TRAMmoniTTR Study Genetic Screening of an At-risk Population for hATTR and Monitoring of TTR Positive Subjects

Study Overview
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Brief Summary
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National, multicenter, epidemiological, longitudinal protocol to investigate the hATTR prevalence in an at-risk population for Hereditary Transthyretin Amyloidosis (hATTR) and subjects diagnosed with hATTR, to monitor the clinical status in TTR positive subjects and to establish hATTR biomarker/s

Detailed Description
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Hereditary TransThyRetin Amyloidosis (hATTR) is a slowly progressive condition, that is transmitted as an autosomal dominant trait and is characterized by abnormal extracellular deposits of fibrillar, misfolded proteins (amyloid fibrils) in the body. Amyloid fibrils can be deposited in different body compartments, such as the nerves, heart, gastrointestinal tract, kidneys and brain, causing severe structural changes. More than 30 proteins can trigger the formation of amyloid fibrils, 5 of which can infiltrate the heart and cause cardiac amyloidosis. One of these amyloidogenic protein is transthyretin, formerly known as prealbumin. Transthyretin (TTR) is found primarily in the serum (secreted by the liver) and cerebrospinal fluid (secreted by the choroid plexus) and functions as a carrier for the hormone thyroxine (T4) and retinol-binding protein (bound to retinol or vitamin A). The destabilization of the TTR protein and the formation of misfolded TTR. It is the goal of this study to investigate the prevalence of Hereditary Transthyretin-related Amyloidosis (hATTR) in a cohort of 5.000 subjects are at risk for Hereditary Transthyretin Amyloidosis (hATTR) and subjects diagnosed with hATTR, to monitor the clinical status in TTR positive subjects and to establish hATTR biomarker/s.

Official Title
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Genetic Screening of an At-risk Population for Hereditary TransthyRetin-related AMyloidosis and Longitudinal Monitoring of TTR Positive Subjects- A Multicenter Epidemiological Longitudinal Protocol

Conditions
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Transthyretin Amyloidosis, Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Polyneuropathies, Cardiomyopathies

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent is obtained from the participant The participant is 18 years of age or older The participant has no diagnosis of alcoholism according to international guidelines The participant has not undergone chemotherapy for any carcinoma AND The participant is at risk for hATTR due to two or more the factors listed below: cardiomyopathy or polyneuropathy with no obvious etiology atypical Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or Motor Neuron Disease (MND) autonomic dysfunction hypertrophic cardiomyopathy or heart failure with preserved ejection fraction Left Ventricular Hypertrophy (LVH) bilateral carpal tunnel syndrome spinal stenosis or spinal radiculopathy gait disorders ocular changes involving vitreous opacities unexplained weight loss >5kg renal abnormalities family history of hATTR based on imaging or biopsy suspected for the wild type TTR (ATTR) and not genetically tested for hATTR OR • The participant is diagnosed with hATTR OR • The participant is a 1st or 2nd degree relative of the TTR positive subject Exclusion Criteria Informed consent is not obtained from the participant The participant is younger than 18 years of age The participant has a diagnosis of alcoholism according to International guidelines The participant has undergone chemotherapy for any carcinoma The participant is not at risk for hATTR

Ages Eligible for Study
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Minimum Age: 18 Years

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 |
| --- | --- |
| Participants at risk for hATTR and participants diagnosed with hATTR<br>Participants 18 years of age or older | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of prevalance of hATTR mutations among a cohort of participants at risk for hATTR. | DBS-based genetic analyses of TTR gene will be perfomed via the combination of the Next-Generation Sequencing (the mutation will be confirmed by Sanger sequencing) and the Multiplex ligation-dependent probe amplification. | 4 years | 
| To monitor clinical status in TTR positive subjects. | 8 Follow up visits within 24 months | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Establishment of biomarker/s in TTR positive cohort. | hATTR-positive samples will be analyzed for the identification of potential biomarkers (based on MS/MS-Tandem spectroscopy) and compared with the merged control samples in order establish a HAE specific biomarker. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Nervous System Diseases, Transthyretin Amyloidosis, Transthyretin-related familial amyloid polyneuropathy, Transthyretin-related familial amyloid cardiomyopathy