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Identification a novel mononucleotide deletion mutation in GAA in pompe disease patients.

ABSTRACT: BACKGROUND:Mutations in the acid alpha-glucosidase (GAA) gene usually lead to reduced GAA activity. In this study, we analyzed the mutations of GAA and GAA enzyme activity from one sibling suspected Pompe disease and their first-degree relatives. MATERIALS AND METHODS:In this cross-sectional study, GAA enzyme activity assay was assessed using tandem mass spectrometry. Polymerase chain reaction and Sanger sequencing were performed for GAA analysis. RESULTS:GAA enzyme activity was significantly decreased in patients compared to the normal range (P = 0.02). Two individuals showed ten alterations in the GAA sequence, in which one of them (c. 1650del G) has not been previously described in the literature. A single Guanine deletion (del-G) was detected at codon 551 in exon 12. CONCLUSION:According to the literature, the detected change is a novel mutation. We hypothesized that the discovered deletion in the GAA might lead to a reduced activity of the gene product.

SUBMITTER: Ebrahimi M

PROVIDER: S-EPMC5583621 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification a novel mononucleotide deletion mutation in <i>GAA</i> in pompe disease patients.

Ebrahimi Milad M Behnam Mahdieh M Behranvand-Jazi Nafiseh N Yari Ladan L Sheikh-Kanlomilan Sajad S Salehi Mansoor M Tahmasebi Pardis P Amini Mohaddeseh M Behjati Mohaddeseh M Hosseini Nafisehsadat N

Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences 20170816

<h4>Background</h4>Mutations in the acid alpha-glucosidase (<i>GAA</i>) gene usually lead to reduced <i>GAA</i> activity. In this study, we analyzed the mutations of <i>GAA</i> and <i>GAA</i> enzyme activity from one sibling suspected Pompe disease and their first-degree relatives.<h4>Materials and methods</h4>In this cross-sectional study, <i>GAA</i> enzyme activity assay was assessed using tandem mass spectrometry. Polymerase chain reaction and Sanger sequencing were performed for <i>GAA</i> a ...[more]

PMID: 28900456

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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

Identification a novel mononucleotide deletion mutation in GAA in pompe disease patients.

Publications

Identification a novel mononucleotide deletion mutation in <i>GAA</i> in pompe disease patients.

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