Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib

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.

Neurological Characteristics of Pediatric Glycogen Storage Disease

“…The frequency of G6PC mutations observed in this study population was similar to that reported for Caucasians in the USA (18), northwestern Europe (17,19), and Rio Grande do Sul, Brazil (20,21), with the c.247C>T and c.1039C>T polymorphisms being the most common mutations. The c.508C>T mutation in G6PC was previously identified in Japanese (22) and Dutch (17) populations, in which it accounted for about 6% of the mutations identified, similar to its proportion in our population.…”

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“…Thus, the observed storage/increase in glycogen is probably due to the disruption of glucose metabolism. Similar reports by Lei et al 40 show disruption of G6Pase and concomitant GSD (Glycogen Storage Disease). Further, post Artesunate treatment increase in hepatic glycogen has also been observed.…”

Consanguinity and Geographic Origin of Patients With Autosomal Recessive Metabolic Disorders Evaluated in a Reference Service in Campinas, Brazil

“…Glycogen storage disease type Ia was more frequent than GSD Ib in our population, and the p.R83C mutation in G6PC gene was the most prevalent in this series. 15 The GM1 gangliosidosis presented the lowest consanguinity rate (17.6%) in the group of multiple cases. Interestingly, 11 of the 17 families presented the later onset (juvenile and adult forms) phenotype, and only 1 of them was born to consanguineous parents.…”

“…Patients submitted to genotype analysis in our service, mainly in the last 10 years, were included in laboratorial support programs like MPS Brazil Network or Niemann-Pick type C Diagnostic Program. Temporary research protocols also allowed investigation of a limited number of conditions, usually the most frequent, including phenylketonuria (PKU) and other hyperphenylalaninemias, 12,13 glycogen storage disease (GSD) type I, 14,15 glutaric academia, 16 galactosemia, 17 metachromatic leukodystrophy, 18 and GM1 gangliosidosis. 19 Altogether, they account for fewer than 40% of the families in this series.…”

“…Glycogen storage disease type Ia was more frequent than GSD Ib in our population, and the p.R83C mutation in G6PC gene was the most prevalent in this series. 15…”