# GMPPB‐CDG Results in Lysosomal Dysfunction and Acid Alpha‐Glucosidase Deficiency

## TL;DR

This study shows that GMPPB deficiency causes lysosomal dysfunction and reduced GAA activity, leading to glycogen buildup in cells.

## Contribution

The paper reveals a secondary lysosomal impairment in GMPPB deficiency and demonstrates correction with recombinant GAA.

## Key findings

- GMPPB deficiency leads to glycogen accumulation in cytosol and lysosome-like vesicles.
- GAA activity is reduced in GMPPB-deficient cells with impaired protein maturation and localization.
- Recombinant GAA fully restores GAA activity and clears glycogen storage in GMPPB cells.

## Abstract

GDP‐mannose pyrophosphorylase B (GMPPB) deficiency is a congenital disorder of glycosylation due to pathogenic variants of the GMPPB gene. GMPPB catalyzes GDP‐mannose synthesis, an early step in multiple glycosylation pathways, including N‐glycosylation, O‐mannosylation, C‐mannosylation, and glycosylphosphatidylinositol‐anchor formation. In fibroblasts (N = 3), myoblasts (N = 4) and in muscle biopsies (N = 4) from a total of 7 GMPPB‐deficient patients we found evidence of glycogen accumulation, both in cytosol and in lysosome‐like vesicles, presence of heterogeneous storage material, and expansion of the lysosomal compartment. Due to the excess of glycogen in cells and tissues, we investigated acid alpha‐glucosidase (GAA) in cultured GMPPB fibroblasts. GAA activity was reduced in GMPPB cells, with an impaired protein maturation and lysosomal localization. Incubation of cells with human recombinant GAA (rhGAA), that is fully glycosylated, showed complete correction of GAA activity, normal processing and lysosomal trafficking, with complete clearance of glycogen storage. These results suggest a secondary impairment of specific lysosomal functions in GMPPB deficiency and add information on the complexity of the pathophysiology of this disorder.