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Glycogen storage diseases: Twenty-seven new variants in a cohort of 125 patients.

ABSTRACT: BACKGROUND:Hepatic glycogen storage diseases (GSDs) are a group of rare genetic disorders in which glycogen cannot be metabolized to glucose in the liver because of enzyme deficiencies along the glycogenolytic pathway. GSDs are well-recognized diseases that can occur without the full spectrum, and with overlapping in symptoms. METHODS:We analyzed a cohort of 125 patients with suspected hepatic GSD through a next-generation sequencing (NGS) gene panel in Ion Torrent platform. New variants were analyzed by pathogenicity prediction tools. RESULTS:Twenty-seven new variants predicted as pathogenic were found between 63 variants identified. The most frequent GSD was type Ia (n = 53), followed by Ib (n = 23). The most frequent variants were p.Arg83Cys (39 alleles) and p.Gln347* (14 alleles) in G6PC gene, and p.Leu348Valfs (21 alleles) in SLC37A4 gene. CONCLUSIONS:The study presents the largest cohort ever analyzed in Brazilian patients with hepatic glycogenosis. We determined the clinical utility of NGS for diagnosis. The molecular diagnosis of hepatic GSDs enables the characterization of diseases with similar clinical symptoms, avoiding hepatic biopsy and having faster results.

SUBMITTER: Sperb-Ludwig F

PROVIDER: S-EPMC6825860 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Glycogen storage diseases: Twenty-seven new variants in a cohort of 125 patients.

Sperb-Ludwig Fernanda F Pinheiro Franciele Cabral FC Bettio Soares Malu M Nalin Tatiele T Ribeiro Erlane Marques EM Steiner Carlos Eduardo CE Ribeiro Valadares Eugênia E Porta Gilda G Fishinger Moura de Souza Carolina C Schwartz Ida Vanessa Doederlein IVD

Molecular genetics & genomic medicine 20190911 11

<h4>Background</h4>Hepatic glycogen storage diseases (GSDs) are a group of rare genetic disorders in which glycogen cannot be metabolized to glucose in the liver because of enzyme deficiencies along the glycogenolytic pathway. GSDs are well-recognized diseases that can occur without the full spectrum, and with overlapping in symptoms.<h4>Methods</h4>We analyzed a cohort of 125 patients with suspected hepatic GSD through a next-generation sequencing (NGS) gene panel in Ion Torrent platform. New v ...[more]

PMID: 31508908

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Project description:Background: Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism affecting the synthesis or breakdown of glycogen in the liver. This study, for the first time, systematically assessed vitamin B12 status in a large cohort of hepatic GSD patients. Methods: Plasma vitamin B12, total plasma homocysteine (tHcy) and methylmalonic acid concentrations were measured in 44 patients with hepatic GSDs and compared to 42 healthy age- and gender-matched controls. Correlations of vitamin B12 status with different disease markers of GSDs (including liver transaminase activities and triglycerides) as well as the vitamin B12 intake were studied. Results: GSD patients had significantly higher plasma vitamin B12 concentrations than healthy controls (p = 0.0002). Plasma vitamin B12 concentration remained elevated in GSD patients irrespective of vitamin B12 intake. Plasma vitamin B12 concentrations correlated negatively with triglyceride levels, whereas no correlations were detected with liver transaminase activities (GOT and GPT) in GSD patients. Merging biomarker data of healthy controls and GSD patients showed a positive correlation between vitamin B12 status and liver function, which suggests complex biomarker associations. A combined analysis of biomarkers permitted a reliable clustering of healthy controls versus GSD patients. Conclusions: Elevated plasma concentration of vitamin B12 (irrespective of B12 intake) is a common finding in patients with hepatic GSD. The negative correlation of plasma vitamin B12 with triglyceride levels suggests an influence of metabolic control on the vitamin B12 status of GSD patients. Elevated vitamin B12 was not correlated with GOT and GPT in our cohort of GSD patients. Merging of data from healthy controls and GSD patients yielded positive correlations between these biomarkers. This apparent dichotomy highlights the intrinsic complexity of biomarker associations and argues against generalizations of liver disease and elevated vitamin B12 in blood. Further studies are needed to determine whether the identified associations are causal or coincidental, and the possible impact of chronically elevated vitamin B12 on GSD.

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Glycogen storage diseases: Twenty-seven new variants in a cohort of 125 patients.

Publications

Glycogen storage diseases: Twenty-seven new variants in a cohort of 125 patients.

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