~ R f~~~ l~ l A~ l O~ VS: TTR= transthyretin; ATTR= familial transthyretin amyloidosis;,. IS= mass spectrometry; Da= dalton; A h= autonomic neuropathy; CTS= carpal tunnel syndrome; LM= leptonzeningeal; PA'= polyneuropathy uman transthyretin (TTR; MIM# 176300)'is a secretory, thyroid-hormone binding protein found in H plasma (20-40 mg/dL) and cerebral spinal fluid (10-40 pg/mL). Formerly known as prealbumin because it displays an electrophoretic migration position more anodal than albumin, TTR circulates as a tetramer composed of four identical, non-covalently associated subunits. Each monomer is composed of 127 amino acid residues and has a molecular mass of approximately 14000 daltons. Although the liver is the major site of TTR synthesis, extrahepatic sites including the choroid plexus and retina have also been identified. In the bloodstream, TTR is found coupled to both thyroxine and retinol-binding protein complexed to vita-min A. The precise function ofthe protein is unknown, but it is thought that TTR is responsible for transporting L-thyroxine (T,) to the brain.

The gene that codes for TTR is located on chromosome 18 (1 8q12. 1) and spans 6,956 bases including 4 exons and 5 introns. Over the last several decades, 100 TTR gene mutations and/or protein variants have been identified, including several compound variants. The vast majority of the gene sequence variations result in translation products that are pathologic. In most cases, the pathologic nature of these variant proteins lies in their propensity to form amyloid fibril deposits probably as a result of protein misfolding rnechani~ ms.~-~ Familial forms of TTR-associated amyloidosis (ATTR) are autosomal dominant disorders and, while the phenotypes are varied, common clinical