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

Abstract

Background: 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. Results: Fifty-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. Conclusion: In 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.

Molecular Diagnosis of Panel-Based Next-Generation Sequencing Approach and Clinical Symptoms in Patients With Glycogen Storage Disease: A Single Center Retrospective Study

“…Subsequently, the GSD-NGS panel revealed 8 recurrent mutations in 11 patients with GSD Ia, and 1 novel mutation (c.576_577insT) and 3 reported mutations in 2 patients with GSD Ib. The reported splice variant in exon 5 (c.648G > T) of the G6PC gene was the most common mutation (8 of 22 alleles, 36.4%) among our Chinese patients with GSD Ia, which is in contrast with observations in a Korean cohort (81 of 94 alleles, 86.2%) and in a Japanese cohort (88 of 102 alleles, 86.4%) (11). Early symptoms and signs at first admission include severe intolerance to fasting, growth retardation, and hepatomegaly.…”

NOVEL MUTATIONS OF THE G6PC GENE IN MALAYSIANS WITH GLYCOGEN STORAGE DISEASE 1a (GSD1a)

“…The most common mutation found in this study is the silent mutation L216L which accounts for 50% of the total mutant alleles. This mutation was reported to be the major causative mutation for GSD1a in both the Japanese and Chinese population (Kajihara et al, 1995;Lam et al, 1998), while a more recent report included the Korean population in the list, with an allele frequency as high as 86.2% (Froissart et al, 2011;Kim, et al, 2020). The fact that this mutation was observed in both the Malay (60.7%) and Chinese ethnicities (28.6%) supports the notion that perhaps this is indeed a common mutation among Asian patients.…”

Case Report: Glycogen Storage Disease Type Ia in a Chinese Child Treated With Growth Hormone

“…In this study, we present a case of GSD type Ia diagnosed by genetic testing; the patient's height increased significantly after growth hormone intervention. Currently, over 105 different mutations causing GSD Ia have been described in humans, and the typical metabolic disturbances are fairly consistent (10). The 2014 guidelines of the American College of Medical Genetics and Genomics recommended noninvasive molecular genetic testing to confirm GSD Ia when the clinical and laboratory evaluation suggest the diagnosis (1).…”