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

NCT07506083 | Active Not Recruiting DMC

• 1 other identifier: 2021.45
• Study Type: observational
• Target: 31
• Locations: 1 country
• Sites: 1

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).

Conditions

Fabry Disease

Keywords

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

Outcome Measures

Primary Outcomes (22)

• 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 Outcomes (11)

• Disease progression - Plasma lyso-Gb3

  Baseline, 12- and 24 months

• Disease progression - NT-proBNP

  Baseline, 6-, 12-, 18- and 24 months follow-up

• Disease progression - Troponins

  Baseline, 6-, 12-, 18- and 24 months follow-up

• Disease progression - Urinary protein

  Baseline, 6-, 12-, 18- and 24 months follow-up

• Disease progression - Albumin

  Baseline, 6-, 12-, 18- and 24 months follow-up

Study Arms (2)

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.

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

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.

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Chinese University of Hong Kong: lead

Study Sites (1)

Division of Cardiology, Department of Medicine and Therapeutics Faculty of Medicine, The Chinese University of Hong Kong

Shatin, New Territories, Sha Tin, Hong Kong

Location

MeSH Terms

Conditions

Fabry Disease

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; Vascular Diseases; 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

Study Officials

• Alex PW Lee, Professor

  Chinese University of Hong Kong

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 26, 2026
• First Posted: April 1, 2026
• Study Start: October 20, 2022
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: April 1, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

HK (1)