The research, conducted at a single Polish center and published in the journal Clinical Research in Cardiology, focused on a question that has lingered at the margins of Fabry research for years: does the dysfunction of the vascular endothelium—the delicate single-cell lining of arteries that regulates vessel tone, blood clotting, and inflammation—actually correlate with the measurable structural changes seen in the heart on echocardiography? The evidence addressing that question has been scarce, particularly when it comes to understanding whether men and women, who experience very different disease trajectories because of the X-linked inheritance pattern, show different relationships between vessel health and cardiac remodeling.

To answer it, the team recruited 31 patients with confirmed Fabry disease—17 men and 14 women—who had no history of cardiovascular events such as heart attack or stroke, meaning any abnormalities detected could be attributed to the disease process itself rather than to overt clinical complications. Each patient was compared with a control matched for age, sex, and body mass index, allowing the researchers to isolate the effects of Fabry disease from the ordinary wear and tear of aging and obesity. The participants then underwent a battery of carefully standardized vascular and cardiac tests designed to capture both the function and the structure of the cardiovascular system.

The centerpiece of the vascular assessment was flow-mediated dilatation, or FMD, a technique that has become the gold standard for non-invasively measuring endothelial function in humans. In this test, an inflatable cuff is placed around the forearm and inflated to cut off blood flow for several minutes. When the cuff is released, the sudden rush of blood into the arm creates shear stress on the brachial artery wall, which in a healthy vessel triggers the endothelium to release nitric oxide, a potent vasodilator. Ultrasound imaging captures the resulting expansion of the artery, expressed as the percentage change in diameter. A robust FMD response signals a healthy, responsive endothelium; a blunted response signals dysfunction and, epidemiological studies have repeatedly shown, elevated future cardiovascular risk.

The results were unambiguous. Fabry patients exhibited a 54.8 percent reduction in their FMD response compared with matched controls—a near-halving of the artery’s ability to dilate on demand. This is not a subtle statistical signal but a physiologically dramatic finding, indicating that the glycosphingolipid deposits accumulating in the endothelial cells of these patients are already crippling one of the body’s most important protective mechanisms. When the endothelium cannot produce nitric oxide in adequate amounts, arteries constrict more readily, platelets stick together more easily, and inflammatory cells migrate into vessel walls—each of which accelerates the process of vascular disease.

Complementing the FMD measurements, the researchers assessed intima-media thickness, or IMT, of the common carotid artery using high-resolution ultrasound. IMT measures the combined thickness of the two innermost layers of the artery wall, and its enlargement is widely regarded as a marker of early atherosclerosis and arterial remodeling. Here, too, the Fabry patients fared significantly worse: their carotid IMT was 25.0 percent greater than that of controls. Taken together, the two findings paint a coherent picture of a vascular system under dual assault—functionally impaired in its ability to dilate, and structurally thickened in a way that presages atherosclerotic disease. For patients who have never experienced a cardiovascular event, this combination represents a latent but substantial risk reservoir.

But the study’s most novel contribution lies in its integration of echocardiography, the ultrasound examination of the heart, into this vascular picture. Transthoracic echocardiography allows clinicians to measure the dimensions of the heart’s chambers, the thickness of the muscular walls, and the efficiency of the heart’s pumping and filling. In Fabry disease, the heart is one of the principal battlegrounds: glycosphingolipid deposits accumulate within cardiac muscle cells, leading to a characteristic thickening of the left ventricular wall—a condition that can mimic hypertrophic cardiomyopathy—as well as subtle distortions of cardiac mechanics that precede overt heart failure. Because the endothelium plays a role in regulating coronary blood flow and myocardial health, the researchers hypothesized that the degree of endothelial dysfunction might track with the degree of cardiac structural change.

The analysis confirmed that echocardiographic changes are indeed present in this cohort of event-free patients, and that these changes correlate with the vascular abnormalities in ways that illuminate the natural history of the disease. The connection matters clinically because it suggests that the vascular and cardiac manifestations of Fabry disease are not parallel but unrelated processes; rather, they appear to be intertwined facets of a single progressive pathology. Endothelial dysfunction may contribute directly to the cardiac changes, by impairing coronary microvascular perfusion and promoting the fibrotic and hypertrophic remodeling of the myocardium, or both may simply reflect the burden of glycosphingolipid storage in different tissues. Either way, the measurement of endothelial function could serve as an early warning system for cardiac involvement.

Perhaps the most clinically consequential aspect of the study is its attention to sex differences. Because Fabry disease is X-linked, men—who carry only a single copy of the X chromosome—typically experience the disease in a severe, “classic” form, with essentially absent or nonfunctional alpha-galactosidase A, the enzyme whose deficiency causes lipid accumulation. Women, with two X chromosomes and random X-inactivation in each cell, usually have a mosaic of functional and dysfunctional cells, leading to a milder and later-onset course that has historically caused their disease to be underdiagnosed and undertreated. The Polish study’s data on how male and female patients differ in endothelial function and echocardiographic findings therefore carries weight beyond the numbers themselves: it reinforces the emerging consensus that Fabry disease in women is a real, progressive, and cardiologically relevant condition, not a benign carrier state.

The implications for patient management are considerable. Enzyme replacement therapy and the oral chaperone migalastat have transformed Fabry disease from an untreatable curiosity into a manageable chronic condition, but the timing of treatment initiation remains one of the field’s most debated questions. If endothelial dysfunction and early cardiac remodeling are already detectable in patients who have never had a cardiovascular event—as this study demonstrates—then the window for intervention may be narrower than many clinicians assume. Waiting for symptoms to appear may mean treating a cardiovascular system that has already sustained irreversible structural damage.

There are also methodological lessons in the study’s design. By excluding patients with prior cardiovascular events and matching controls on age, sex, and body mass index, the investigators sharpened the causal inference that Fabry disease itself drives the vascular and cardiac abnormalities. FMD, though technically demanding and subject to strict procedural requirements, remains among the most validated non-invasive windows into endothelial health; combining it with carotid IMT yields complementary functional and structural information. Pairing these vascular metrics with standard transthoracic echocardiography—widely available in routine clinical practice—means the assessment strategy described in this study could be adopted by metabolic and cardiology centers without exotic equipment.

The findings also resonate with a broader shift in cardiovascular medicine toward recognizing the endothelium as both a sentinel and a culprit. In diabetes, hypertension, chronic kidney disease, and now lysosomal storage disorders, the failure of the endothelial monolayer emerges as an early and quantifiable harbinger of downstream organ damage. For the global community of Fabry patients—estimated at roughly one in 40,000 to 60,000 men, with growing recognition that women are affected far more often than older textbooks suggested—studies like this one translate laboratory biochemistry into concrete clinical vigilance: measure the vessels, image the heart, and act before the damage becomes destiny.

As the Fabry research community continues to refine when and how to treat, this Polish cohort study provides a compelling argument that the blood vessels tell the story of the disease early, honestly, and in a sex-specific language that clinicians would do well to learn to read.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in GLA, the gene responsible for producing alpha-galactosidase A. This enzyme normally breaks down particular glycosphingolipids inside lysosomes, the membrane-bound compartments that function as a cell’s recycling centers. When alpha-galactosidase A activity is absent or markedly reduced, globotriaosylceramide, often abbreviated GL3 or Gb3, accumulates inside cells. The stored material can affect the kidneys, nervous system, skin, eyes, blood vessels and heart. Because males have only one X chromosome, they often develop symptoms earlier and more severely than females, although the disease can vary widely even among members of the same family.

The biological effects of GL3 accumulation extend beyond simple cellular storage. Deposits can form in cardiac muscle cells, vascular endothelial cells and valve-supporting fibroblasts, potentially disturbing the structure and function of the cardiovascular system. The accumulated lipids may also activate immune pathways, including Toll-like receptors and CD1d-dependent mechanisms. This can promote the release of cytokines and cellular adhesion molecules, encouraging inflammatory interactions between immune cells and the vessel wall. Over time, persistent low-grade inflammation may contribute to fibrosis, a process in which normal tissue is gradually replaced by stiff scar-like material. In Fabry disease, this progression is particularly important in the heart and kidneys.

The cardiovascular hallmark of Fabry disease is usually left ventricular hypertrophy, a thickening of the main pumping chamber that develops as storage and fibrosis alter the myocardium. Other complications can include abnormal heart rhythms, impaired electrical conduction, valve leakage, high blood pressure and coronary artery disease. These problems generally emerge gradually and may remain silent during childhood. In untreated patients, left ventricular hypertrophy has been reported in more than half of males and roughly one-third of females, with prevalence increasing over time. Coronary artery disease in Fabry disease is usually discussed in the context of adults, where accelerated atherosclerosis can narrow arteries and raise the risk of heart attack. Before this report, coronary artery disease had not been documented in a pediatric patient with Fabry disease.

The infant described in the report had no notable medical history before developing persistent fever. During 21 days of illness, he did not show the classic combination of symptoms often associated with Kawasaki disease, such as conjunctival redness, rash, changes in the hands or feet, swollen neck lymph nodes or alterations of the lips and mouth. Antibiotics and fever-reducing medicines prescribed outside the hospital failed to control the fever. At admission, he was febrile and had a rapid heart rate, but his blood pressure and breathing rate were normal. Apart from inflammation in the throat, examination did not reveal a clear source of infection or a characteristic systemic inflammatory syndrome.

Laboratory testing showed a striking inflammatory profile. The boy was anemic, with a hemoglobin concentration of 8 grams per deciliter, and had an extremely elevated platelet count of 1,018,000 per microliter. His erythrocyte sedimentation rate was 130 millimeters per hour, compared with a reference range of 0 to 10, while his C-reactive protein level was 52, substantially above the laboratory’s negative threshold of 10. Ferritin was also elevated. Repeated blood cultures, urine tests and chest imaging failed to identify an infection, and testing for Epstein–Barr virus, cytomegalovirus, adenovirus and parvovirus B19 was unrevealing. Autoimmune studies, including antinuclear antibodies, anti-double-stranded DNA antibodies and antineutrophil cytoplasmic antibodies, were negative. The prolonged fever and inflammatory markers pointed toward an inflammatory disease, but the clinical picture did not fit neatly into a familiar diagnosis.

Echocardiography provided the most alarming clue. Imaging showed both fusiform and saccular aneurysms involving the right coronary artery, the left anterior descending artery and the left circumflex artery. An aneurysm is a localized enlargement of a blood vessel caused by weakening of its wall; when it becomes very large, turbulent blood flow can encourage the formation of a mural thrombus, or clot attached to the inner surface. The infant had mural thrombosis within the coronary aneurysms, creating a risk that clot could obstruct blood flow or break loose and travel downstream. Because Kawasaki disease can cause coronary artery inflammation and aneurysm formation, physicians treated him for an atypical form of that illness using intravenous immunoglobulin, high-dose methylprednisolone, infliximab, aspirin, low-molecular-weight heparin and a beta blocker.

The treatment controlled the immediate inflammatory crisis: the fever subsided after 48 hours, and a follow-up echocardiogram showed that the thrombosis had resolved. Yet the giant aneurysms themselves remained unchanged. Their persistence, the unusually prolonged fever, the lack of several hallmark Kawasaki features and the child’s very young age led the medical team to search for an inherited cause. The parents were consanguineous, further increasing the clinicians’ suspicion that a genetic disorder might be involved. Whole-exome sequencing, which examines the protein-coding regions of thousands of genes, detected the GLA variant c.427G>A, resulting in the amino-acid substitution p.Ala143Thr. The boy also had markedly reduced alpha-galactosidase activity, providing biochemical support for the genetic finding. Testing showed that his mother carried the same disease-associated variant.

The report’s authors emphasize that the relationship between Fabry disease and the coronary aneurysms remains uncertain. One possibility is that the child had Fabry disease and atypical Kawasaki disease independently, with the inflammatory infection-like illness causing the vascular damage. Another is that chronic immune activation associated with GL3 storage made the coronary arteries more vulnerable to a Kawasaki-like inflammatory process. A third possibility is that the aneurysms represent a previously unrecognized direct cardiac manifestation of Fabry disease in infancy. The distinction matters because Kawasaki disease typically produces transmural inflammatory destruction of the coronary artery wall, whereas Fabry-related coronary disease has generally been linked to lipid accumulation and accelerated atherosclerosis, mechanisms that are not equivalent. A single case cannot determine whether the mutation initiated the aneurysms, intensified another disease or merely coexisted with it.

The specific p.Ala143Thr GLA variant has been associated with a predominantly cardiac form of Fabry disease, in which some residual enzyme activity may produce a later-onset and milder phenotype than classic disease. Its discovery in an infant with giant coronary aneurysms therefore expands the range of presentations clinicians may need to consider, even though it does not establish a new disease mechanism. The case also highlights the value and limitations of genetic diagnosis. Enzyme assays can support Fabry disease, while sequencing can identify mutations in patients whose symptoms are atypical or whose family history suggests inherited disease; however, not every genetic variant predicts the same clinical course, and some findings require careful interpretation. Treatments such as enzyme replacement therapy or pharmacological chaperones can slow disease progression in appropriate patients, making early recognition important. For now, the infant’s aneurysms remain a medical mystery with a compelling genetic clue: Fabry disease may have played a role, but only additional cases and mechanistic studies can reveal whether this rare metabolic disorder can truly produce coronary aneurysms at such an extraordinarily young age.

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