Hepatic glycogen storage disease: Deciphering the genotype-phenotype conundrum

Abstract

Glycogen storage diseases (GSDs) are a group of inherited disorders caused by genetic defects in various enzymes involved in glycogen production or breakdown. Hepatic GSDs often have overlapping clinical features, making subtyping or prognostication difficult. With the availability and advancement of next-generation sequencing, definitive molecular diagnosis is now available for most patients, with newer variants being increasingly identified. Molecular diagnosis could help in systematic follow-up, anticipating complications and prognostications. However, the mutations reported in the published literature display wide variations across racial and geographical groups. Hence, natural history, long-term outcome, and genotype-phenotypic correlation studies in patients with various hepatic GSDs are needed for a deeper understanding. Considering the emerging evidence of genetic profiling of patients with hepatic GSDs, including the recent study by Vanduangden et al, this editorial aims to review the various clinical subtypes, the spectrum of genetic mutations, and genotype-phenotype correlations for various hepatic GSDs.

Keywords: Hepatic glycogen storage disease; Genotype-phenotype correlation; Children; Next-generation sequencing; Metabolic control

Core Tip: Glycogen storage diseases (GSDs) are a group of clinically and genetically heterogeneous diseases. The various subtypes of hepatic GSDs are often clinically overlapping, especially in hepatic GSDs. Early diagnosis and proper dietary therapy are paramount for optimal clinical outcomes. Certain clinical features and laboratory derangements such as hypoglycemia, elevated liver enzymes and abnormal lipid profile are helpful in diagnosis. Liver biopsy is an invasive diagnostic test, which has recently been replaced by genetic testing. Next-generation sequencing is now being used more frequently for definitive diagnosis of GSD.