Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Takeda | INDUSTRY |
Not provided
Not provided
Not provided
This study aims to gain a deeper understanding of endothelial dysfunction in patients with Fabry disease through a prospective study of the retinal microvasculature and to identify an objective, non-invasive marker to assess disease severity and cardiovascular risk in patients.
The main questions addressed are: Do dynamic and static retinal vessel analysis parameters differ from those in healthy individuals? Can these parameters predict cardiovascular and/or Fabry-related events during follow-up? Do these parameters change during follow-up in patients with a non-stable disease?
Fabry disease is a rare genetic disorder characterized by the pathological accumulation of glycosphingolipids, specifically globotriaosylceramide (Gb3), within lysosomes in various cells of the body. This accumulation leads to damage in the cardiovascular, cerebrovascular, and renal systems and is characterized by dysfunction of endothelial cells. This dysfunction results in disturbances in the microcirculation and damage to the supplied systems, leading to a significantly increased cardiovascular risk in patients with Fabry disease. Studies have shown that these patients have a higher risk of premature death due to these risk factors compared to the general population.
Early diagnosis and adequate monitoring of enzyme replacement therapy (ERT) are crucial in reducing the risk of cardiovascular events associated with Fabry disease. Currently, LysoGb3 (lysosphingolipid globotriaosylceramide) is considered a biomarker for the diagnosis and monitoring of Fabry disease. Elevated levels of LysoGb3 have been observed in the blood of patients with Fabry disease, and its measurement has been proposed as a diagnostic tool. Additionally, measuring LysoGb3 levels before and after treatment with ERT can be used as a tool to monitor the effectiveness of the therapy in reducing the accumulation of glycosphingolipids in cells and improving symptoms and outcomes in patients with Fabry disease.
However, the performance of LysoGb3 as a predictor of cardiovascular events in patients with Fabry disease is not well understood, and more research is needed to confirm its utility in this regard.
Therefore, there is a need for additional reliable measurements of the microcirculation that can be performed non-invasively and represent a low burden for participants. The use of non-invasive markers of microcirculation can aid in the early diagnosis and monitoring of Fabry disease, which is crucial for the effective use of ERT.
In summary, this study aims to validate new microcirculation markers that can be measured non-invasively in a prospective cohort of patients with Fabry disease and to correlate these markers with established clinical and laboratory parameters. By validating these markers, the study seeks to improve the management of Fabry disease, reduce the burden on participants, and ultimately reduce the incidence of cardiovascular events associated with the disease.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dynamic retinal vessel analysis (DVA) | Diagnostic Test | Dynamic retinal vessel analysis (DVA) is an established, non-invasive technique for evaluating the responsiveness of retinal vessels to flickering light stimuli. This technique allows for the measurement of changes in retinal vessel diameter in response to changes in blood flow, providing insight into the microcirculatory function of the retina. In the case of DVA, patients will asked to focus on a needle, and one arteriole and venule diameter were automatically and continuously recorded. Arteriole and venule segments between 0.5 to 1 mm will be analyzed approximately 2-disc diameters away from the optic nerve in a lower-temporal direction. The baseline recording will be 50 seconds, followed by a flickering phase of 20 seconds and then a recovery period of 80 seconds. Three of these cycles were performed. Based on this, we will calculate the percentage of maximum arteriolar (aFID) and venular dilation (vFID) to baseline. | ||
| Biochemistry and immune phenotyping | Diagnostic Test | Collection of blood samples from participants for the purpose of performing clinical chemistry analysis. Peripheral blood mononuclear cells (PBMCs) will be isolated from the collected blood samples using standard techniques, such as density gradient centrifugation, and will be analyzed using fluorescence-activated cell sorting (FACS) | ||
| Questionnaires (Patient reported outcomes) | Diagnostic Test | This study involves a comprehensive evaluation of life quality, pain, and gastrointestinal (GI) symptoms using a set of established and validated questionnaires. The tools employed include the SF-36 (Short Form-36 Health Survey) to assess overall health-related quality of life across multiple domains, the COMPASS-31 (Composite Autonomic Symptom Score) to evaluate autonomic dysfunction symptoms, and the Brief Pain Inventory (BPI) to measure pain severity and its impact on daily activities. Additionally, the Gastrointestinal Symptom Rating Scale (GSRS) is used to quantify the severity and frequency of GI symptoms, covering dimensions such as reflux, abdominal pain, indigestion, diarrhea, and constipation. Together, these questionnaires provide a multidimensional assessment of the patient's physical, emotional, and symptomatic experiences, allowing for a robust understanding of their health status and quality of life. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Retinal Arteriolar Diameter (CRAE) | What will be measured: Central Retinal Arteriolar Equivalent (CRAE) in micrometers (µm). Unit of Measure: Micrometers (µm). How it will be reported: Mean CRAE values at baseline for Fabry disease patients compared with age- and sex-matched healthy controls. | From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4. |
| Change in Retinal Arteriolar Diameter (CRVE) | What will be measured: Central Retinal Arteriolar Equivalent (CRVE) in micrometers (µm). Unit of Measure: Micrometers (µm). How it will be reported: Mean CRAE values at baseline for Fabry disease patients compared with age- and sex-matched healthy controls. | From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4. |
| Change in arteriolar-venular ration (AVR) | What will be measured: AVR as a quotient out of CRAE/CRVE Unit of Measure: no unit How it will be reported: Mean or Median AVR values at baseline for Fabry disease patients compared with age- and sex-matched healthy controls. | From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4. |
| Change in Flicker-Induced Venular Dilation (vFID) | What will be measured: Maximum percentage change in retinal venular diameter during flicker stimulation. Unit of Measure: Percentage (%). How it will be reported: Mean vFID percentage change at baseline for Fabry disease patients compared with age- and sex-matched healthy controls. |
| Measure | Description | Time Frame |
|---|---|---|
| Correlation Between Retinal Vessel Parameters and Symptom Severity (DS3) | What will be measured: Correlation of static retinal vessel analysis parameters (CRAE, CRVE, AVR) and dynamic parameters (vFID, aFID) with the Fabry disease severity score (DS3, Giannini et al. 2009). Unit of Measure: Micrometers (µm) for CRAE, CRVE, AVR; percentage (%) for vFID and aFID; unitless for DS3 score (range 0-32). Measurement Tools: Dynamic Retinal Vessel Analyzer (IMEDOS Systems, Jena, Germany), Static Retinal Vessel Analyzer (IMEDOS Systems, Jena, Germany), and the DS3 scoring system. How it will be reported: Statistical correlation coefficients (e.g., Spearman or Pearson). |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Patients included in this study are recruited through our in-house metabolic outpatient clinic (Stoffwechselambulanz), which specializes in the diagnosis, treatment, and long-term management of rare metabolic disorders, including Fabry disease. The clinic serves as a comprehensive care center, offering multidisciplinary services such as genetic counseling, laboratory diagnostics, and individualized treatment planning. Patients are identified and approached during routine follow-ups or initial consultations after confirmation of a Fabry disease diagnosis through genetic testing or measurement of globotriaosylceramide (Gb3) activity in leukocytes. This structured recruitment process ensures the inclusion of well-characterized patients who meet the study's eligibility criteria.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Christoph Schmaderer, Prof. Dr. | Contact | 089 4140 5053 | christoph.schmaderer@mri.tum.de | |
| Claudia Regenbogen | Contact | 0894140 5644 | claudia.regenbogen@mri.tum.de |
| Name | Affiliation | Role |
|---|---|---|
| Roman Günthner, PD Dr. | Abteilung für Nephrologie | Principal Investigator |
| Timon Kuchler | Abteilung für Nephrologie | Principal Investigator |
| Matthias Braunisch, Pd Dr. |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of nephrology, Klinikum rechts der Isar | Recruiting | München | Bavaria | 81675 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19951842 | Background | Giannini EH, Mehta AB, Hilz MJ, Beck M, Bichet DG, Brady RO, West M, Germain DP, Wanner C, Waldek S, Clarke JT, Mengel E, Strotmann JM, Warnock DG, Linhart A. A validated disease severity scoring system for Fabry disease. Mol Genet Metab. 2010 Mar;99(3):283-90. doi: 10.1016/j.ymgme.2009.10.178. Epub 2009 Oct 30. | |
| 36543533 | Background |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Blood samples are collected from the participants.
| Cardio MRI | Diagnostic Test | Cardiovascular magnetic resonance imaging (CMR or cardio MRI) will be utilized in patients with Fabry disease. This imaging technique will enable detailed assessment and monitoring of key cardiac abnormalities, including thickening of the heart walls, left ventricular hypertrophy, and decreased blood flow in the coronary vessels. Additionally, T1 relaxation time measurement will be conducted, offering a non-invasive means to detect myocardial tissue abnormalities such as fibrosis and sphingolipid accumulation, which are hallmarks of Fabry disease. Together, these measures provide a comprehensive evaluation of cardiac structure, function, and tissue characteristics in affected patients. |
| Optical coherence tomography (OCT) | Diagnostic Test | Optical coherence tomography (OCT) is a non-invasive, high-resolution imaging technique that utilizes low-coherence light to capture cross-sectional images of the ocular fundus. Based on the principle of interferometry, OCT employs low-coherence light, which is scattered by the tissue, to produce detailed, high-resolution images of the retina and its layers. This technology enables precise visualization of the different retinal layers, including the nerve fiber layer, the ganglion cell layer, and the inner and outer plexiform layers. Additionally, OCT can be used to detect and monitor subtle structural changes in the retina, offering critical insights into retinal microarchitecture and potential manifestations of systemic diseases such as Fabry disease. |
| Echocardiography | Diagnostic Test | Detection of signs of left ventricular hypertrophy, diastolic dysfunction, and valvular disease, which are common cardiac complications associated with Fabry disease, will be a key focus of the assessment. These abnormalities are indicative of the progressive cardiac involvement characteristic of the disease. Left ventricular hypertrophy reflects the thickening of the heart muscle, often caused by sphingolipid accumulation, while diastolic dysfunction highlights impaired relaxation and filling of the left ventricle. Valvular disease, including regurgitation or stenosis, further contributes to the cardiac burden in Fabry disease. Identifying and monitoring these conditions are essential for timely intervention and effective management of cardiac manifestations in affected patients. |
| 24 hour pulse wave analysis | Diagnostic Test | Pulse wave analysis (PWA) is a non-invasive method used to assess the cardiovascular system. It uses a sensor to measure the pressure waves generated by the heart's contraction and the subsequent blood flow through the peripheral vessels. By analyzing these pressure waves, PWA can provide information about the elasticity of the arterial walls, the blood flow in the peripheral vessels, the blood pressure, and the arterial stiffness. |
| 24-hour blood pressure measurement | Diagnostic Test | Blood pressure measurement to asses cardiovascular risk. |
| 1 hour ECG | Diagnostic Test | One hour ECG to asses autonomic dysfunction in patients with Fabry disease. |
| Ophthalmological consultation | Diagnostic Test | Evaluation and monitoring of ocular manifestations of Fabry disease. |
| Static retinal vessel analysis (SVA) | Diagnostic Test | Comparable to DVA, SVA is a non-invasive and quick tool to examine the retinal microvasculature. SVA pictures will be analyzed using Vesselmap 2® (IMEDOS Systems GmbH, Jena, Germany). One eye will be examined, and three images will be taken with a focus on the optic disc at an angle of 50°. Roughly one disc diameter away from the optic disc, retinal veins and arterioles segments will be semi-automatically labeled. The Paar-Hubbard formula averages the central retinal arteriolar (CRAE) and central venular (CRVE) equivalents. The arteriolar-venular ratio will be calculated as CRAE/CRVE. |
| From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4 |
| Change in Flicker-Induced Venular Dilation (aFID) | What will be measured: Maximum percentage change in retinal arteriolar diameter during flicker stimulation. Unit of Measure: Percentage (%). How it will be reported: Mean vFID percentage change at baseline for Fabry disease patients compared with age- and sex-matched healthy controls. | From enrollment (T0) to the occurrence of death or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4 |
| Predictive Value of SVA and DVA Parameters in Fabry Disease Outcomes | What will be measured: The predictive value of Static Retinal Vessel Analysis (SVA) parameters (CRAE, CRVE, AVR) and Dynamic Retinal Vessel Analysis (DVA) parameters (vFID, aFID) in forecasting Fabry disease-associated events (FACE) FACE are measured as preciously described (https://pmc.ncbi.nlm.nih.gov/articles/PMC10359570/) Unit of Measure: Micrometers (µm) for CRAE, CRVE; unitless ratio for AVR; percentage (%) for vFID and aFID. Measurement Tools: Retinal vessel analyzers (Static Retinal Vessel Analyzer and Dynamic Retinal Vessel Analyzer, IMEDOS Systems, Jena, Germany), echocardiography, clinical laboratory markers (e.g., LysoGb3), and DS3 scoring system. FACE. How it will be reported Hazard Ratios (HR): Derived from Cox proportional hazard models Odds Ratios (OR): For binary outcomes Multivariable Regression Models Receiver Operating Characteristic (ROC) Analysis: Correlation Coefficients: (e.g., Pearson or Spearman) | From enrollment (T0) to the occurrence of death /FACE or the end of the study, whichever comes first, assessed over an estimated period of up to 4 years. Measurements will be conducted annually, starting at T0, then at 1 year (T1), 2 year (T2), T3 and T4 |
| Measurement at enrollment (T0) |
| Patients with Fabry disease and impaired retinal microcirculation Elevated Markers of Endothelial Dysfunction and Chronic Inflammation in Patients With Impaired Retinal Microcirculation | What will be measured: Concentration of markers of endothelial dysfunction (sICAM, sVCAM, Thrombomodulin, P-Selectin, E-Selectin, ADMA, SADMA, Endothelin-1) and chronic inflammation (IFN-β, IFN-λ1, TNF-α). Unit of Measure: Nanograms per milliliter (ng/mL) for most markers; other units (e.g., µmol/L for ADMA) as specified. Measurement Tools: ELISA, flow cytometry (e.g., FACS analysis for PBMCs). How it will be reported: Mean concentrations or median with interquartile range (IQR). | Measurement at enrollment (T0) |
| Correlation Between Retinal Microcirculation Markers and Cardiac Damage | What will be measured: Static retinal vessel analysis parameters (CRAE, CRVE, AVR) and dynamic parameters (vFID, aFID) correlated with cardiac measurements ( thickness of interventricular septum, posterior wall thickness, left ventricular end diastolic diameter) and incidence of cardiovascular events (e.g., heart failure, arrhythmia). Unit of Measure: Micrometers (µm) for retinal vessel parameters; millimeters (mm) for cardiac measurements. Measurement Tools: Retinal vessel analyzers (IMEDOS Systems, Jena, Germany) and echocardiography. How it will be reported: Statistical correlation coefficients (e.g., Spearman or Pearson). | Measurement at enrollment (T0) |
| Correlation Between Genetic Phenotypes and Retinal Vessel Parameters | What will be measured: Static retinal vessel analysis parameters (CRAE, CRVE, AVR) and dynamic parameters (vFID, aFID) correlated with genetic classifications (classical, non-classical Fabry disease) and pathogenicity of GLA gene variants. Unit of Measure: Micrometers (µm) for retinal vessel parameters; categorical classifications for genetic phenotypes (classical, non-classical). Measurement Tools: Retinal vessel analyzers (IMEDOS Systems, Jena, Germany) and genetic analysis using ACMG guidelines. How it will be reported: Mean retinal parameters for each genetic phenotype group; statistical correlations. | Measurement at enrollment (T0) |
| Polymorphisms in the Human Endothelial Nitric Oxide Synthase Gene (eNOS) | What will be measured: Frequency and type of gene polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene. Unit of Measure: Proportion of participants (%) with specific polymorphisms. Measurement Tools: Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. How it will be reported: Percentage of participants with each polymorphism type. | Measurement at enrollment (T0) |
| Comparison of Vessel Density in OCT-A Between Fabry Patients and Healthy Cohort | What will be measured: Vessel density in the retina using optical coherence tomography angiography (OCT-A). Unit of Measure: Percentage (%) of vessel density. Measurement Tools: Optical coherence tomography angiography (OCT-A). How it will be reported: Mean vessel density values for Fabry patients versus healthy controls. | Measurement at enrollment (T0) |
| Abteilung für Nephrologie |
| Principal Investigator |
| Claudia Regenbogen | Abteilung für Nephrologie | Study Chair |
| Christoph Schmaderer | Abteilung für Nephrologie | Study Director |
| Hughes DA, Bichet DG, Giugliani R, Hopkin RJ, Krusinska E, Nicholls K, Olivotto I, Feldt-Rasmussen U, Sakai N, Skuban N, Sunder-Plassmann G, Torra R, Wilcox WR. Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes. J Med Genet. 2023 Jul;60(7):722-731. doi: 10.1136/jmg-2022-108669. Epub 2022 Dec 21. |
| 41545379 | Derived | Wallraven T, Regenbogen C, Gunthner R, Ribeiro A, Carbajo-Lozoya J, Hannane N, Wunderle M, Assaf A, Lech M, Hanssen H, Streese L, Hughes D, Haller B, Kotliar K, Heemann U, Schmaderer C. Endothelial dysfunction in Fabry disease: retinal biomarkers link cardiac GLA gene variants with chronic inflammation. NPJ Genom Med. 2026 Jan 16;11(1):6. doi: 10.1038/s41525-025-00540-1. |
| ID | Term |
|---|---|
| D000795 | Fabry Disease |
| D014652 | Vascular Diseases |
| ID | Term |
|---|---|
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D059345 | Cerebral Small Vessel Diseases |
| D002561 | Cerebrovascular Disorders |
| D002318 | Cardiovascular Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008661 | Metabolism, Inborn Errors |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D052439 | Lipid Metabolism Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| D041623 | Tomography, Optical Coherence |
| D004452 | Echocardiography |
| D063177 | Pulse Wave Analysis |
| D001795 | Blood Pressure Determination |
| D004562 | Electrocardiography |
| ID | Term |
|---|---|
| D041622 | Tomography, Optical |
| D061848 | Optical Imaging |
| D003952 | Diagnostic Imaging |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D014054 | Tomography |
| D008919 | Investigative Techniques |
| D057791 | Cardiac Imaging Techniques |
| D014463 | Ultrasonography |
| D006334 | Heart Function Tests |
| D003935 | Diagnostic Techniques, Cardiovascular |
| D010808 | Physical Examination |
| D004568 | Electrodiagnosis |
Not provided
Not provided