Predominance of the c.648G > T G6PC gene mutation and late complications in Korean patients with glycogen storage disease type Ia

Yoo-Mi Kim,Han-Wook Yoo,Kyung-Mo Kim,Gu-Hwan Kim,Jin-Ho Choi,Beom-Hee Lee

doi:10.1186/s13023-020-1321-0

Abstract

BackgroundGlycogen storage disease (GSD) Ia, caused by mutations in the glucose-6-phosphatase (G6PC) gene, is characterized by hepatomegaly, hypoglycemia, lactic acidosis, dyslipidemia, and hyperuricemia. This study aimed to investigate clinical and molecular features and late complications in Korean patients with GSD Ia.ResultsFifty-four Korean patients (33 males and 21 females) from 47 unrelated families, who were diagnosed with GSD Ia, based on genetic and biochemical data, between 1999 and 2017, were included in this study. The median age at diagnosis was 3.9 years (range: 5 months to 42 years), and the follow-up period was 8.0 ± 6.8 years. Most patients presented with hepatomegaly during infancy, but hypoglycemic symptoms were not predominant. Genetic analysis showed that all the patients had at least one c.648G > T allele. Homozygous c.648G > T mutations in the G6PC gene were identified in 34 families (72.3%), and compound heterozygotes with c.648G > T were found in the other families. The allele frequency of c.648G > T was 86.2% (81/94), and p.F51S, p.R83H, p.G122D, p.Y128*, p.G222R, and p.T255A were identified. Of 26 adult patients, 14 had multiple hepatic adenomas, and two were diagnosed with hepatocellular carcinoma. Thirteen patients showed renal complications, and seven patients presented gout, despite preventive allopurinol treatment. Twelve patients had osteoporosis, and two patients had pulmonary hypertension. The final heights were 157.9 cm (standard deviation score: − 3.1) in males and 157.8 cm (standard deviation score: − 0.6) in females.ConclusionIn our Korean patients with GSD Ia, the most common mutation in the G6PC gene was c.648G > T, suggesting a founder effect. Because of only mild hypoglycemia, the patients tended to be diagnosed late. Thus, adult patients with GSD Ia eventually developed diverse and serious complications, which indicates a need for careful monitoring and proper management of this disease.

Highlights

Glycogen storage disease (GSD) Ia, caused by mutations in the glucose-6-phosphatase (G6PC) gene, is characterized by hepatomegaly, hypoglycemia, lactic acidosis, dyslipidemia, and hyperuricemia
Our study demonstrated that c.648G > T was the most common mutation (81/94 alleles; 86.2%) in Korean patients with GSD Ia, which was similar to its frequency in a Japanese patient cohort (88/102 alleles; 86.4%) and different from that in a Chinese population (36%) [4, 11, 12]
In conclusion, our study showed a prevalent mutation, c.648G > T, in the G6PC gene in Korean patients with GSD Ia, and adult patients showed diverse and serious complications, despite mild hypoglycemia and improvement in their biochemical test results

Summary

Introduction

Glycogen storage disease (GSD) Ia, caused by mutations in the glucose-6-phosphatase (G6PC) gene, is characterized by hepatomegaly, hypoglycemia, lactic acidosis, dyslipidemia, and hyperuricemia. This study aimed to investigate clinical and molecular features and late complications in Korean patients with GSD Ia. Glycogen storage disease (GSD) type Ia (OMIM #232200) is a rare inborn metabolic disorder, caused by glucose-6phosphatase (G6PC) deficiency, and the overall incidence is considered to be one in 100,000 [1, 2]. Glycogen storage disease (GSD) type Ia (OMIM #232200) is a rare inborn metabolic disorder, caused by glucose-6phosphatase (G6PC) deficiency, and the overall incidence is considered to be one in 100,000 [1, 2] This disease leads to defects in glycogenolysis and gluconeogenesis, Kim et al Orphanet Journal of Rare Diseases (2020) 15:45 gene, encoding G6PC, has been mapped to chromosome 17q21 [7], and 110 mutations in G6PC have been reported until now. This study aimed to investigate clinical and molecular features and late complications in Korean patients with GSD Ia, with a particular focus on c.648G > T-carrying patients 70 missense mutations, 14 nonsense mutations, 21 insertions/deletions, and five splicing mutations have been reported (Human Gene Mutation Database: http://www.hgmd.cf.ac.uk). c.648G > T is considered a common mutation in Korean and Japanese patients with GSD Ia [8, 9]; there have only been a few reports on clinical characteristics and long-term outcomes of c.648G > T-carrying patients with GSD Ia in a large cohort.

Objectives

Methods

Results

Conclusion