A new review is reframing Fabry disease as far more than a disorder caused by the buildup of a single metabolic substance. By bringing together findings from transcriptomics, proteomics, metabolomics, and other “multi-omics” approaches, researchers are revealing a complicated biological network that links the disease’s genetic origin to progressive injury in the kidneys, heart, nervous system, and other organs. The analysis, published in Genes & Diseases, suggests that these technologies could improve early detection, clarify why patients develop different complications, and help guide more individualized treatment.
Fabry disease is an inherited condition caused by mutations in the GLA gene. These mutations reduce or eliminate the activity of α-galactosidase A, an enzyme required to break down globotriaosylceramide and related lipids inside cells. When the enzyme is deficient, these substances accumulate within lysosomes, the cell’s recycling compartments. The resulting storage is especially damaging in tissues such as the vascular endothelium, kidney, heart, and nervous system. Fabry disease is X-linked, meaning that it can affect males and females, although the severity and pattern of symptoms can vary substantially even among people carrying similar genetic variants.
For decades, the central explanation of Fabry disease focused on substrate accumulation. The review emphasizes that storage is only the first step in a much broader cascade of cellular disruption. Lipid accumulation can interfere with organelle function, alter membrane signaling, and activate inflammatory pathways. Oxidative stress may damage proteins, DNA, and cellular membranes, while mitochondrial dysfunction can reduce energy production in tissues with high metabolic demands. Abnormal signaling, immune activation, fibrosis, and changes in cell death pathways may then reinforce one another, gradually transforming a biochemical defect into irreversible organ damage.
Multi-omics technologies are allowing scientists to observe these changes at several biological levels simultaneously. Transcriptomics measures patterns of RNA expression, showing which genes are switched on or off in diseased tissue. Proteomics examines changes in proteins, including enzymes, receptors, structural molecules, and signaling factors. Metabolomics captures shifts in small molecules that reflect the state of cellular metabolism. When combined with lipidomics, epigenomics, and single-cell analysis, these methods can identify disease-associated signatures that may be invisible when researchers study only one molecule or pathway at a time.
The kidneys are among the most vulnerable organs in Fabry disease. Specialized cells called podocytes help maintain the filtration barrier that prevents large proteins from escaping into urine. Storage material and secondary stress can injure these cells, leading to proteinuria, scarring, and declining filtration capacity. The review highlights evidence that disrupted energy metabolism, complement activation, immune-cell signaling, and ferroptosis may contribute to renal injury. Ferroptosis is an iron-dependent form of regulated cell death associated with oxidative damage to cell membranes. Understanding how these pathways interact could help explain why kidney disease sometimes progresses despite treatment.
Cardiac involvement is another major cause of illness and premature death. Fabry disease can produce left ventricular hypertrophy, in which the muscular wall of the heart becomes abnormally thick, as well as fibrosis, rhythm disturbances, and heart failure. Multi-omics findings point to several contributors, including oxidative stress, defective mitochondrial energy production, altered lipid handling, and abnormal protein trafficking. These mechanisms may help explain why a heart can continue to deteriorate even when therapy reduces the primary storage burden. Detecting molecular signs of cardiac injury before extensive fibrosis develops could become an important goal for future clinical care.
The nervous system is affected through multiple routes. Patients may experience burning or chronic pain, reduced sensitivity, gastrointestinal and autonomic symptoms, transient ischemic attacks, or stroke. Vascular abnormalities can restrict blood flow, while inflammation and oxidative damage may directly disrupt neurons and supporting cells. Changes in nerve signaling and small-fiber function can produce pain that is difficult to control. By mapping gene activity, proteins, and metabolites in affected tissues and blood, researchers hope to distinguish the biological pathways responsible for different neurological symptoms rather than treating them as a single uniform complication.
The review also places Fabry disease within a rapidly expanding therapeutic landscape. Enzyme replacement therapy supplies a manufactured form of α-galactosidase A, helping cells clear accumulated substrates, although responses can differ and treatment does not always reverse established organ damage. Pharmacological chaperones can stabilize certain mutant forms of the enzyme and improve their delivery to lysosomes in eligible patients. Substrate reduction therapy aims to decrease production of the molecules that accumulate, while gene therapy seeks to provide cells with a functional copy of GLA. Multi-omics may help determine which patients are most likely to benefit from each approach and identify biological signs of treatment response.
Important challenges remain before these technologies become routine tools in the clinic. Molecular signatures must be validated in large and diverse patient groups, standardized across laboratories, and connected to outcomes that matter to patients, such as kidney function, arrhythmia risk, or stroke. Researchers must also determine whether a biomarker reflects active, reversible injury or damage that has already become permanent. Even so, the review presents multi-omics as a powerful bridge between genetic diagnosis and precision medicine. By showing how metabolic storage, inflammation, mitochondrial failure, immune activity, and fibrosis converge across organs, the field is moving toward earlier intervention and a more detailed biological portrait of every person living with Fabry disease.
Subject of Research: Fabry disease, multi-omics, organ injury, biomarkers, and therapeutic development
Article Title: Pathophysiological mechanisms of organ injury in Fabry disease: Update via multi-omics
Web References: https://doi.org/10.1016/j.gendis.2025.101949
References: Zhiyuan Wei, Junlan Yang, Zhongyu Han, Xiaoliang Zhang, Bin Wang, “Pathophysiological mechanisms of organ injury in Fabry disease: Update via multi-omics,” Genes & Diseases, Volume 13, Issue 5, 2026, Article 101949.
Image Credits: Genes & Diseases
Keywords: Fabry disease, GLA gene, α-galactosidase A, multi-omics, transcriptomics, proteomics, metabolomics, kidney disease, cardiac disease, neuroinflammation, biomarkers, enzyme replacement therapy, gene therapy
