Assessing disease severity in Pompe disease: The roles of a urinary glucose tetrasaccharide biomarker and imaging techniques

Abstract

Defining disease severity in patients with Pompe disease is important for prognosis and monitoring the response to therapies. Current approaches include qualitative and quantitative assessments of the disease burden, and clinical measures of the impact of the disease on affected systems. The aims of this manuscript were to review a noninvasive urinary glucose tetrasaccharide biomarker of glycogen storage, and to discuss advances in imaging techniques for determining the disease burden in Pompe disease. The glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc(4) ), is a glycogen-derived limit dextrin that correlates with the extent of glycogen accumulation in skeletal muscle. As such, it is more useful than traditional biomarkers of tissue damage, such as CK and AST, for monitoring the response to enzyme replacement therapy in patients with Pompe disease. Glc(4) is also useful as an adjunctive diagnostic test for Pompe disease when performed in conjunction with acid alpha-glucosidase activity measurements. Review of clinical records of 208 patients evaluated for Pompe disease by this approach showed Glc(4) had 94% sensitivity and 84% specificity for Pompe disease. We propose Glc(4) is useful as an overall measure of disease burden, but does not provide information on the location and distribution of excess glycogen accumulation. In this manuscript we also review magnetic resonance spectroscopy and imaging techniques as alternative, noninvasive tools for quantifying glycogen and detailing changes, such as fibrofatty muscle degeneration, in specific muscle groups in Pompe disease. These techniques show promise as a means of monitoring disease progression and the response to treatment in Pompe disease. © 2012 Wiley Periodicals, Inc.

Baseline Urinary Glucose Tetrasaccharide Concentrations in Patients with Infantile- and Late-Onset Pompe Disease Identified by Newborn Screening

“…Furthermore, median baseline Glc 4 in the NBS-IOPD group was clearly lower than that of the slightly older (by approximately 4-8 weeks) clinical comparator CLIN-IOPD group. These observations are consistent with (1) baseline clinical manifestations in the NBS-IOPD group including cardiomyopathy and elevated CK, despite a normal physical exam and tone (Chien et al 2009), (2) the notable increase in baseline Glc 4 values with age in untreated patients with IOPD ascertained clinically before 12 months of age (Young et al 2012), and (3) the rapidly progressive nature of the infantile form of the disease. The variability of late-onset Pompe disease is demonstrated by differences in the age of onset of clinical signs and symptoms of the disease within the NBS-LOPD group, of which one third of patients required treatment with ERT before 3 years of age (Chien et al 2011).…”

“…Glc 4 can be useful in the diagnosis of Pompe disease and for monitoring the response to ERT (Young et al 2009(Young et al , 2012. We assessed the usefulness of urinary Glc 4 , measured as the total hexose tetrasaccharide (Hex 4 ) fraction in urine, in the follow-up of infants with low GAA activity identified by the Taiwanese pilot NBS program.…”

Newborn screening for lysosomal storage disorders

“…Based on severity of symptoms, affected patients exhibit elevated muscle enzymes in blood (creatine kinase, transaminases, and lactate dehydrogenase) and increased urinary glucotetrasaccharides that derive from glycogen breakdown. 43 Treatment by ERT has made early diagnosis of Pompe disease desirable, since early initiation of treatment improves the prognosis. 44,45 The estimated incidence varies between ethnic populations from 1:14,000 in African-Americans to 1:600,000 live births in Portugal.…”

Rapid Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry Assay for a Characteristic Glycogen-Derived Tetrasaccharide in Pompe Disease and Other Glycogen Storage Diseases

“…About 10 years ago, clinical trials were started in patients with Pompe disease with the administration of recombinant human ␣-glucosidase from transgenic rabbit milk (12 ) and from Chinese hamster ovary cells (13 ). Glc 4 has been reported to be a useful biomarker for the long-term monitoring of disease progression and the therapeutic response of these patients to enzyme replacement therapy (14,15 ). Urinary Glc 4 , in contrast to the conventional serum markers creatine kinase, aspartate aminotransferase, and alanine aminotransferase correlated closely with skeletal muscle glycogen content and clinical response (14 ).…”