Natural History in Fabry Disease With IVS4+919G>A Mutations

Natural History in Fabry Disease With IVS4+919G>A Mutations: A Longitudinal Study (FABULOUS)

Fabry disease (FD) is a genetic condition where mutations in the GLA gene cause low activity of an important enzyme (alpha-Galactosidase A). This leads to harmful substances building up in the body. A key marker is lyso-Gb3, which can damage organs. FD commonly affects the heart, causing left ventricular hypertrophy (LVH), fibrosis, and worsening heart function over time.

In East Asian populations, the exact natural progression of FD is not well understood, even though a specific mutation called IVS4+919G>A is relatively common due to a "founder effect" seen in places like Taiwan and also in Hong Kong. People with this mutation often develop heart problems later in life, with LVH typically increasing after about age 40.

Researchers use advanced heart scans to detect early disease. Cardiac MRI (CMR) native T1 mapping (without contrast) can distinguish normal heart tissue from FD-related changes. CMR measures can reflect different stages of heart damage-starting with accumulation, then inflammation and muscle thickening, and finally fibrosis and impaired function. Some women may not have clear blood test abnormalities yet can still develop ongoing heart damage.

Because some MRI findings (like late gadolinium enhancement, LGE) may represent inflammation as well as fibrosis, and because heart damage can progress even before symptoms appear, non-invasive monitoring is important. Imaging methods like strain echocardiography and repeated T1 mapping can track progression, including in patients without obvious early heart thickening.

Finally, since most previous studies have included fewer East Asian patients, the study aims to better define the natural history of FD in Chinese patients with the IVS4+919G>A mutation by following them over time with regular health checks, blood and enzyme testing, kidney and heart function tests, and family/genetic mapping. The goal is to improve guidelines for screening, monitoring, and deciding when to start treatment (ERT).

Study Overview

• Status: Active, not recruiting
• Conditions: Fabry Disease

• Study Type: Observational
• Enrollment (Actual): 31

Contacts and Locations

Study Locations

• Hong Kong
  • New Territories
    • Shatin, New Territories, Hong Kong, Sha Tin
      • Division of Cardiology, Department of Medicine and Therapeutics Faculty of Medicine, The Chinese University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Potential study participants will be identified from a cohort of genetically confirmed FD patients and their affected relatives diagnosed in Prince of Wales Hospital, Hong Kong and referred from the other regional hospitals/FD centres.

Description

Inclusion Criteria:

• ERT-naive group:
• Age ≥18-year-old
• East Asian ethnicities
• Not on ERT
• Capable of giving signed informed consent
• IVS4+919G>A GLA mutation AND at least ONE of the followings:
• • An increase of plasma LysoGb3 level
• • Demonstration of characteristic storage in the affected organ (e.g. heart, kidney)
• ERT comparator group:
• Age ≥18-year-old
• Capable of giving signed informed consent
• East Asian ethnicities
• On ERT or planned to start ERT
• IVS4+919G>A mutation

Exclusion Criteria:

• Known infiltrative cardiomyopathy including amyloidosis
• Known genetic (e.g. sarcomeric, metabolic mutations) hypertrophic cardiomyopathy
• Pregnancy or suspected pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
ERT-naive group; Participants with Fabry disease due to the GLA IVS4+919G>A mutation who have not started enzyme replacement therapy at enrollment (to characterize natural history/progression).
ERT cohort; Participants with Fabry disease (IVS4+919G>A) who are receiving enzyme replacement therapy (or are expected to start/continue it), included so changes can be observed in relation to treatment timing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease progression - Left Ventricular mass index	The Left Ventricular mass index quantifies the mass of the left ventricle, the heart's main pumping chamber, relative to an individual's body size. This will be measured using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - Papillary muscle mass index	Papillary muscle mass refers to the total amount of tissue (mass) in the papillary muscles located within the left ventricle. These muscles help support the mitral valve and play an important role in how the left ventricle pumps blood during systole. This measurement will be obtained using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - LVEF	LVEF, or Left Ventricular Ejection Fraction, indicates how well the left ventricle pumps blood. This will be measured using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - LVEDV	LVEDV, or Left Ventricular End-Diastolic Volume, is the amount of blood in the left ventricle at the end of diastole, right before the heart contracts. This will be measured using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - LVESV	LVESV stands for Left Ventricular End-Systolic Volume and refers to the volume of blood remaining in the left ventricle after pumping. This will be measured using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - Native T1 mapping	Native T1 is a heart MRI measurement that looks at the properties of the heart muscle tissue without using contrast dye. It helps detect early or subtle tissue changes, such as inflammation or remodeling, even when scarring isn't yet obvious. This will be obtained during cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - LGE volume	LGE volume refers to the measurement of Late Gadolinium Enhancement, a cardiac MRI method used to estimate how much heart muscle has developed fibrosis (scarring). This measurement will be obtained using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - Number of LGE-positive segments	LGE positive refers to Late Gadolinium Enhancement and is used to visualise and assess myocardial damage or scarring. This measurement will be obtained using cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - ECV	Extracellular Volume (ECV) it's a measurement from cardiac MRI that estimates how much of the heart muscle's space is in the outside (between-cell) area, which can increase when there's things like fibrosis (scarring) or other tissue remodeling. This measurement will be obtained with T1 mapping during cardiac MRI.	Baseline, 12 months follow-up and 24 months follow-up
Disease progression - LV end-diastolic septal thickness	Left Ventricle end-diastolic septal thickness is the thickness of the septum, the wall between the left and right sides of the heart, measured at the end of diastole, just before the heart contracts. This measurement indicates how thick that part of the heart wall is when the ventricle is fully filled. This will be measured during echocardiography.	Baseline, 6-, 12-, 18-and 24-month follow-up
Disease progression - LV end-diastolic posterior wall thickness	Left Ventricle end-diastolic posterior wall thickness is a measure of how thick the back wall of the left ventricle is at the end of heart filling. This measurement will be obtained during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - LV maximal wall thickness	Left ventricular maximal wall thickness measures how thick the heart muscle is at its thickest point on the left ventricle wall. This measurement will be taken during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Left Ventricular Ejection Fraction (LVEF)	Left Ventricular Ejection Fraction (LVEF) is a measure of how well the left side of the heart pumps. It shows what percentage of blood in the left ventricle is pushed out with each heartbeat. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Left Ventricular End-Diastolic Volume (LVEDV)	Left Ventricular End-Diastolic Volume (LVEDV) is the amount of blood left in the left ventricle at the end of diastole. This measurement will be taken during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Left ventricular end-systolic volume (LVESV)	Left ventricular end-systolic volume (LVESV) is the amount of blood left in the left ventricle right after it contracts. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Left Atrium Volume (LA volume)	Left Atrium Volume (LA volume) means the size of the left atrium and is a measurement of how much space or blood the left atrium holds. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Right Ventricle Volume (RV Volume)	Right ventricular volume refers to the amount of blood in the right ventricle, usually measured at end-diastole (when the heart is filling) and end-systole (when it has squeezed). This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Right Ventricular Systolic Pressure (RVSP)	Right Ventricular Systolic Pressure (RVSP) measures the pressure generated by the right ventricle as it pumps blood into the pulmonary artery. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - LV global longitudinal strain (GLS)	LV global longitudinal strain (GLS) is a measurement of how well the left ventricle is squeezing by looking at how much the heart muscle shortens in length during each heartbeat. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Left Atrial strains (LA strains)	Left Atrial strains (LA strains) is a measurement of how well the left atrium is working, by tracking how much it stretches and squeezes during the heartbeat. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Right Ventricle free wall	The Right Ventricle free wall refers to the outer/free edge of the right ventricle and is used to assess how well the right ventricle is contracting and working.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Septal longitudinal strain	Septal longitudinal strain is a measure of how much the septum (the wall in the middle of the heart that separates the left and right sides) lengthens and shortens from the base to the tip of the heart during each heartbeat. This will be measured during echocardiography.	Baseline, 6-, 12-, 18- and 24 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease progression - Plasma lyso-Gb3	Plasma lyso-Gb3 is a blood test that measures a substance called lyso-globotriaosylsphingosine (lyso-Gb3). In Fabry disease, the body can't properly break down certain fats, because of that, lyso-Gb3 can build up. This is used as a biomarker to diagnose Fabry disease and to monitor disease progression. This will be obtained during a blood test.	Baseline, 12- and 24 months
Disease progression - NT-proBNP	NT-proBNP is a blood biomarker released by the heart that indicates cardiac stress and helps diagnose and monitor heart failure. This will be obtained during a blood test.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Troponins	Cardiac troponins are proteins that leak into the bloodstream when the heart muscle is injured. They are used to help diagnose heart attacks and other types of heart damage. This will be measured using a blood test.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Urinary protein	Measuring urinary protein is an important way to check how well the kidneys are working. This will be measured by collecting a urine sample.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression - Albumin	Albumin is a protein made by the liver and is essential for maintaining fluid balance and transporting substances throughout the body. This will be measured by collecting a blood test.	Baseline, 6-, 12-, 18- and 24 months follow-up
Disease progression and disease severity - MSSI (Mainz Severity Score Index)	MSSI (Mainz Severity Score Index) will be used to measure how severe the disease is overall and how the participants' health changes overtime or in response to treatment. A higher MSSI score means the disease is more severe.	Baseline, 6-, 12-. 18- and 24-month follow-up
Disease progression - NYHA class	A NYHA class (New York Heart Association) questionnaire will be used to assess the heart failure severity and the impact on the patients' daily activities and overall functional capacity. The scores are divided into Class I (1) to Class IV (4) with Class I meaning no limitations and Class IV meaning severe limitations.	Baseline, 6-, 12-. 18- and 24-month follow-up
Mortality	Mortality will be recorded during the study period.	This will be assessed from baseline, 6-, 12-, 18- and 24-month follow-up
Disease progression - New onset of Heart Failure	Any new onset of heart failure will be recorded throughout the study. This will be assessed by capturing evidence of cardiac deterioration and heart failure symptoms using standard tools such as the NYHA questionnaire and echocardiography.	This will be assessed starting from baseline, then at 6-, 12-, 18- and 24-month follow-up.
Disease progression - Arrhythmia	Detected rhythm abnormalities/events during follow-up will be documented and analysed as part of disease progression. This will be assessed using standard 12-lead ECG and 24-hour Holter ECG.	The standard 12-lead ECG will be conducted at baseline, 6-, 12-. 18- and 24-month follow-up. The 24-hour Holter ECG will be conducted at 12- and 24-month follow-up
Disease progression - Cardiac hospitalisation	Any hospitalisation due to a cardiac cause will be assessed and recorded throughout the study, and this will be evaluated at the scheduled clinical visits.	Starting from baseline and then at 6-, 12-, 18- and 24-month follow-up

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Investigators: Principal Investigator: Alex PW Lee, Professor, Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2022
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): April 1, 2026

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Fabry Disease; Globotriaosylsphingosine; Lyso-globotriaosylsphingosine; Alpha-Galactosidase A; GLA Gene; IVS4+919G>A Mutation
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lipid Metabolism Disorders; Genetic Diseases, X-Linked; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Sphingolipidoses; Lipidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Fabry Disease
• Other Study ID Numbers: 2021.45

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No