Abstract
Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.
Highlights
The transformation of glucose into glycogen occurs by chemical reactions carried out by specific enzymes (Diament et al, 1994), and a deficiency in one of these leads to the accumulation of glycogen, resulting in hereditary disorders known as glycogen storage diseases (GSD) or glycogenosis (Rubin et al, 2006)
The catalytic subunit of the system is located inside the endoplasmic reticulum (ER) and its defect causes subtype Ia (GSD Ia; OMIM 232200) (Lei et al, 1993)
Since the enzyme is not expressed in tissues such as fibroblasts or lymphocytes, their measurement is only possible by liver biopsy (Burchell, 1990), an invasive procedure considered stressful by many families. cDNA cloning of G6PC and SLC37A4 allowed the screening of mutations responsible for subtypes Ia and Ib, which enabled establishing an alternative, less invasive diagnosis based on molecular biology techniques using blood samples (Parvari et al, 1997)
Summary
Marcelo Paschoalete Carlin1, Daniel Zanetti Scherrer1, Adriana Maria Alves De Tommaso2, Carmen Silvia Bertuzzo1 and Carlos Eduardo Steiner1 1Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brazil. 2Departamento de Pediatria, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brazil.
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