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

Overview

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.

Interventions

• Diagnostic test Dynamic retinal vessel analysis (DVA)
  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. Arteri
• Diagnostic test Biochemistry and immune phenotyping
  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)
• Diagnostic test Questionnaires (Patient reported outcomes)
  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. Additi
• Diagnostic test Cardio MRI
  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 sphingolipi
• Diagnostic test Optical coherence tomography (OCT)
  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, an
• Diagnostic test Echocardiography
  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 o
• Diagnostic test 24 hour pulse wave analysis
  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.
• Diagnostic test 24-hour blood pressure measurement
  Blood pressure measurement to asses cardiovascular risk.
• Diagnostic test 1 hour ECG
  One hour ECG to asses autonomic dysfunction in patients with Fabry disease.
• Diagnostic test Ophthalmological consultation
  Evaluation and monitoring of ocular manifestations of Fabry disease.

Primary outcome measures

• Change in Retinal Arteriolar Diameter (CRAE) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: 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 [Time frame: 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]

Secondary outcome measures (6)

• Correlation Between Retinal Vessel Parameters and Symptom Severity (DS3) [Time frame: 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 [Time frame: Measurement at enrollment (T0)]
• Correlation Between Retinal Microcirculation Markers and Cardiac Damage [Time frame: Measurement at enrollment (T0)]
• Correlation Between Genetic Phenotypes and Retinal Vessel Parameters [Time frame: Measurement at enrollment (T0)]
• Polymorphisms in the Human Endothelial Nitric Oxide Synthase Gene (eNOS) [Time frame: Measurement at enrollment (T0)]
• Comparison of Vessel Density in OCT-A Between Fabry Patients and Healthy Cohort [Time frame: Measurement at enrollment (T0)]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-control

Study locations

Germany · 1 center

• Department of nephrology, Klinikum rechts der Isar — München

Publications

• 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. PMID 19951842
• 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. PMID 36543533
• 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. PMID 41545379

Identifiers

NCT: NCT06758648 · FD062020

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗