Last updated on September 2016

Biomarker for Patients With Transthyretin-Related Familial Amyloidotic Polyneuropathy


Brief description of study

Development of a new MS-based biomarker for the early and sensitive diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy from plasma. Testing for clinical robustness, specificity and long-term stability of the biomarker.

Detailed Study Description

Diseases of diverse etiology can be correlated to the term "polyneuropathy"(PNP). The pathogenesis may be of inflammatory, autoimmune, metabolic, toxic or hereditary nature. Careful clinical and electrodiagnostic assessment, with attention to the pattern of involvement and the types of nerve fibers most affected, narrows the differential diagnosis and helps to focus the laboratory evaluation. Beside the frequent genetic etiologies in PNP (pmp22, MFN2) one cause of a polyneuropathy may be a hereditary amyloidosis. This term describes the accumulation of misfolded protein in the interstitial space. The abnormal accumulation of β-fibrils can be detected histologically by Congo pink staining. Aside from acquired amyloidotic neuropathies (e.g. PNP caused by AL-amyloidosis there are also hereditary amyloidotic neuropathies. These have been described as endemic in Sweden, Portugal or Japan. More recent studies provided evidence for the presence of hereditary amyloidotic neuropathies amongst the German population and that they are currently underdiagnosed. The most common form of the hereditary familial amyloidotic neuropathy (FAP) is the Transthyretin-related FAP, however two other amyloidogenic proteins have been described: Apolipoprotein A-I and Gelsolin. The TTR-FAP is an autosomal dominant disease, the exact prevalence of which is unknown but estimated to be around 1:100,000 to 1:1,000,000 in the normal population. By limiting the study population to patients with PNP of unknown etiology it should be possible to gain evidence for the prevalence of the disease in Germany by investigating fewer patients. While the diagnosis of the amyloidotic neuropathy can be conducted histologically, a molecular genetic approach is necessary to diagnose TTR-FAP. Even though more than 100 point mutations are known to cause the disease, the most common amino acid change is V30M. The mutation in the TTR gene causes the destabilization of the physiologically tetrameric protein. Usually transthyretin consists of four identical monomeric subunits and binds the thyroxin circulating in the blood plasma. The monomeric subunits exhibit a pronounced β-sheet structure which leads to the accumulation of unsoluble β-fibrils when they are destabilised as in TTR-FAP. This accumulation of misfolded TTR can lead to three phenotypes known as - cardiac TTR amyloidosis, - leptomeningeal TTR amyloidosis and the - TTR-FAP. The TTR-FAP has a very heterogeneous phenotype which can manifest starting at the age of 18 and may lead to death within 10 years. The symptoms can be categorized in three groups: Dysfunction of peripheral nerves: - Dissociated anesthesia - Muscle paresis and atrophy - Dysaesthesia and paraesthesia - Reduced skin temperature - Coldness - Hoarseness Autonomic dysfunction: - Dysuria - Diarrhea - Constipation - Orthostatic dysregulation - Erectile dysfunction - Nausea Constitutional conditions - Anemia - Weight loss - Arrhythmia - Edema - Acroparaesthesia The currently available therapeutic approaches are either liver transplantation (as the liver mainly produces transthyretin this is a feasible approach) or as of more recently also a TTR-tetramer stabilizing agent (Tafamidis). Tafamidis (Vyndaqel®) gained the European approval under "exceptional circumstances"in November 2011 for treating FAP in adults with a symptomatic polyneuropathy.In light of the potential therapy of this very rare disease this study aims to determine the prevalence of TTR-FAP in a selected, clinical subpopulation. New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood (plasma) 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 plasma of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.

Clinical Study Identifier: NCT02713880

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Arndt Rolfs, Prof.

Albrecht-Kossel-Institute for Neuroregeneration (AKos) Centre for Mental Health Disease University of Rostock
Rostock, Germany
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