Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study

Recruiting

• Conditions: Fabry Disease; Endothelial Dysfunction; Microvasculature

• Registration Number: NCT06758648
• Lead Sponsor: Technical University of Munich

Brief Summary

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?

Detailed Description

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.

Study Timeline

• Study Start: 2020-06-25
• Primary Completion: 2021-09-01
• Study First Submitted: 2023-04-17
• Status Verified: 2024-12
• Study First Submitted QC: 2024-12-30
• Last Update Submitted: 2024-12-30
• Study First Posted: 2025-01-06
• Last Update Posted: 2025-01-06
• Study Completion: 2025-11-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 63

Inclusion Criteria

• Age > 18 years
• Diagnosis of Fabry disease by genetic testing or GB3 activity in leukocytes.
• Signed informed consent form

Exclusion Criteria

• Active infection or cancer
• Surgery less than 2 weeks prior to inclusion in the study
• Known glaucoma
• Lack of capacity to give consent; lack of informed consent.
• Known epilepsy

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Change in Retinal Arteriolar Diameter (CRAE)	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.	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.
Change in Retinal Arteriolar Diameter (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.	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.
Change in arteriolar-venular ration (AVR)	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.	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.
Change in Flicker-Induced Venular Dilation (vFID)	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	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.
Change in Flicker-Induced Venular Dilation (aFID)	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	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.
Predictive Value of SVA and DVA Parameters in Fabry Disease Outcomes	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	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)

Secondary Outcome Measures

Name	Time	Method
Correlation Between Retinal Vessel Parameters and Symptom Severity (DS3)	Measurement at enrollment (T0)	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).
Patients with Fabry disease and impaired retinal microcirculation Elevated Markers of Endothelial Dysfunction and Chronic Inflammation in Patients With Impaired Retinal Microcirculation	Measurement at enrollment (T0)	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).
Correlation Between Retinal Microcirculation Markers and Cardiac Damage	Measurement at enrollment (T0)	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).
Correlation Between Genetic Phenotypes and Retinal Vessel Parameters	Measurement at enrollment (T0)	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.
Polymorphisms in the Human Endothelial Nitric Oxide Synthase Gene (eNOS)	Measurement at enrollment (T0)	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.
Comparison of Vessel Density in OCT-A Between Fabry Patients and Healthy Cohort	Measurement at enrollment (T0)	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.

Trial Locations

Locations (1)

Department of nephrology, Klinikum rechts der Isar; 🇩🇪 München, Bavaria, Germany