Guideline of transthyretin-related hereditary amyloidosis for clinicians

Abstract

Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.

Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

“…7 Revusiran is an investigational RNAi therapeutic agent for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis), a rare, multisystemic disease affecting $50,000 people worldwide, resulting from the deposition of insoluble TTR amyloid fibrils in various organs and tissues. 8,9 Autosomal dominant mutations of the TTR gene destabilize the liver-expressed native tetramer, yielding amyloidogenic TTR monomers and oligomers in circulation that form amyloid deposits in the heart, peripheral nerves, and gastrointestinal tract, leading to either cardiomyopathy and/or polyneuropathy. More than 100 different TTR mutations leading to hereditary ATTR amyloidosis (h-ATTR amyloidosis) have been described, and clinical presentation varies according to the TTR gene mutation.…”

“…12 Regardless of the form of ATTR amyloidosis, disease progression following symptom onset is associated with a substantial deterioration in patients' quality of life and, ultimately, leads to death within approximately 5-15 years of diagnosis. 8,12 Revusiran is comprised of a 2 0 -deoxy-2 0 -fluoro-and 2 0 -O-methylcontaining siRNA directed against a region of the human TTR mRNA shown to be conserved in WT and all documented variants of the TTR gene, conjugated to GalNAc, and is amenable to subcutaneous delivery. 7,13 This hepatocyte-selective GalNAc-mediated delivery approach is well suited to targeting TTR, given that the majority of circulating TTR (>95%) is derived from hepatocytes.…”

Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis

“…One type is a hereditary systemic amyloidosis (familial amyloid polyneuropathy), which is induced by mutant transthyretin. [4][5][6] The other type is senile systemic amyloidosis, which is an age-related sporadic systemic amyloidosis that is induced by wild-type transthyretin. [7][8][9] Besides full-length wild-type transthyretin, C-terminal wild-type transthyretin fragments beginning at positions 46-52 usually occur in amyloid deposits obtained from patients with senile systemic amyloidosis as well as many cases with hereditary transthyretin amyloidosis.…”

Transthyretin-Related Familial Amyloid Polyneuropathy: In the Light of New Developments

“…Presentation with isolated cardiac involvement but very mild neurologic involvement with Val122Ile mutations, and leptomeningeal amyloidosis with Asp18Gly, Ala25Thr, and Gly53Glu mutations have also been reported (6,12,13,14). These clinical differences vary between different mutations, and there are also phenotypic differences between family members with the same mutation (1).…”

“…After being defined in a 37-year-old female as mal dos pesinos (foot disease) by Corino Andrade (1,2) approximately 65 years ago, there have been numerous developments in genetics, pathophysiology, and treatment of transthyretin-related familial amyloid polyneuropathy (TTR-FAP), in which amyloid fibrils containing mutant TTR protein deposit in various tissues and organs, especially peripheral nerves. Previously known as prealbumin, the TTR protein carries vitamin A and thyroxine in blood.…”