Genotype-phenotype correlation of 17 cases of Pompe disease in Spanish patients and identification of 4 novel GAA variants

Orphanet J Rare Dis 2021 May 21;16(1):233.

PMID: 34020684

Paula Hernández-Arévalo, José D Santotoribio, Rocío Delarosa-Rodríguez

Highlights: The aim of this study was to identify genetic variations and clinical features in Spanish subjects to establish genotype-phenotype correlation.

Abstract

Background: Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA), which induce lysosomal acid α-1,4-glucosidase defects. To demonstrate genotype-phenotype correlation, we sought to uncover genetic variants and clinical characteristics in Spanish patients.

Methods: In this observational study, a total of 2637 samples of patients with PD symptoms or susceptible signs were included. Fluorometric methods were used to detect enzymatic activity, and Next-Generation Sequencing was used to do the genetic analysis.

Results: Seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7-64) and a 2-day-old boy with IOPD had 14 distinct genetic variants discovered, four of which had never been described in the literature before, including a homozygous variant. The activity of α-glucosidase was reduced in all of them. Patients complained of muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia, and myalgia.

Conclusions: This study identifies four novel genetic variants that contribute to the GAA gene's pathogenic variants spectrum. We confirm that patients in Spain have a typical European genetic profile, with c.-32-13T>G being the most common variant. It was also established that the homozygous c.236_246delCCACACAGTGC pathogenic variant is linked to early disease and a poor prognosis.

Keywords: Pompe, Alpha-glucosidase enzyme, GAA gene, Genotype–phenotype correlation