Benign or not benign? Deep phenotyping of liver Glycogen Storage Disease IX

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Abstract

Introduction

Liver 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.

Methods

A 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.

Results

There 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.

Conclusion

Our 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.

Introduction

With an incidence of 1:100,000 live births, Glycogen Storage Disease Type IX (GSD IX) is one of the most common glycogen storage diseases [1,2]. GSD IX is caused by a deficiency of phosphorylase kinase (PhK), an essential hetero-tetrameric regulatory enzyme in glycogenolysis. The first enzyme in the glycogenolysis pathway, PhK is responsible for phosphorylating and activating muscle and liver glycogen phosphorylase. This facilitates the release of the outer glucose-1-phosphate from glycogen, the first step in debranching of glycogen. Glucose continues to be mobilized through the activity of phosphorylases at first and eventually through the debranching enzyme when the glucose chain is less than five residues, leading to increased free glucose for energy usage [3]. PhK is comprised of four copies of each subunit; alpha, beta, gamma, and delta (αβγδ), each encoded by unique genes [3]. The γ subunit houses the catalytic site which is regulated by the α, β, and δ subunits, as well as extrinsic calmodulin, which is structurally indistinct from the δ subunits [3]. There are muscle and liver specific isomers of PhK, deficiencies of which are caused by pathogenic variants in different genes and lead to different phenotypic manifestations. This review focuses on liver PhK deficiency, also classified broadly as liver GSDIX, and its subtypes [4].

The α subunit is coded by PHKA1 (OMIM *311870) in muscle and PHKA2 (OMIM *300798) in liver, both on the X chromosome; the β subunit is coded by PHKβ; the γ subunit is coded by PHKG1 (OMIM *172470) in muscle and PHKG2 (OMIM *172471) in liver; the δ subunit is coded by CALM1 (OMIM *114180), CALM2 (OMIM *114182), and CALM3 (OMIM *114183) [[5], [6], [7]]. The genes PHKA1 and PHKG1 encode the muscle specific isoform and are responsible for various subtypes of muscle PhK deficiency [4]. The genes PHKA2, PHKB, and PHKG2 encode the liver isoform α2, β, and γ2 subunits, respectively and are responsible for the various subtypes of liver PhK deficiency [4]. Mutations in the δ subunit and the CALM 1, 2, 3 genes has not yet been definitively linked to a specific phenotype and will not be further addressed in this paper [3].

Mutations in the α2 subunit are most common, X-linked recessive, and responsible for roughly 75% of liver PhK deficiency; mutations in the γ2 subunit are second most common, autosomal recessive, and responsible for almost 25% of liver PhK deficiency; mutations in the β subunit are also autosomal recessive and are far less common [[8], [9], [10], [11]]. In this paper we will focus on liver PhK deficiency, also classified broadly as liver GSDIX, and its subtypes [4].

There is a large amount of variability in the nomenclature of the different liver GSD IX subtypes, with the most recent 2019 American College of Medical Genetics and Genomics guideline proposing utilizing the Roman lettering “a, b, c” to stand for mutations in PHKA2, PHKB, and PHKG2 genes respectively [12]. The Online Mendelian Inheritance in Man Database also classifies the subtype of liver GSD IX utilizing the roman letter “a, b, c” to represent mutations in the PHKA2, PHKB, and PHKG2 genes respectively. For example, GSD IXa refers to a mutation in the PHKA2 gene. However, in this paper we propose referring to the subtype of liver GSD IX utilizing the Greek lettering referring to the mutated subunit of the PhK enzyme, as this is the most concise and clear nomenclature. For example, from now on the disease caused by a mutation in PHKA2 gene, leading to a mutation in the α subunit will be called GSD IX α2. Mutations in PHKB gene encoding the β subunit will be referred to as GSD IX β. Mutations in the PHKG2 gene encoding the γ2 subunit will be referred to as GSD IX γ2.

Until the recent availability of gene panels and exome sequencing, the diagnosis of liver GSD IX did not allow for clear differentiation of these subtypes. However, based on prior case reports, there is growing body of evidence for some genotype-phenotype correlation [8,[13], [14], [15]]. Most liver GSD IX patients present between infancy and two years with hepatomegaly, elevated liver transaminases, elevated triglycerides, motor delay, growth delay, and/or episodes of ketotic hypoglycemia [10]. The clinical presentation of the majority of GSD IX α2 and GSD IX β patients is reported to become milder with age as metabolic demands decrease; however, the symptoms of GSD IX γ2 patients have been shown to persist with age, potentially progressing to cirrhosis, liver failure, hepatocellular carcinoma, and death [4,[13], [14], [15], [16], [17], [18], [19], [20], [21], [22]].

We present the first comprehensive literature review of liver GSD IX in order to characterize the natural history of GSD IX α2, GSD IX γ2 and GSD IX β, and further investigate genotype-phenotype correlations.

Section snippets

Literature review

To obtain all relevant, published case reports with liver type GSD IX α2, β, and γ2, a comprehensive literature review was conducted through September 2020 using PubMed. Working with a medical librarian at Duke Medical Sciences Research Library, the following search strategy was crafted and performed: “Glycogen storage disease type IX OR GSD IX OR glycogenosis type IX OR Glycogen storage disease type 9 OR Glycogen storage disease type nine”; National Library of Medicine Medical Subject Headings

Diagnosis and initial presentation

A total of 183 patients with liver type GSD IX α2 were gathered from the literature. Of the 183 patients there were 15 families (34 patients total) with family history of GSD IX α2 of which nine families had sibling pairs with GSD IX α2. The remaining 149 patients were singletons with no family history of GSD IX α2.

Of the 132 patients which reported age at diagnosis, the mean age at diagnosis was 4 years with a range of 0.24–37 years.

Initial presentation was reported for 157 patients. Of the

Discussion

Here, we present the first comprehensive literature review including all subtypes of liver GSD IX - GSD IX α2, β, and γ2. From this literature review, we have confirmed previously published findings for liver GSD IX. Presenting signs include hepatomegaly, growth delay, and developmental delay. Common lab findings include ketotic hypoglycemia, hypertriglyceridemia, hypercholesterolemia, elevated AST/ALT, and low enzyme activity [13,20]. Generally, these presenting signs and symptoms have been

Conclusion

In this paper we present the first comprehensive literature review for liver GSD IX. We provide a standard nomenclature based on mutated subtype, demonstrate evidence for a genotype-phenotype correlation among the subtypes of liver GSD IX, and discuss the clinical variability in GSD IX α2.

Our comprehensive review demonstrates quantitatively that the clinical presentation of GSD IX γ2 patients is generally more severe than that of GSD IX α2 or β patients. We suggest that this is perhaps due to

Declaration of Competing Interest

Priya S. Kishnani has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics; consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Vertex Pharmaceuticals and Asklepios Biopharmaceutical, Inc. (AskBio). She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies; and has equity in Actus Therapeutics, which is developing gene therapy for Pompe disease.

Acknowledgements

We would like to acknowledge Leticia Flores, Jonathan Stern, and Yajur Sriraman for their contributions.

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