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

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

Status

Active, not recruiting

Phases

Unknown

Study type

Observational

Source

ClinicalTrials.gov

Registry ID

NCT07506083

Enrollment

Registered

2026-04-01

Start date

2022-10-20

Completion date

2026-09-30

Last updated

2026-04-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fabry Disease

Keywords

Fabry Disease, Globotriaosylsphingosine, Lyso-globotriaosylsphingosine, Alpha-Galactosidase A, GLA Gene, IVS4+919G>A Mutation

Brief summary

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).

Interventions

None listed

Study design

Observational model

COHORT

Time perspective

PROSPECTIVE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Disease progression - Left Ventricular mass index	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - Papillary muscle mass index	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - LVEF	Baseline, 12 months follow-up and 24 months follow-up	LVEF, or Left Ventricular Ejection Fraction, indicates how well the left ventricle pumps blood. This will be measured using cardiac MRI.
Disease progression - LVEDV	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - LVESV	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - Native T1 mapping	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - LGE volume	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - Number of LGE-positive segments	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - ECV	Baseline, 12 months follow-up and 24 months follow-up	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.
Disease progression - LV end-diastolic septal thickness	Baseline, 6-, 12-, 18-and 24-month follow-up	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.
Disease progression - LV end-diastolic posterior wall thickness	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - LV maximal wall thickness	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Left Ventricular Ejection Fraction (LVEF)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Left Ventricular End-Diastolic Volume (LVEDV)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Left ventricular end-systolic volume (LVESV)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Left Atrium Volume (LA volume)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Right Ventricle Volume (RV Volume)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Right Ventricular Systolic Pressure (RVSP)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - LV global longitudinal strain (GLS)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Left Atrial strains (LA strains)	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Right Ventricle free wall	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Septal longitudinal strain	Baseline, 6-, 12-, 18- and 24 months follow-up	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.

Secondary

Measure	Time frame	Description
Disease progression - Plasma lyso-Gb3	Baseline, 12- and 24 months	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.
Disease progression - NT-proBNP	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Troponins	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression - Urinary protein	Baseline, 6-, 12-, 18- and 24 months follow-up	Measuring urinary protein is an important way to check how well the kidneys are working. This will be measured by collecting a urine sample.
Disease progression - Albumin	Baseline, 6-, 12-, 18- and 24 months follow-up	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.
Disease progression and disease severity - MSSI (Mainz Severity Score Index)	Baseline, 6-, 12-. 18- and 24-month follow-up	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.
Disease progression - NYHA class	Baseline, 6-, 12-. 18- and 24-month follow-up	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.
Mortality	This will be assessed from baseline, 6-, 12-, 18- and 24-month follow-up	Mortality will be recorded during the study period.
Disease progression - New onset of Heart Failure	This will be assessed starting from baseline, then at 6-, 12-, 18- and 24-month follow-up.	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.
Disease progression - Arrhythmia	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	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.
Disease progression - Cardiac hospitalisation	Starting from baseline and then at 6-, 12-, 18- and 24-month follow-up	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.

Countries

Hong Kong

Contacts

PRINCIPAL_INVESTIGATORAlex PW Lee, Professor

Chinese University of Hong Kong

Outcome results