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

Background: Pompe disease is a rare, progressive, and life-threatening autosomal recessive disorder. In its late-onset form, the disease is primarily characterised by mild progressive proximal limb and respiratory muscle weakness. Mutations in the acid alpha-glucosidase () gene cause lysosomal enzyme GAA to be significantly reduced or missing altogether, for which supplementation can be given through enzyme replacement therapy.

Methods: Fourteen patients diagnosed with late-onset Pompe disease (LOPD) in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were enrolled. GAA activity was measured based on enzymatic activity in dried blood spots, and next-generation sequencing was used to detect mutations in the gene. The impacts of novel missense variants were determined by five different prediction algorithms. The structural figures of novel variants and their wide types were processed with PyMOL.

Results: The study included 14 patients with LOPD (male-to-female ratio, 1:1) from eastern China. The median age at symptom onset and diagnosis was 15.0 years (7-36 years) and 21.5 years (8-47 years), respectively. The median diagnostic delay from onset was 3.0 years (0-22 years). Proximal muscle weakness was the first prominent symptom in 8 patients, while the other 6 patients experienced respiratory failure, chest congestion and asthma, and scoliosis. The most frequent mutation of the GAA gene was c.2238G>C (p.W746C), which was observed at an allele frequency of 14.3% (4/28) and in 28.6% of patients (4/14). Four novel variants potentially related to the pathogenicity of LOPD were found: c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78).

Conclusions: The c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China. This study has identified four novel variants in patients with LOPD. Predicting the pathogenicity of these novel variants may increase the understanding of the genetic mutation spectrum in LOPD. Our findings may also improve recognition of the characteristics of Chinese patients with LOPD.