National consensus on the diagnosis, treatment, monitoring and prevention of hereditary transthyretin amyloidosis

2023

Abstract

Introduction to Hereditary Transthyretin Amyloidosis (TTRA)
Amyloidosis refers to an extensive group of diseases associated with changes in protein structures which cause the normally soluble protein tetramers, following destabilization of their quaternary structure with subsequent dissociation to free monomeric proteins, to form insoluble extracellular deposits of fibrils, thus resulting in organ dysfunction. All types of amyloids contain a major fibril protein which determines the type of amyloid and other, minor components. More than 20 diverse amyloidosis-related fibril proteins have been described in patients, with each type featuring different clinical presentations. One such protein, which makes up human amyloid fibrils, is transthyretin (Ando et al., 2005)
TTR acts as a transport protein for plasma thyroxine. TTR also transports retinol (vitamin A) by binding with the retinol-binding protein. It circulates as a tetramer comprising four identical subunits. TTR may be found in plasma and in cerebrospinal fluid. It is synthesized mostly in the liver and in the choroid plexus of the brain, and also in smaller amounts in plasma. The TTR gene is located on the long shoulder of chromosome 18 and contains 4 exons and 3 introns.
Systemic amyloidoses are designated by the capital letter A (for amyloid), followed by an abbreviation indicating the chemical nature of the fibril protein. Thus, for example, TTR amyloidosis is abbreviated as ATTR and amyloidosis with immunoglobulin light chain deposits is abbreviated to AL (Saraiva M. et al., 1984; Connors L. et al., 2003; Ando Y. et al. 2005).
Classifying the known genetic types is exceptionally important in molecular genetics assays and their interpretation. The pathogenicity evaluation of any of the genetic types should be based on scientific evidence and should follow the unified nomenclature and rules. In view of the above, the terms „mutation‟ and „polymorphism,‟ which are in extensive use at present, have been replaced by a classification of genetic variants which distinguishes the following 5 categories: pathogenic, likely pathogenic, variants of unclear clinical significance, likely non-pathogenic, and non-pathogenic (Richards S. et al., 2015; Nykamp K. et al., 2017).