Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Jan 25:11:8.
doi: 10.1186/s13023-016-0390-6.

Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing

Sébastien Lévesque  1 , Christiane Auray-Blais  2 , Elaine Gravel  2 , Michel Boutin  2 , Laura Dempsey-Nunez  2 , Pierre-Etienne Jacques  3 , Sébastien Chenier  2 , Sandrine Larue  4 , Marie-France Rioux  5 , Walla Al-Hertani  6 , Amelie Nadeau  7 , Jean Mathieu  8 , Bruno Maranda  2 , Valérie Désilets  2 , Paula J Waters  2 , Joan Keutzer  9 , Stephanie Austin  10 , Priya Kishnani  10
Affiliations

Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing

Sébastien Lévesque et al. Orphanet J Rare Dis. .

Abstract

Background: 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.

Methods: We 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.

Results: At 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.

Conclusion: This 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.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Inclusion and exclusion criteria
See this image and copyright information in PMC

References

    1. Hoefsloot LH, Hoogeveen-Westerveld M, Kroos MA, van Beeumen J, Reuser AJ, Oostra BA. Primary structure and processing of lysosomal alpha-glucosidase; homology with the intestinal sucrase-isomaltase complex. EMBO J. 1988;7:1697–704. - PMC - PubMed
    1. Hobson-Webb L, Proia AD, Thurberg BL, Banugaria S, Prater SN, Kishnani PS. Autopsy findings in late-onset Pompe disease: a case report and systematic review of the literature. Mol Genet Metab. 2012;106:462–9. doi: 10.1016/j.ymgme.2012.05.007. - DOI - PubMed
    1. Kishnani PS, Beckemeyer AA, Mendelsohn NJ. The new era of Pompe disease: advances in the detection, understanding of the phenotypic spectrum, pathophysiology, and management. Am J Med Genet C: Semin Med Genet. 2012;160:1–7. doi: 10.1002/ajmg.c.31324. - DOI - PubMed
    1. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267–88. doi: 10.1097/01.gim.0000218152.87434.f3. - DOI - PMC - PubMed
    1. Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671–6. doi: 10.1016/j.jpeds.2005.11.033. - DOI - PubMed

Publication types