Natural History in Fabry Patients With IVS4+919G>A Mutation

July 16, 2017 updated by: vghtpe user, Taipei Veterans General Hospital, Taiwan

Study of Natural History Among Patients With Chinese Hotspot Late-onset Fabry Mutation IVS4+919G>A Through Family Pedigree Analysis

Fabry disease is caused by the deficiency or absence of alpha-galactosidase A (α-Gal A) activity, leading to progressive deposition of glycosphingolipids, mainly globotriaosylceramide (Gb3), in the lysosomes of multiple tissues and organs. In Taiwan, Dr. Niu first revealed a surprisingly high incidence (approximately one in 1,600 males) of a cardiac variant GLA splicing mutation, IVS4+919G>A, in newborn screening. Patients who carried the IVS4 + 919G > A mutation and were older than 40 years had a higher prevalence of hypertrophic cardiomyopathy. Endocardial biopsy of these patients with hypertrophic cardiomyopathy showed significant Gb3 accumulation in the cardiomyocytes. Although the hotspot IVS4+919G>A mutation is now being observed with greater frequency, understanding of the natural course of cardiac variant Fabry disease with this specific mutation remains limited. Therefore, our study would like to conduct a study to approach the natural history among patients with Chinese hotspot late-onset Fabry mutation IVS4+919G>A through family pedigree analysis.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Fabry disease is caused by the deficiency or absence of alpha-galactosidase A (α-Gal A) activity, leading to progressive deposition of glycosphingolipids, mainly globotriaosylceramide (Gb3), in the lysosomes of multiple tissues and organs. The frequency of classic Fabry disease has been estimated as one in 40,000, and its symptoms typically manifest during childhood, including acroparesthesias, angiokeratoma, corneal opacities, and anhidrosis (Desnick et al. 2001; Ries et al. 2005). Originally thought to be less severe in females (Desnick et al. 2001), more recent evidence indicates that symptoms of this X-linked disorder can manifest as severely in females as in males (Mehta et al. 2004; Wilcox et al. 2008), although they generally occur later in life and show greater variation in severity among female patients (Deegan et al. 2006).

Atypical, late-onset phenotypes have been reported that lack these classic symptoms but instead present with cardiac (Nakao et al. 1995), renal (Nakao et al. 2003), or cerebrovascular disease (Brouns et al. 2010). The frequency of atypical Fabry disease is unknown, but it has been suggested to be more common than previously believed (Nakao et al. 1995). In Taiwan, Dr. Niu first revealed a surprisingly high incidence (approximately one in 1,600 males) of a cardiac variant GLA splicing mutation, IVS4+919G>A, in newborn screening (Chong et al. 2008). Affected males with IVS4+919G>A mutation typically lack the angiokeratomas, acroparesthesias, hypohidrosis, gastrointestinal abnormalities and corneal opacities that are characteristic of the classic, early-onset, more severe phenotype and may manifest cardiac disease with LVH leading to HCM in the third to sixth decades of life (Desnick et al. 2001, von Scheidt W, et al. 1991, Nakao et al. 1995, Nakao et al. 2003). In Dr. Niu's study, patients who carried the IVS4 + 919G > A mutation and were older than 40 years had a higher prevalence of hypertrophic cardiomyopathy (72% of males and 35% of females) (Tai et al., 2012). Endocardial biopsy of these patients with hypertrophic cardiomyopathy showed significant Gb3 accumulation in the cardiomyocytes which is the typical pathological change in patient with classical Fabry disease. Lin et al's previous study (Lin et al. 2010) showed that a high proportion of adults (>40 years of age) carrying the IVS4 +919G>A mutation experienced microalbuminuria and retinal vessel tortuosity, but symptoms involving these organs were very mild and did not cause significant morbidity. Although the hotspot IVS4+919G>A mutation is now being observed with greater frequency, understanding of the natural course of cardiac variant Fabry disease with this specific mutation remains limited.

Primary objective :

  • To map the IVS4 family tree and identify obligate carriers with Chinese hotspot late-onset Fabry mutation IVS4+919G>A through pedigree analysis.
  • To explore and enhance the understanding of the clinical manifestation, disease severity and natural history of patient with Chinese hotspot late-onset Fabry mutation IVS4+919G>A in Taiwan.

Primary End Point :

- Completeness of IVS4 family tree mapping and obligate carrier identification within their family pedigree.

Definition of family tree completeness:

- Enroll first generation (newborn), at least one member from second (parent) and third generation (grandparent) for a complete IVS4 family tree mapping.

Secondary endpoint :

- Collect and analyze medical history, genetic and biochemical assessment data. Perform eGFR and albumin to creatinine ratio (ACR) measurement for renal function assessment, Perform echocardiography and electrocardiography for cardiac function assessment.

Study Type

Observational

Enrollment (Anticipated)

80

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • ADULT
  • OLDER_ADULT
  • CHILD

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

This prospective family screening study aim to enrol family members from pre-identified IVS4 female newborn's family. IVS4 female newborn's family member will be invited to join the family screening study with written informed consent prior to any specific study procedure. After written informed consent process, a series of screening examination will be conducted at screening visit which included medical history interview, physical examination, α-Gal A enzyme activity test, genetic test, plasma lyso-GB3, renal function and cardiac function assessment as well as pedigree data analysis for IVS4 family tree mapping.

Description

Inclusion Criteria:

  • Fabry IVS4 female newborn family members.
  • Patients and/or their legal representatives who are willing to provide written informed consent

Exclusion Criteria:

  • No blood relatives to the IVS4 female newborn family

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Completeness of IVS4 family tree mapping and obligate carrier identification within their family pedigree
Time Frame: First patient in : 30-Sep-2017; Last Patient out : 1-June-2020
First patient in : 30-Sep-2017; Last Patient out : 1-June-2020

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Taipei Veterans General Hospital, Taiwan

Collaborators

Sanofi

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

September 1, 2017

Primary Completion (ANTICIPATED)

June 1, 2020

Study Completion (ANTICIPATED)

September 30, 2020

Study Registration Dates

First Submitted

July 16, 2017

First Submitted That Met QC Criteria

July 16, 2017

First Posted (ACTUAL)

July 19, 2017

Study Record Updates

Last Update Posted (ACTUAL)

July 19, 2017

Last Update Submitted That Met QC Criteria

July 16, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Fabry Version 1.0 VGHTP 2016

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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