Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene
Introduction
Deficiency of liver phosphorylase b kinase (PhK), also known as glycogen storage disease type IX (GSD IX), is one of the most common forms of glycogen storage disease. It accounts for about 25% of cases and has an estimated frequency of 1 in 100,000 [1]. PhK is a key regulatory enzyme in glycogen breakdown and metabolism. In response to physiological conditions, PhK activates glycogen phosphorylase which catalyzes the sequential cleavage of glucosyl units from glycogen to release glucose 1-phosphate [2], [3]. PhK is a heterotetramer that is composed of four copies each of alpha, beta, gamma, and delta (calmodulin) subunits [4]. The gamma subunit contains the catalytic site. Its activity is regulated by the phosphorylation state of the alpha and beta subunits, as well as by calmodulin via calcium levels [4]. Different isoforms of PhK exist due to tissue-specific expression and alternative splicing of different subunit genes. In liver, the alpha, beta, and gamma subunits are encoded by the PHKA2 gene (OMIM# 300798; Xp22.2-p22.1), the PHKB gene (OMIM# 172490; 16q12-q13), and PHKG2 gene (OMIM# 172471; 16p12.1-p11.2) respectively. However, recent studies have suggested that these genes are more widely expressed than previously thought [5]. To date, mutations in each of these genes have been identified in individuals with liver PhK deficiency [1], [6], [7], [8], [9], [10].
Children with liver PhK deficiency typically present in the first two years of life with hepatomegaly, growth retardation, and elevated serum transaminases and plasma triglycerides. Ketotic hypoglycemia and hypotonia may also be present. Available literature suggests that the clinical course is usually mild when compared to other common liver GSDs, and that symptoms typically improve with age [3], [6], [11], [12]. Liver cirrhosis and adenomas, which are common in some other types of liver GSD, have been reported less frequently in individuals with liver PhK deficiency [13]. Over recent years, however, a wide variation in clinical severity among patients with liver PhK deficiency has been recognized and some general correlations between the gene defect and clinical severity have been made [7], [8], [14], [15]. Mutations in the X-linked PHKA2 gene are the most common cause of liver PhK deficiency, accounting for about 75% of cases [7], [8]. Although historically reported to have a relatively benign course, a wide spectrum of clinical severity resulting from mutations in PHKA2 has emerged recently [7], [14], [15], [16], [17], [18]. Mutations in the PHKB gene cause an autosomal recessive form of liver PhK deficiency that, so far, has been associated with mild symptoms [7], [8], [10], [19], [20]. By contrast, mutations in the PHKG2 gene often cause more pronounced biochemical and clinical abnormalities including an increased risk for developing liver cirrhosis in childhood [1], [7], [8], [21], [22], [23], [24]. Here, we report the clinical symptoms, laboratory findings, and PHKG2 gene changes in five individuals with liver PhK deficiency in order to further delineate the variability in clinical phenotype caused by mutations in this gene.
Section snippets
Patients
The patients were recruited under a research protocol in accordance with the Institutional Review Board requirements of Duke University or the University of Florida Health Center. PHKG2 gene sequence analysis was performed by the Duke Molecular Diagnostics Laboratory (patients 1, 2 and 5) or in another clinical diagnostic laboratory (patients 3 and 4). Medical records, including clinic notes and reports from clinical laboratory testing, were reviewed. Laboratory data obtained included blood
Clinical history
A summary of the clinical and laboratory features for the five patients included in this study is shown in Table 1. All patients in our case series had hepatomegaly, elevated serum transaminases, and fasting hypoglycemia, although disease severity was variable. Ketosis was observed in some cases. Over time, with age and treatment, there was general improvement in the biochemical abnormalities for all of the patients. In four of the patients, hepatomegaly has lessened, or even normalized
Discussion
Mutations in PHKG2 have been associated with more severe clinical and biochemical abnormalities. These may include extremely low PhK activity in liver, pronounced tendencies to hypoglycemia, abnormal glucagon response, and increased risk of liver cirrhosis [1], [7], [8], [21], [22], [23], [24], [30]. To date, 17 individuals (16 probands and one sibling) with PhK deficiency, caused by PHKG2 mutations, have been reported in full length papers in the medical literature (Supplementary Table 1).
Acknowledgments
We would like to thank the patients and families who participated in this research study. We are grateful to the Association for Glycogen Storage Diseases, US and the YT and Alice Chen Pediatric Genetics and Genomics Center at Duke for funding this research. Support for this project was also provided by the National Institutes of Health (NIH)/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR000064, Matthew's GSD Type IX Fund, and the Sturtz GSD Research Fund
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These authors contributed equally.