Clinical, biochemical, and genetic perspectives in hepatic glycogen storage diseases: HEPA-GSD study

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders resulting from genetic deficiencies in enzymes involved in glycogen synthesis or breakdown, transport proteins, or proteins that regulate glycogen metabolism. Liver GSDs are further subdivided into subtypes based on the specific enzyme deficiency. This multicenter, cross-sectional, descriptive retrospective study, conducted across 24 centers, aimed to document the clinical and genotypic findings in patients with hepatic GSD. The study included 282 patients (152 males, 53.9%) from 278 unrelated families. At the time of diagnosis, 248 patients (88.3%) had hepatomegaly, and 170 patients (60.3%) had hypoglycemia. In this cohort, GSD type IIIa was the most common hepatic GSD. The mean time to diagnosis was 23.0 ± 53.2 months, and the follow-up period was 82.2 ± 76.0 months. Hepatosteatosis was present on abdominal imaging in 154 patients (54.6%). Hepatic adenomas and liver transplantation were more frequently observed in patients with GSD type Ia. Growth retardation was detected in 105 patients (37.2%) during follow-up. A total of 141 distinct variants were identified in molecular genetic analyses. According to the Human Gene Mutation Database (HGMD) and the available literature at the time of analysis, 83 variants had been previously reported, whereas 58 variants were not documented and were therefore considered previously unreported. Three patients are dead during follow-up. This cohort represents one of the largest patient populations reported to date and provides some of the longest-term follow-up data available in the literature on hepatic GSDs.