Biomarker for Patients With Fabry Disease (BioFabry)

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

Detailed Description
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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.

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

Conditions
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Angiokeratomas, Chronic Kidney Disease, Ocular Abnormalities, Hearing Loss

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Observation<br>Patients with Fabry disease or high-grade suspicion for Fabry disease | |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fabry Disease, Biomarker