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

NCT06758648 | Recruiting

• 1 other identifier: FD062020
• Study Type: observational
• Target: 63
• Locations: 1 country
• Sites: 1

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?

Conditions

Fabry Disease; Endothelial Dysfunction; Microvasculature

Keywords

Chronic inflammation; retinal microvasculature; retinal vessel analysis; vasculopathy

Outcome Measures

Primary Outcomes (6)

• 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.

  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

Secondary Outcomes (6)

• Correlation Between Retinal Vessel Parameters and Symptom Severity (DS3)

  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

  Measurement at enrollment (T0)

• Correlation Between Retinal Microcirculation Markers and Cardiac Damage

  Measurement at enrollment (T0)

• Correlation Between Genetic Phenotypes and Retinal Vessel Parameters

  Measurement at enrollment (T0)

• Polymorphisms in the Human Endothelial Nitric Oxide Synthase Gene (eNOS)

  Measurement at enrollment (T0)

Interventions

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.

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.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

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

You may not qualify if:

• Active infection or cancer
• Known glaucoma
• Lack of capacity to give consent; lack of informed consent.
• Known epilepsy

Sponsors & Collaborators

• Technical University of Munich: lead
• Takeda: collaborator

Study Sites (1)

Department of nephrology, Klinikum rechts der Isar

München, Bavaria, 81675, Germany

RECRUITING

Related Publications (3)

• 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 BACKGROUND

• 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 BACKGROUND

• 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. doi: 10.1038/s41525-025-00540-1. Online ahead of print.

  PMID: 41545379 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples are collected from the participants.

MeSH Terms

Conditions

Fabry Disease; Vascular Diseases

Interventions

Tomography, Optical Coherence; Echocardiography; Pulse Wave Analysis; Blood Pressure Determination; Electrocardiography

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Intervention Hierarchy (Ancestors)

Tomography, Optical; Optical Imaging; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Tomography; Investigative Techniques; Cardiac Imaging Techniques; Ultrasonography; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Physical Examination; Electrodiagnosis

Study Officials

• Roman Günthner, PD Dr.

  Abteilung für Nephrologie

  PRINCIPAL INVESTIGATOR

• Timon Kuchler

  Abteilung für Nephrologie

  PRINCIPAL INVESTIGATOR

• Matthias Braunisch, Pd Dr.

  Abteilung für Nephrologie

  PRINCIPAL INVESTIGATOR

• Claudia Regenbogen

  Abteilung für Nephrologie

  STUDY CHAIR

• Christoph Schmaderer

  Abteilung für Nephrologie

  STUDY DIRECTOR

Central Study Contacts

Christoph Schmaderer, Prof. Dr.

CONTACT

089 4140 5053; christoph.schmaderer@mri.tum.de

Claudia Regenbogen

CONTACT

0894140 5644; claudia.regenbogen@mri.tum.de

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 17, 2023
• First Posted: January 6, 2025
• Study Start: June 25, 2020
• Primary Completion: September 1, 2021
• Study Completion: November 1, 2025
• Last Updated: January 6, 2025

Record last verified: 2024-12

Locations

DE (1)