Abstract
BackgroundLate-onset Pompe disease (LOPD) is a rare treatable lysosomal storage disorder characterized by progressive lysosomal glycogen accumulation and muscle weakness, with often a limb-girdle pattern. Despite published guidelines, testing for LOPD is often overlooked or delayed in adults, owing to its low frequency compared to other muscle disorders with similar muscle patterns. Next-generation sequencing has the capability to test concurrently for several muscle disorders. This could potentially lead to increased diagnosis of LOPD, disorders with non-specific muscle weakness or atypical patients.MethodsWe developed a gene panel to further study its clinical utility in a cohort of patients with suspected muscle disorders. We designed a gene panel to analyze the coding sequences and splice site junctions of GAA causing LOPD, along with 77 other genes causing muscle disorders with overlapping phenotypes.ResultsAt a median coverage of ~200X (sequences per base), all GAA exons were successfully covered with >20X and only 0.3 % of exons across all genes were <20X. The panel showed an excellent sensitivity (100 %) and specificity (98 %) across all selected genes, using known variations in Pompe patients and controls. We determined its clinical utility by analyzing 34 patients with suspected muscle disorders of undetermined etiology and various muscle patterns, who were referred or followed in neuromuscular and genetics clinics. A putative diagnosis was found in up to 32 % of patients. The gene panel was instrumental in reaching a diagnosis in atypical patients, including one LOPD case. Acid alpha-glucosidase activity was used to confirm the molecular results in all patients.ConclusionThis work highlights the high clinical utility of gene panels in patients with suspected muscle disorders and its potential to facilitate the diagnosis of patients showing non-specific muscle weakness or atypical phenotypes. We propose that gene panels should be used as a first-tier test in patients with suspected muscle disorders of undetermined etiology, which could further increase overall diagnosis of muscle conditions, and potentially reduce diagnostic delay. Further studies are necessary to determine the impact of first-tier gene panels on diagnostic delay and on treatment outcome for LOPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0390-6) contains supplementary material, which is available to authorized users.
Highlights
Late-onset Pompe disease (LOPD) is a rare treatable lysosomal storage disorder characterized by progressive lysosomal glycogen accumulation and muscle weakness, with often a limb-girdle pattern
We developed a gene panel to simultaneously analyze genes associated with several muscle disorders with overlapping phenotypes in order to increase the diagnosis of LOPD in children and adults, of other disorders with non-specific muscle patterns and of patients with atypical presentations
The gene panel comprises GAA along with 77 other genes causing muscle disorders that are considered in the differential diagnosis of LOPD [4, 24]
Summary
Late-onset Pompe disease (LOPD) is a rare treatable lysosomal storage disorder characterized by progressive lysosomal glycogen accumulation and muscle weakness, with often a limb-girdle pattern. Despite published guidelines, testing for LOPD is often overlooked or delayed in adults, owing to its low frequency compared to other muscle disorders with similar muscle patterns. Next-generation sequencing has the capability to test concurrently for several muscle disorders This could potentially lead to increased diagnosis of LOPD, disorders with non-specific muscle weakness or atypical patients. Classical infantile Pompe disease presents in the first few months of life with hypertrophic cardiomyopathy, generalized muscle weakness, and respiratory distress [5]. Late-onset Pompe disease (LOPD) may present at any age from late infancy onwards, but most frequently develops during adulthood, either with motor delays or limb-girdle muscle weakness [7]. LOPD is likely underdiagnosed in neuromuscular clinics owing to the rarity of the condition and its marked phenotypic variability
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