A multimodal imaging workflow has mapped Fabry disease-associated lipid accumulation in cardiac tissue, revealing uneven molecular distributions that are not captured by bulk measurements or conventional staining.
Fabry disease is a rare inherited metabolic disorder in which globotriaosylceramides (Gb3) are not sufficiently broken down, leading to lipid accumulation in organs such as the heart and kidneys, as well as ocular findings such as cornea verticillata. Although elevated Gb3 levels are already used in disease assessment, bulk measurements and conventional staining provide limited information on where specific lipid species accumulate within tissue.
To build that spatial picture, researchers at the Leibniz-Institut für Analytische Wissenschaften – ISAS paired Raman microscopy with atmospheric-pressure MALDI mass spectrometry imaging (AP-MALDI-MSI). Raman microscopy captured the broader tissue landscape, resolving molecular features associated with nuclei, collagen, structural tissue components, and lipids. AP-MALDI-MSI added the molecular specificity needed to identify and localize individual Gb3 lipoforms in the same cardiac tissue sections.
“Only by combining Raman microscopy with mass spectrometry imaging is it possible to obtain a comprehensive picture of the molecular processes within the tissue,” said Sven Heiles, head of the Lipidomics junior research group at ISAS, in a press release. “For a reliable diagnostic assessment, it’s important to know exactly where in the tissue Gb3 molecules accumulate.”
The team applied the workflow to heart tissue from mouse models of Fabry disease. AP-MALDI-MSI showed that Gb3 accumulation was not evenly distributed across the tissue, but appeared in localized hotspots. Different Gb3 variants also showed distinct spatial patterns, suggesting an additional layer of lipid heterogeneity that cannot be captured by staining approaches alone.
Raman imaging helped place those molecular signals in their tissue context. Using multivariate analysis, the researchers mapped broader biochemical features across the same sections, including lipid-rich regions, nuclei, and collagen-associated structures. An automated coregistration workflow then aligned the Raman and AP-MALDI-MSI data, allowing Gb3 distributions to be overlaid with the corresponding tissue architecture.
“The genetic cause of Fabry disease and elevated Gb3 levels in the blood have long been known,” said Kristina Lorenz, head of Translational Research at ISAS. “However, the distribution of lipids in human tissue at the cellular and subcellular levels – as well as the associated inter-individual heterogeneity – had previously been inadequately characterized.”
The authors now plan to extend the workflow to tissue samples from patients with Fabry disease. If those spatial lipid patterns can be linked to disease manifestations or treatment response, the approach could help move assessment beyond bulk Gb3 measurements toward a more tissue-resolved view of disease.
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