Clinical manifestations and acid alpha-glucosidase mutation characterization of a cohort of patients with late-onset Pompe disease in eastern China

Ann Transl Med. 2021 Dec;9(24):1803. doi: 10.21037/atm-21-3710.

PMID: 35071497

Hui-Hui Zhao, Zhi Ma, Zi-Xuan Ying

Highlights: This study has identified four novel variants in patients with LOPD. The c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China.

Abstract

Background: Pompe disease is an autosomal recessive condition that is rare, progressive, and fatal. The condition is characterized by mild progressive proximal limb and respiratory muscle weakening in its late-onset form. Because of mutations in the acid alpha-glucosidase (GAA) gene, the lysosomal enzyme GAA is greatly decreased or absent, and enzyme replacement therapy can be used to augment it.

Methods: From 2017 to 2021, 14 patients diagnosed with late-onset Pompe disease (LOPD) at Nanjing Medical University's First Affiliated Hospital were included. GAA activity was determined using enzymatic activity in dried blood spots, and mutations in the GAA gene were detected using next-generation sequencing. Five separate prediction algorithms were used to determine the effects of new missense variants. PyMOL was used to process the structural figures of novel variations and their various categories.

Results: The study comprised 14 LOPD patients from eastern China (male-to-female ratio: 1:1). At the time of symptom onset and diagnosis, the median age was 15.0 years (7-36 years) and 21.5 years (8-47 years), respectively. The median time from onset to diagnosis was 3.0 years (0-22 years). Eight individuals had proximal muscle weakness as their first symptom, while the other six had respiratory failure, chest congestion and asthma, as well as scoliosis. The most common mutation in the GAA gene was c.2238G>C (p.W746C), which was found in 14.3% (4/28) of alleles and 28.6 % (4/14) of patients. c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78) are four new variants that may be linked to the pathogenicity of LOPD.

Conclusions: In 14 LOPD patients from eastern China, the c.2238G>C (p.W746C) mutation was the most prevalent. In patients with LOPD, our investigation discovered four new variations. Predicting the pathogenicity of these novel variants could help researchers better comprehend the LOPD genetic mutation spectrum. Our findings could help physicians better recognize the characteristics of Chinese patients with LOPD.

Keywords: GAA mutation, Late-onset Pompe disease (LOPD), acid alpha-glucosidase (GAA), glycogen storage disease type II (GSD II), next-generation sequencing