Multi-omics research is identifying potential biomarkers that could improve the detection and monitoring of Fabry disease, particularly when established laboratory tests do not fully reflect organ involvement, according to a review published in Genes & Diseases.
Fabry disease is an X-linked lysosomal storage disorder caused by variants in the GLA gene. These variants reduce alpha-galactosidase A activity, leading to accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). Over time, the disease can affect multiple organs, particularly the kidneys and heart.
Diagnosis can be difficult because clinical presentation varies considerably. Testing typically combines clinical and family history with alpha-galactosidase A activity, Gb3 or Lyso-Gb3 measurements, genetic testing, and assessment of affected organs. However, no single test provides a complete picture of the disease. Enzyme activity can be unreliable for diagnosing heterozygous female patients, genetic variants may be difficult to interpret, and Lyso-Gb3 levels do not consistently reflect the extent of organ damage.
The review examined how transcriptomics, proteomics, and metabolomics could supplement these approaches by detecting molecular changes associated with Fabry disease and its complications.
Several proteomic studies highlighted in the review identified candidate biomarkers in blood and urine. One analysis of 50 patients with Fabry disease and 50 healthy controls found that the plasma proteins APOA4, FETUA, and APOC3 were associated with disease complications. Other studies identified urinary proteins and peptide patterns associated with early or progressive organ involvement. Metabolomic studies have also detected differences in plasma and urinary metabolites, although Gb3-related molecules remain the best-established metabolic markers.
Kidney involvement was a particular focus because renal damage may progress to kidney failure. Transcriptomic analysis of Fabry podocytes identified 247 genes with altered expression, involving processes such as oxidative stress, inflammation, apoptosis, and autophagy. Proteomic studies also pointed to lysosomal and mitochondrial dysfunction and other mechanisms of podocyte injury. These observations suggest that kidney damage involves biological processes beyond Gb3 accumulation alone.
The review also pointed to similar findings that have emerged in cardiac disease. Molecular studies identified changes associated with oxidative stress, lipid metabolism, myocardial fibrosis, and cardiomyocyte dysfunction. Some of these molecular signals are being investigated as possible markers of cardiac involvement or treatment response.
The review highlights a potential future role for molecular profiles alongside enzyme assays, biochemical biomarkers, genetic testing, and organ-specific evaluation. Such profiles could ultimately help identify organ injury earlier or provide additional information when conventional results are inconclusive.
However, the evidence is not yet sufficient to support routine multi-omics testing. Many studies involved small and heterogeneous patient groups, and proposed biomarkers require validation in larger, multicenter cohorts. The researchers also identified assay cost, accessibility, data integration, and determining which molecular changes are clinically meaningful as barriers to implementation.
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