Phenotypic implications of pathogenic variant types in Pompe disease

Manuel A. Viamonte, Stephanie L. Filipp, Zara Zaidi, Matthew J. Gurka, Barry J. Byrne, Peter B. Kang

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7 Scopus citations


Newborn screening and therapies for Pompe disease (glycogen storage disease type II, acid maltase deficiency) will continue to expand in the future. It is thus important to determine whether enzyme activity or type of pathogenic genetic variant in GAA can best predict phenotypic severity, particularly the presence of infantile-onset Pompe disease (IOPD) versus late-onset Pompe disease (LOPD). We performed a retrospective analysis of 23 participants with genetically-confirmed cases of Pompe disease. The following data were collected: clinical details including presence or absence of cardiomyopathy, enzyme activity levels, and features of GAA variants including exon versus intron location and splice site versus non-splice site. Several combinations of GAA variant types for individual participants had significant associations with disease subtype, cardiomyopathy, age at diagnosis, gross motor function scale (GMFS), and stability of body weight. The presence of at least one splice site variant (c.546 G > C/p.T182 = , c.1076–22 T > G, c.2646 + 2 T > A, and the classic c.−32–13T > G variant) was associated with LOPD, while the presence of non-splice site variants on both alleles was associated with IOPD. Enzyme activity levels in isolation were not sufficient to predict disease subtype or other major clinical features. To extend the findings of prior studies, we found that multiple types of splice site variants beyond the classic c.−32–13T > G variant are often associated with a milder phenotype. Enzyme activity levels continue to have utility for supporting the diagnosis when the genetic variants are ambiguous. It is important for newly diagnosed patients with Pompe disease to have complete genetic, cardiac, and neurological evaluations.

Original languageEnglish (US)
Pages (from-to)1089-1099
Number of pages11
JournalJournal of Human Genetics
Issue number11
Early online dateMay 11 2021
StatePublished - Nov 2021

Bibliographical note

Funding Information:
Conflict of interest Dr MAV was supported in part by an unrestricted educational fellowship from Sanofi Genzyme. Ms SLF reports no disclosures. Dr ZZ reports no disclosures. Dr MJG reports no disclosures. Dr BJB is a member of the Pompe Registry Scientific Advisory Board, and has received grant support from Sanofi Genzyme and Amicus Therapeutics. Dr PBK was the uncompensated grantee of the unrestricted fellowship from Sanofi Genzyme that supported Dr MAV. He has served as a consultant for AveXis and ChromaDex, and on an advisory board for Sarepta Therapeutics. This study was supported in part by an unrestricted educational fellowship from Sanofi Genzyme (2015–2017). Neither Sanofi Genzyme nor any individuals or organizations employed/contracted by Sanofi Genzyme participated in study design, data collection, data analysis, drafting of the paper writing, editing of the paper, or decision to submit this paper for publication.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to The Japan Society of Human Genetics.

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