Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments

Abstract

Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan. Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.

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

“…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. 10,11 In addition to the inherited form of the disease, deposition of wild-type (WT) TTR in the heart can also occur, leading to cardiomyopathy. 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.…”

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

“…These mutations result in destabilization of the tetrameric structure of the TTR protein, causing it to dissociate, misfold and aggregate as amyloid in peripheral nerve tissues, the heart and other organs [1,2]. Accumulation of TTRderived amyloid fibrils results in severe, disabling sensorimotor disturbances (loss of sensation, pain, pre-disposition to severe tissue damage from inadvertent injuries, muscle weakness and loss of ambulation) and varying degrees of autonomic, cardiovascular, gastrointestinal, renal, leptomeningeal and urogenital dysfunction [1].…”

Misdiagnosed case of transthyretin amyloidosis in a fully investigated patient

“…Фенотипическая гетерогенность заболевания [2], даже у монозиготных близнецов [3,4], позднее начало симптомов, отсутствие семейного анамнеза часто за-держивают постановку правильного диагноза на годы; нередко пациент длительно наблюдается с неверным диагнозом [5,6]. На примере исследования итальян-ской популяции частота ошибочных диагнозов соста-вила около 32 % со средней задержкой постановки верного диагноза от момента появления первых симп-томов до 4 лет [7].…”