Predicting subtypes of glycogen storage disease type IV: Challenges of hepatic subtypes and genotype-phenotype...

Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disease caused by the deficiency of the glycogen branching enzyme encoded by GBE1. GSD IV can present with variable age of onset and severity of disease processes involving liver, central and peripheral nerves, muscles, and heart. Adult Polyglucosan Body Disease (APBD) is now increasingly recognized as a continuum of the GSDIV spectrum. If the clinical disease presentation includes progressive liver failure, treatment may require liver transplant to prevent morbidity and mortality. The variable presentation of GSD IV, including the hepatic phenotypes, creates diagnostic and treatment challenges. Here we describe a girl presenting with hypotonia and hepatomegaly at age 4 years; genetic analysis revealed compound heterozygosity in GBE1: c.1621A>G p.(Asn541Asp) and c.1655C>T p.(Pro552Leu). Based on her presentation and genotypes, her phenotypic prognosis was not immediately clear. She was monitored closely for liver disease progression including, synthetic dysfunction, cholestasis, or cirrhosis, but her liver function proved stable over time. Recent analysis suggested that liver disease progression is a spectrum and some develop a progressive/severe hepatic form and others stabilize with an attenuated hepatic form. Previous reviews of GSD IV genotype-phenotype correlations have not adequately addressed the prediction of hepatic phenotype based on GBE1 genotypes. We performed an updated comprehensive literature search and genotype-phenotype analysis, while updating the GBE1 genotypes according to the HGVS nomenclature. Our detailed and comprehensive review of GSDIV adds to the previously published literature available on GSD IV genotypes (Li et al. 2010, Iijima 2018, Souza et al. 2021).