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

Orphanet Journal of Rare Diseases

Research

Lock-Hock Ngu¹  Huey-Yin Leong¹  Mei-Yan Chan¹  Hui-Bein Chew¹  Jeya Bawani Sivabalakrishnan²  Julaina Abdul Jalil³  Ernie Zuraida Ali⁴  Siti Aishah Abdul Wahab⁵  Yusnita Yakob⁵  Mohd Khairul Nizam Mohd Khalid⁵ 

[1] Department of Genetics, Hospital Kuala Lumpur, Ministry of Health Malaysia, Jalan Pahang, 50586, Kuala Lumpur, Malaysia;Department of Pediatric Cardiology, Hospital Tunku Azizah, Ministry of Health Malaysia, Kuala Lumpur, Malaysia;Unit of Biochemistry, Institute for Medical Research, Ministry of Health Malaysia, Kuala Lumpur, Malaysia;Unit of Inborn Errors of Metabolism and Genetic, Nutrition, Metabolism and Cardiovascular Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Kuala Lumpur, Malaysia;Unit of Molecular Diagnostics, Specialised Diagnostics Centre, National Institutes of Health, Ministry of Health Malaysia, Kuala Lumpur, Malaysia;

关键词: Acid alpha-glucosidase;    Enzyme replacement therapy;    GAA;    Infantile-onset Pompe disease;    Lysosomal storage disease;   

DOI  :  10.1186/s13023-023-02848-6

 received in 2022-06-03, accepted in 2023-07-28,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPompe disease is a rare glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to glycogen deposition in multiple tissues. Infantile-onset Pompe disease (IOPD) patients present within the first year of life with profound hypotonia and hypertrophic cardiomyopathy. Treatment with enzyme replacement therapy (ERT) has significantly improved survival for this otherwise lethal disorder. This study aims to describe the clinical and molecular spectrum of Malaysian IOPD patients, and to analyze their long term treatment outcomes.MethodsSeventeen patients diagnosed with IOPD between 2000 and 2020 were included in this retrospective cohort study. Clinical and biochemical data were collated and analyzed using descriptive statistics. GAA enzyme levels were performed on dried blood spots. Molecular analysis of the GAA gene was performed by polymerase chain reaction and Sanger sequencing. Structural modelling was used to predict the effect of the novel mutations on enzyme structure.ResultsOur cohort had a median age of presentation of 3 months and median age of diagnosis of 6 months. Presenting features were hypertrophic cardiomyopathy (100%), respiratory insufficiency (94%), hypotonia (88%), failure to thrive (82%), feeding difficulties (76%), and hepatomegaly (76%). Fourteen different mutations in the GAA gene were identified, with three novel mutations, c.1552-14_1552-1del, exons 2–3 deletion and exons 6–10 deletion. The most common mutation identified was c.1935C > A p.(D645E), with an allele frequency of 33%. Sixteen patients received ERT at the median age of 7 months. Overall survival was 29%. Mean age of death was 17.5 months. Our longest surviving patient has atypical IOPD and is currently 20 years old.ConclusionsThis is the first study to analyze the genotype and phenotype of Malaysian IOPD patients, and has identified the c.1935C > A p.(D645E) as the most common mutation. The three novel mutations reported in this study expands the mutation spectrum for IOPD. Our low survival rate underscores the importance of early diagnosis and treatment in achieving better treatment outcomes.

【 授权许可】

CC BY   
© Institut National de la Santé et de la Recherche Médicale (INSERM) 2023

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Fig. 2