A new clinical trial called TRAM aims to determine the prevalence of genetic mutations in the transthyretin (Ttr) gene, the underlying cause of TTR familial amyloid polyneuropathy (TTR-FAP).
The trial (NCT03237494) is for adult patients with polyneuropathy disease or cardiomyopathy of unknown causes and is currently recruiting participants.
Mutations (errors) in the gene for transthyretin leads to an abnormal TTR protein. Until now, more than 100 different TTR gene mutations have been reported. The misfolded protein — which carries an incorrect and aberrant conformation — that arises from these mutations is the underlying cause for TTR amyloidosis. This is because the misfolded TTR has a tendency to form aggregates which deposit in the body’s tissues, mainly in the nerves and heart.
The disease presents a wide spectrum of clinical manifestations, from exclusive neurological involvement to a predominant cardiac presentation. In the first scenario, the disease is called TTR familial amyloid polyneuropathy (TTR-FAP), while the second is called TTR amyloid cardiomyopathy (TTR-CM). However, the symptoms may occur simultaneously, and in fact more than 62 percent of patients exhibit both conditions.
TTR-FAP has a very heterogeneous presentation, and symptoms are usually categorized in three groups: dysfunction of peripheral nerves, autonomic dysfunction, and constitutional conditions. The peripheral nerves are those controlling sensation and movement in the arms and legs, while autonomic nerves control automatic body functions, such as blood pressure, the digestive system, and sexual function.
In this clinical trial, sponsored by the University of Rostock in Germany in collaboration with Centogene, researchers’ primary objective is to determine the prevalence of TTR in patients with polyneuropathy or cardiomyopathy of undetermined causes. The TRAM study’s secondary endpoint is to know the number of correctly identified patients with hereditary TTR-related amyloidosis.
Centogene is a company that focuses on rare diseases and has developed genetic tests to allow a rapid medical diagnosis of inherited conditions, such as TTR-FAP.
The TRAM trial expects to enroll 5,000 patients ages 18 to 70 who are diagnosed either with polyneuropathy or/and cardipmyopathy of undetermined cause based on the results of biochemical tests, including glucose, electrolytes, urea, transaminases, thyroid-stimulating hormone (TSH), immunoglobulins, vitamin B12, RF, ANA, and antibodies against Lyme borrelia.
In the trial, patients DNA samples will be used for molecular genetic diagnosis of the TTR disease. An estimated primary completion date for primary outcome measure is June 2019.
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