Biomarker for Patients With Fabry Disease (BioFabry) (BioFabry)

Biomarker for Fabry Disease: BioFabry AN INTERNATIONAL, MULTICENTER, EPIDEMIOLOGICAL PROTOCOL

Development of a new mass spectrography-based biomarker for the early and sensitive diagnosis of Fabry disease from the blood

Study Overview

• Status: Withdrawn
• Conditions: Chronic Kidney Disease; Hearing Loss; Angiokeratomas; Ocular Abnormalities

Detailed Description

Fabry disease is a progressive, inherited, multisystemic lysosomal storage disease characterized by specific neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular manifestations.

Annual incidence is reported to be 1 in 80,000 live births but this figure may underestimate disease prevalence. When late-onset variants of the disease are considered, a prevalence of approximately 1 in 3,000 has been suggested. Fabry disease is pan-ethnic.

Fabry disease is a disorder of glycosphingolipid metabolism caused by deficient or absent lysosomal alpha-galactosidase A activity related to mutations in the GLA gene (Xq21.3-q22) encoding the alpha-galactosidase A enzyme. Deficient activity results in accumulation of globotriaosylceramide (Gb3) within lysosomes, believed to trigger a cascade of cellular events.

Fabry disease is transmitted as an X-linked trait. The existence of atypical, late-onset, variants and the availability of specific therapy complicate genetic counseling.

The clinical picture covers a wide spectrum ranging from mild cases in heterozygous females, to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. These patients may have all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular (hearing loss and vertigo) and cerebrovascular (transient ischemic attacks, strokes) symptoms of the disease.

Female patients may have very mild to severe symptoms. Pain is a common early symptom of Fabry disease (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises characterized by agonizing burning pain). Pain may resolve in adulthood.

Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance. Other signs include corneal changes ("cornea verticilata"), Definitive laboratory diagnosis involves demonstration of marked enzyme deficiency in hemizygous males. Enzyme analysis may occasionally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation, making molecular testing (genotyping) of females mandatory.

With age, progressive damage to vital organ systems develops, possibly leading to organ failure. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit the life-expectancy .

New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.

Therefore it is the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.

• Study Type: Observational

Contacts and Locations

Study Locations

• Germany
  • Rostock, Germany, 18055
    • CENTOGENE GmbH
• India
  • Mumbai, India, 400705
    • NIRMAN-University of Mumbai-Institute of Research in Mental and Neurological handicap
• Sri Lanka
  • Colombo 8, Sri Lanka, 00800c
    • Lady Ridgeway Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with Fabry disease or high-grade suspicion for Fabry disease

Description

INCLUSION CRITERIA:

• Informed consent will be obtained from the patient or the parents before any study related procedures.
• Patients of both genders older than 2 months
• The patient has a diagnosis of Fabry disease or a high-grade suspicion for Fabry disease

• High-grade suspicion present, if one or more inclusion criteria are valid:

  • Positive family anamnesis for Fabry disease
  • Pin and burning in the hands and feet
  • Angiokeratomas
  • Gastrointestinal problems
  • Heart problems
  • Kidney problems

EXCLUSION CRITERIA:

• No Informed consent from the patient or the parents before any study related procedures.
• Patients of both gender younger than 2 months
• No diagnosis of Fabry disease or no valid criteria for profound suspicion of Fabry disease

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Observation; Patients with Fabry disease or high-grade suspicion for Fabry disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sequencing of the Fabry disease related gene	Next-Generation Sequencing (NGS) of the GLA gene will be performed. The mutation will be confirmed by Sanger sequencing.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Fabry disease specific biomarker candidates finding	The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.	24 months

Collaborators and Investigators

• Sponsor: CENTOGENE GmbH Rostock

Publications and helpful links

Helpful Links

• Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 20, 2018
• Primary Completion (ACTUAL): February 28, 2021
• Study Completion (ACTUAL): February 28, 2021

Study Registration Dates

• First Submitted: May 18, 2016
• First Submitted That Met QC Criteria: May 18, 2016
• First Posted (ESTIMATE): May 19, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 13, 2023
• Last Update Submitted That Met QC Criteria: February 9, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Biomarker; Fabry Disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Urologic Diseases; Neurologic Manifestations; Renal Insufficiency; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Otorhinolaryngologic Diseases; Ear Diseases; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Sensation Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Neoplasms, Vascular Tissue; Hearing Disorders; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Kidney Diseases; Renal Insufficiency, Chronic; Hearing Loss; Fabry Disease; Angiokeratoma
• Other Study ID Numbers: BFA 06-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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