Targeting transthyretin deposition in lumbar spinal stenosis: a mechanistic rationale for tafamidis

Transthyretin (TTR) is a 127-amino acid protein that forms a homotetramer, whose main function is to transport thyroxine and retinol-binding protein-retinol (vitamin A) complex (1external link, opens in a new tab). Misfolding of TTR leads to transthyretin amyloidosis (ATTR), which is associated with cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN). There are two types of ATTR: a wild-type (previously called senile; ATTRwt) and a variant-type (genetic variation; ATTRvt) (2external link, opens in a new tab). More than 150 pathogenic TTR proteins have been identified in ATTRvt, the most common being Val122Ile (TTRVal122Ile), and the one with the most penetrance, TTRVal30Met (3external link, opens in a new tab). Furthermore, in a recent survey, TTRVal30Met was responsible for more than half of amyloidosis cases, followed by ATTRwt and TTRVal122Ile, and it was noted that ATTRwt was a more common cause of symptomatic amyloidosis in North America (59.5%).