an AUC of 1.00 (95%CI 1.00–1.00; p < 0.0001). PAS-positive lymphocyte cutoff level of >10 yielded sensitivity of 100% (95%CI 78–100%), specificity of 100% (95%CI 96–100%), and positive predictive value of 100%. Patients studied before and after ERT showed a dramatic decrease of PAS-positive vacuolated lymphocytes number (p = 0.016). In other MGSDs, PAS-positive lymphocytes were significantly lower that untreated LOPD patients but higher than controls.Conclusions: Our data suggest that the Blood Smear Examination (BSE) for PAS-positive lymphocytes quantification could be used as a simple and sensitive test for a quick screening of suspected Pompe disease. The quantification of vacuolated lymphocytes appears to be also a valuable tool for monitoring the efficacy of treatment in LOPD patients.
Highlights
We studied a total of 26 Late Onset Pompe Disease (LOPD) patients, 82 healthy individuals and 19 patients with other MGSD, enrolled from April 2015 until March 2017
In all Pompe patients, we found, on a blood smear, a high percentage of vacuolated Periodic Acid-Schiff (PAS)-positive lymphocytes ranging from 10 to 57% in untreated and from 2 to 28% in treated patients that resulted significantly different than controls (p < 0.01 and p < 0.001, respectively) (Table 2)
In 2005, a retrospective review of 2.550 blood films of patients with a clinical history suggestive of metabolic diseases, identified vacuolated lymphocytes in 156 cases, 23% were recognized as Pompe disease (15 IOPD and 8% LOPD) PAS staining was performed to better characterize glycogen storage in the lymphocytes vacuoles [22]
Summary
Pompe disease (glycogen storage disease type II, OMIM#232300) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), a lysosomal enzyme that is responsible for the cleavage of the α-1,4- and α-1,6glycosidic bonds of glycogen to glucose [1, 2].GAA deficiency leads to the accumulation of glycogen in the lysosomes of several tissues, demonstrating a multisystemic disorder cardiac and skeletal muscles involvement remains more prominent [3, 4].Two different clinical forms are conventionally described: a severe infantile form (IOPD) characterized by muscular hypotonia, hypertrophic cardiomyopathy and respiratory failure, and a more heterogeneous late onset form (LOPD) with a predominant progressive proximal, axial and respiratory muscle weakness [5,6,7].In LOPD, initial clinical manifestations as muscle weakness, exercise intolerance, myalgia, or even isolated hyperCKemia appear often unspecific and may mimic a large variety of other muscle disorders as limb-girdle muscular dystrophies (LGMD), congenital, metabolic or inflammatory myopathies [8,9,10,11].muscle biopsy remains an important tool in the evaluation of muscle disorders; in most of Pompe disease cases, the morphological study shows a pattern of vacuolar myopathy with glycogen storage but sometimes it can result unspecific [17].Since 2006, Enzyme Replacement Therapy (ERT) with recombinant human α-glucosidase (rGAA) became available. Two different clinical forms are conventionally described: a severe infantile form (IOPD) characterized by muscular hypotonia, hypertrophic cardiomyopathy and respiratory failure, and a more heterogeneous late onset form (LOPD) with a predominant progressive proximal, axial and respiratory muscle weakness [5,6,7]. In LOPD, initial clinical manifestations as muscle weakness, exercise intolerance, myalgia, or even isolated hyperCKemia appear often unspecific and may mimic a large variety of other muscle disorders as limb-girdle muscular dystrophies (LGMD), congenital, metabolic or inflammatory myopathies [8,9,10,11]. Muscle biopsy remains an important tool in the evaluation of muscle disorders; in most of Pompe disease cases, the morphological study shows a pattern of vacuolar myopathy with glycogen storage but sometimes it can result unspecific [17]. Primary aim was to investigate the diagnostic value of PAS-positive vacuolated lymphocytes on blood smear in Late Onset Pompe Disease (LOPD) patients and, secondly, to evaluate its potential utility in monitoring treatment effects
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