Systemic Disease Progression and Neurodegeneration in the Gbe1Mouse Model of Glycogen Storage Disease Type IV.

Abstract

Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen branching enzyme (GBE1) deficiency, resulting in the accumulation of insoluble polyglucosan. The Gbe1mouse model, carrying the p.Y329S variant, recapitulates features of adult-onset GSD IV, also known as adult polyglucosan body disease. However, the natural progression of the disease in this model is not fully understood. This study presents a longitudinal analysis of Gbe1mice from 1 to 12 months of age, quantitatively tracking polyglucosan accumulation and correlating it with progressive histopathologic, motor, and behavioral changes. Polyglucosan bodies were detected as early as 1 month, with significant neurodegeneration and astrogliosis by 6 months. Notably, serum neurofilament light chain levels increased with disease progression, identifying neurofilament light chain as a potential noninvasive biomarker of neurodegeneration in GSD IV. Systemic involvement, including severe splenomegaly and gastrointestinal abnormalities, indicates broader effects of GBE1 deficiency beyond the central nervous system. These findings provide important insights into the natural history of GSD IV, establish key disease milestones for therapeutic intervention, and refine the clinical understanding of GSD IV and adult polyglucosan body disease.