# Sphingolipids in Gaucher disease: a systematic review

## TL;DR

This review explores how sphingolipid levels change in Gaucher disease across different tissues and cells, revealing inconsistent patterns that may contribute to disease pathology.

## Contribution

The study systematically reviews sphingolipid alterations in Gaucher disease across multiple models and tissues, highlighting variability and potential tissue-specific effects.

## Key findings

- DHC, trihexosylceramide, and gangliosides GM3, GM2, GM1, GD3, and GD2 were elevated in 79% of reports.
- Complex GT gangliosides were largely decreased (75%), while GD1a, GD1b, and GQ1b showed inconsistent changes.
- Ceramide levels varied significantly across tissues like spleen, brain, and skin, with no consistent pattern in skin.

## Abstract

Gaucher disease (GD) is a rare lysosomal disorder of sphingolipid catabolism, characterised by a block in the degradation of glucosylceramide (GlcCer) to ceramide. The resulting effect is lysosomal accumulation of GlcCer and its deacylated derivative, glucosylsphingosine. Secondary alterations in the sphingolipid metabolic pathway have been reported, including elevated concentrations of ceramide, lactosylceramide (dihexosylceramide (DHC)), and gangliosides, however, there are notable inconsistencies across different cell and tissue types and their relevance to GD pathology is not well-understood. Sphingolipids are crucial for the regulation of intra- and extracellular functions and different cell types have different requirements. For example, neurons have a high demand for complex sphingolipids due to their extensive membrane remodelling networks necessary for their communication role. We therefore performed literature searches of PubMed, Scopus, and Web of Science databases to coalesce reports of sphingolipids in different animal and cell models of GD, as well as human cells and tissues from 1965 to 2024, totalling 54 studies. We found that DHC, trihexosylceramide, and simple gangliosides, GM3, GM2, GM1, GD3, and GD2, were elevated in most reports (79%), complex GT gangliosides were largely decreased (75%), and GD1a, GD1b, and GQ1b were inconsistently reported to be both increased and decreased in individual studies. Similarly, ceramide was highly discrepant between various cell and tissue types: spleen ceramide was elevated in two of three reports, brain ceramide was largely unchanged (82%), and ceramide concentrations in the skin were not consistent by any variable, including assay technique or GD sub-variant. Some of these discrepancies may be explained by biological variability and differences in methods used to measure sphingolipids, mass spectrometry being the most common, but it is clear that there are sphingolipid alterations in GD, which likely contribute to tissue-specific pathology. Evidence that sphingolipid metabolic regulation is variable across cells and tissues highlight the importance of characterising individual sphingolipid profiles on a model-to-model basis as a driving force behind cell pathology.

The online version contains supplementary material available at 10.1186/s13023-025-04015-5.