Unifying the communities of early-onset glycogen storage disease type IV and adult polyglucosan body disease through a genetic prevalence study of GBE1-related disease

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by pathogenic variants in GBE1, resulting in deficient glycogen branching enzyme (GBE) activity and formation of abnormal glycogen ("polyglucosan"). GSD IV manifests across a spectrum of clinical dimensions - including hepatic, neurologic, muscular, and cardiac involvement - which vary in severity. The early-onset forms, historically referred to as Andersen disease, present at different stages ranging from in utero to adolescence. The adult-onset form, referred to as adult polyglucosan body disease (APBD), typically presents in middle to late adulthood. To date, no epidemiological study of GSD IV has been performed. Understanding the global prevalence of GSD IV is critical to increase disease awareness, improve diagnostic rates, inform therapeutic development, and engage pharmaceutical companies. In collaboration with the Rare Genomes Project at the Broad Institute of MIT and Harvard and the APBD Research Foundation, this study curated variants in GBE1 and calculated prevalence across nine genetic ancestry groups. The estimated global carrier frequency of GSD IV is 1 in 243 individuals, and the global genetic prevalence is 1 in 235,784 individuals. Based on the 2024 world population, the estimated number of affected individuals with GSD IV is approximately 34,800. These estimates highlight a significant underdiagnosis of GSD IV and underscore the urgent need for increased awareness of this metabolic disorder. This model of collaboration between researchers, patient advocacy organizations, and genetic data sharing programs provides a framework for estimating the prevalence of other rare diseases in the global population. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/25342386v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1a1ad7dorg.highwire.dtl.DTLVardef@1851576org.highwire.dtl.DTLVardef@442c19org.highwire.dtl.DTLVardef@1ab2ddb_HPS_FORMAT_FIGEXP M_FIG Created in BioRender. Koch, R. (2025) https://BioRender.com/j0sg30n. C_FIG