1. TRAM - Screening for Hereditary Transthyretin Related Amyloidosis

TRAM - Screening for Hereditary Transthyretin Related Amyloidosis

Clinical trial started on July 20, 2017

Synopsis

Transthyretin (TTR) amyloidosis (A-TTR) is a rare protein misfolding, autosomal dominant inherited disease with variable penetrance. It presents with a wide spectrum of clinical manifestations. TTR, the protein implicated in A-TTR, is a tetrameric transport protein. Misfolded TTR protein forms amyloid fibrils causing tissue damage by direct compression and obstruction. In the earliest stages of the disease the symptoms comprise autonomic and/or sensory symptoms. The clinical spectrum of A-TTR (Amyloidosis TTR) varies widely from an exclusive neurological involvement to a predominant cardiac presentation. In the first case, the disease is called TTR familial amyloid polyneuropathy (TTR-FAP). In the second case, the disease is called TTR amyloid cardiomyopathy (TTR-CM). Most likely this classification does not really make sense furtheron, since the clinical picture is in the majority of the patients (>62%) overlapping.TTR-FAP is a fatal illness resulting from autosomal dominantly inherited single-point mutations on the TTR gene. This disease typically strikes people in their 30s to 50s. TTR-CM may occur alone or in conjunction with TTR-FAP. TTR-CM is often associated with genetic variants of TTR but may also occur in the absence of a specific mutation, what is known as wild-type A-TTR (A-TTRwt). A-TTR is probably widely underdiagnosed, mainly because the disease can mimic other causes of left ventricular (LV) hypertrophy (LVH), including hypertensive heart disease and hypertrophic cardiomyopathy (HCM).In an adult, HCM is defined by the presence of a LV wall thickness ≥15 mm in one or more LV myocardial segments that is not explained solely by abnormal loading conditions. Five to ten percent of adult cases are caused by genetic disorders including inherited metabolic and neuromuscular diseases, chromosome abnormalities and genetic syndromes. Some patients have non-genetic disorders that mimic genetic forms of the disease, for example, senile A-TTR (which is a A-TTRwt) and light chain amyloidosis (AL).The diagnosis of HCM is based on the detection of increased LV wall thickness by any imaging modality.Cardiac amyloidosis (CA) is a manifestation of several systemic diseases known as amyloidosis. Clinical features are varied, and although heart failure symptoms predominate, suspicion of CA can also be prompted by syncope, arrhythmias, or unexplained LV wall thickening on echocardiography (ECHO).

Background information

The three most frequent and clinically challenging types of systemic amyloidosis are acquired monoclonal immunoglobulin light chain amyloidosis (AL), the hereditary mutant A-TTR (A-TTRm), and the non-mutant A-TTR, also known as systemic "senile" amyloidosis or A-TTRwt (TTR wild type Amyloidosis). AL and A-TTRm can affect the heart in isolation or with multiorgan involvement, whereas A-TTRwt predominantly affects the heart and the carpal tunnel ligament.The diagnosis of TTR-CM remains challenging. The electrocardiograms (ECGs), transthoracic ECHO (TTE) and cardiac magnetic resonance (CMR) of TTR-CM show similar findings to cardiac AL. The diagnosis strategy for A-TTR combines pathology and molecular genetic testing. TTR is a gene of small size (7 kB), including four exons, and its screening by full sequencing of the coding parts is now easily accessible. In asymptomatic A-TTR carriers, CMR may detect early cardiac involvement by focal myocardial late gadolinium enhancement (LGE).Routine laboratory testings are helpful. High levels of brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular events, heart failure and death. Despite comparable values of LV wall thickness, plasma BNP values are three to five folds higher in patients with TTR-CM than in patients with other causes of HCM.

Non-invasive techniques have been developed in the last years to assist in the diagnosis of TTR-CM, One of the imaging techniques is the bone scintigraphy that has been shown to have excellent results in the diagnosis of TTR-CM. Several studies have suggested that TTR-derived fibrils show avidity for bone tracers, in particular 99m Technetium-3,3-diphosphono-1,2-propano-di-carboxylic acid (99mTc-DPD). For this reason, 99mTc-DPD scintigraphy should be considered in patients in whom TTR-CM is suspected, supporting the diagnosis when histology is not or hardly achievable. 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. Further products are actually under development and in market access stages.

In light of the different potential therapies being available in the market this analysis aims to determine the frequency of TTR based hereditary transthyretin-related amyloidosis in a selected, clinical subpopulation.