Genotype, phenotype and treatment outcomes of 17 Malaysian patients with infantile-onset Pompe disease and the identification of 3 novel GAA variants

Orphanet J Rare Dis. 2023 Aug 4;18(1):231. doi: 10.1186/s13023-023-02848-6.

PMID: 37542277

Mei-Yan Chan, Julaina Abdul Jalil, Yusnita Yakob

Highlights: This is the first study to analyze the genotype and phenotype of Malaysian infantile-onset Pompe disease (IOPD) patients, and has identified the c.1935C > A p.(D645E) as the most common mutation.

Abstract

Background: Glycogen builds up in many tissues in Pompe disease, an uncommon disorder of glycogen storage brought on by a lack of the lysosomal enzyme acid alpha-glucosidase (GAA). Patients with infantile-onset Pompe disease (IOPD) exhibit severe hypotonia and hypertrophic cardiomyopathy within the first year of life. Enzyme replacement treatment (ERT) has considerably increased survival rates for this fatal condition. The purpose of this study is to describe the clinical and molecular characteristics of Malaysian IOPD patients and to evaluate the outcomes of their long-term medical treatment.

Methods: In this retrospective cohort study, 17 patients with IOPD diagnosed between 2000 and 2020 were included. Descriptive statistics were used to compile and analyze clinical and biochemical data. The levels of the GAA enzyme were measured on dried blood spots. Polymerase chain reaction and Sanger sequencing were used to do a molecular study of the GAA gene. The impact of the novel mutations on the structure of the enzyme was predicted using structural modeling.

Results: The median age of presentation in our group was 3 months, while the median age of diagnosis was 6 months. Hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), difficulties with feeding (76%), and hepatomegaly (76%), were the symptoms that were present. The GAA gene has fourteen different mutations, including three novel mutations (c.1552-14_1552-1del, exons 2-3 deletion, and exons 6–10 deletion). The most frequent mutation found had an allele frequency of 33% and was c.1935C > A p.(D645E). At a median age of 7 months, ERT was administered to 16 patients. 29% of people survived overall. 17.5 months on average were the death age. Our patient with the longest survival time, who is currently 20 years old, has atypical IOPD.

Conclusions: This is the first study to examine the genotype and phenotype of Malaysian IOPD patients, and it has determined that the most common mutation is c.1935C > A p.(D645E). The mutation spectrum for IOPD is expanded by the three new mutations reported in this study. Because of our low survival rate, early identification and therapy are crucial to getting better treatment results.

Keywords: Acid alpha-glucosidase, Enzyme replacement therapy, GAA, Infantile-onset Pompe disease, Lysosomal storage disease