Phenotypic Implications of Pathogenic Variant Types in Pompe Disease

J Hum Genet 2021 May 11. doi: 10.1038/s10038-021-00935-9.

PMID: 33972680pmid: 33972680

Manuel A Viamonte , Stephanie L Filipp , Zara Zaidi

Highlights: In Pompe disease, it is crucial to figure out whether enzyme activity or the type of pathogenic genetic variant in GAA best predicts phenotypic severity. Complete genetic, cardiac, and neurological examinations are critical for newly identified Pompe disease patients.

Abstract

Introduction: In the future, newborn screening and treatments for Pompe disease (glycogen storage disorder type II, acid maltase deficiency) will become more common. It's crucial to figure out whether enzyme activity or the type of pathogenic genetic variant in GAA best predicts phenotypic severity, especially the existence of infantile-onset vs late-onset Pompe disease (LOPD).

Materials and methods: A retrospective study of 23 patients with genetically proven Pompe disease was conducted. Clinical information, such as the presence or absence of cardiomyopathy, enzyme activity levels, and GAA variant characteristics, such as exon vs intron location and splice site versus non-splice site, were gathered.

Results: Several combinations of GAA variant types for individual participants exhibited significant correlations with disease subtype, cardiomyopathy, age at diagnosis, gross motor function scale (GMFS), and body weight stability. 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 linked to LOPD, whereas non-splice site variants on both alleles were linked to IOPD. In isolation, enzyme activity levels were not enough to predict disease subtype or other important clinical characteristics. We discovered that splice site variants other than the classic c.-32-13T > G variant are frequently linked with a milder phenotype, extending the findings of previous research.

Conclusion: When the genetic variants are unclear, enzyme activity levels continue to be useful in confirming the diagnosis. Complete genetic, cardiac, and neurological examinations are critical for newly identified Pompe disease patients.

Keywords: Pompe disease, GAA variants, cardiomyopathy, GMFS