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PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.

ABSTRACT: Molecular diagnosis of glycogen storage diseases (GSDs) is important to enable accurate diagnoses and make appropriate therapeutic plans. The aim of this study was to evaluate the PHKA2 mutation spectrum in Korean patients with GSD type IX.Thirteen Korean patients were tested for PHKA2 mutations using direct sequencing and a multiplex polymerase chain reaction method. A comprehensive review of the literature on previously reported PHKA2 mutations in other ethnic populations was conducted for comparison.Among 13 patients tested, six unrelated male patients with GSD IX aged 2 to 6 years at the first diagnostic work-up for hepatomegaly with elevated aspartate transaminase (AST) and alanine transaminase (ALT) were found to have PHKA2 mutations. These patients had different PHKA2 mutations: five were known mutations (c.537 + 5G > A, c.884G > A [p.Arg295His], c.3210_3212delGAG [p.Arg1072del], exon 8 deletion, and exons 27-33 deletion) and one was a novel mutation (exons 18-33 deletion). Notably, the most common type of mutation was gross deletion, in contrast to other ethnic populations in which the most common mutation type was sequence variant.This study expands our knowledge of the PHKA2 mutation spectrum of GSD IX. Considering the PHKA2 mutation spectrum in Korean patients with GSD IX, molecular diagnostic methods for deletions should be conducted in conjunction with direct sequence analysis to enable accurate molecular diagnosis of this disease in the Korean population.

SUBMITTER: Choi R

PROVIDER: S-EPMC4839068 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.

Choi Rihwa R Park Hyung-Doo HD Kang Ben B Choi So Yoon SY Ki Chang-Seok CS Lee Soo-Youn SY Kim Jong-Won JW Song Junghan J Choe Yon Ho YH

BMC medical genetics 20160421

<h4>Background</h4>Molecular diagnosis of glycogen storage diseases (GSDs) is important to enable accurate diagnoses and make appropriate therapeutic plans. The aim of this study was to evaluate the PHKA2 mutation spectrum in Korean patients with GSD type IX.<h4>Methods</h4>Thirteen Korean patients were tested for PHKA2 mutations using direct sequencing and a multiplex polymerase chain reaction method. A comprehensive review of the literature on previously reported PHKA2 mutations in other ethni ...[more]

PMID: 27103379

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Project description:IntroductionLiver Glycogen Storage Disease Type IX (GSD IX) is one of the most common forms of GSD. It is caused by a deficiency in enzyme phosphorylase kinase (PhK), a complex, hetero-tetrameric enzyme comprised of four subunits - α, β, γ, and δ - each with tissue specific isoforms encoded by different genes. Until the recent availability of gene panels and exome sequencing, the diagnosis of liver GSD IX did not allow for differentiation of these subtypes. This study presents the first comprehensive literature review for liver GSD IX subtypes - GSD IX α2, β, and γ2. We aim to better characterize the natural history of liver GSD IX and further investigate if there are subtype-specific differences in clinical presentation.MethodsA comprehensive literature review was performed with the help of a medical librarian at Duke University Medical Center to gather all published patients of liver GSD IX. Our refined search yielded 74 articles total. Available patient data were compiled into an excel spreadsheet. Data were analyzed via descriptive statistics. The number of patients with specific symptoms were individually summed and reported as a percentage of the total number of patients for which data were available or were averaged and reported as a mean numerical value. Published pathology reports were scored using the International Association of the Study of the Liver Scale.ResultsThere were a total of 183 GSD IX α2 patients, 17 GSD IX β patients, and 30 GSD IX γ2 patients. Average age at diagnosis was 4 years for GSD IX α2 patients, 2.34 years for GSD IX β patients, and 1.81 years for GSD IX γ2 patients. Hepatomegaly was reported in 164/176 (93.2%) of GSD IX α2 patients, 16/17 (94.1%) of GSD IX β patients, and 30/30 (100%) of GSD IX γ2 patients. Fasting hypoglycemia was reported in 53/121 (43.8%) of GSD IX α2 patients, 8/16 (50%) of GSD IX β patients, and 18/19 (94.7%) of GSD IX γ2 patients. Liver biopsy pathology reports were available and interpreted for 46 GSD IX α2 patients, 3 GSD IX β patients, and 24 GSD IX γ2 patients. 22/46 (47.8%) GSD IX α2 patients, 1/3 (33.3%) GSD IX β patients, and 23/24 (95.8%) GSD IX γ2 patients with available pathology reports documented either some degree of fibrosis or cirrhosis.ConclusionOur comprehensive review demonstrates quantitatively that the clinical presentation of GSD IX γ2 patients is more severe than that of GSD IX α2 or β patients. However, our study also shows the existence of a severe phenotype in GSD IX α2, evidenced by early onset liver pathology in conjunction with clinical symptoms. There is need for a more robust natural history study to better understand the variability in liver pathophysiology within liver GSD IX; in addition, further study of mutations and gene mapping could bring a better understanding of the relationship between genotype and clinical presentation.

Project description: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.

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PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.

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PHKA2 mutation spectrum in Korean patients with glycogen storage disease type IX: prevalence of deletion mutations.

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