Dataset Information

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

ABSTRACT: Identification of variants in the acid ?-glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry, a long-term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA variants (80 unique novel) were reported. Variants were listed by groups representing Pompe disease phenotypes. Patients were classified as Group A: Symptom onset ??12 months of age with cardiomyopathy; Group B: Symptom onset ??12 years of age (includes patients with symptom onset ??12 months of age without cardiomyopathy); or Group C: Symptom onset >?12 years of age. Likely impact of novel variants was predicted using bioinformatics algorithms. Variants were classified by pathogenicity using ACMG guidelines. Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, add to the number and diversity of GAA variants registered in public databases through published data sharing, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.

SUBMITTER: Reuser AJJ

PROVIDER: S-EPMC6852536 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

Reuser Arnold J J AJJ van der Ploeg Ans T AT Chien Yin-Hsiu YH Llerena Juan J Abbott Mary-Alice MA Clemens Paula R PR Kimonis Virginia E VE Leslie Nancy N Maruti Sonia S SS Sanson Bernd-Jan BJ Araujo Roberto R Periquet Magali M Toscano Antonio A Kishnani Priya S PS On Behalf Of The Pompe Registry Sites

Human mutation 20190807 11

Identification of variants in the acid α-glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and geographic distribution of GAA sequence variants listed in the Pompe Registry, a long-term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA ...[more]

PMID: 31342611

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Project description: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.

Dataset Information

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

Publications

GAA variants and phenotypes among 1,079 patients with Pompe disease: Data from the Pompe Registry.

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