Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care

Abstract

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy) is a rare disease due to mutations in the gene encoding transthyretin (TTR) and characterized by multisystem extracellular deposition of amyloid, leading to dysfunction of different organs and tissues. hATTR amyloidosis represents a diagnostic challenge for neurologists considering the great variability in clinical presentation and multiorgan involvement. Generally, patients present with polyneuropathy, but clinicians should consider the frequent cardiac, ocular and renal impairment. Especially a hypertrophic cardiomyopathy, even if usually latent, is identifiable in at least 50% of the patients. Therapeutically, current available options act at different stages of TTR production, including synthesis inhibition (liver transplantation and/or gene-silencing drugs) or tetramer TTR stabilization (TTR stabilizers), increasing survival at different disease stages.

Graphical abstract

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Keywords:

• amyloid
• polyneuropathy
• clinical care
• therapy
• transthyretin

Abbreviations

^9mTc-DPD, technetium-99m radiolabeled 2,3-dicarboxypropane-1,1-diphosphonate; ^99mTc-HMDP, technetium-99m radiolabeled hydroxymethylene diphosphonate; ^99mTc-PYP, technetium-99m radiolabeled pyrophosphate; ASO, antisense oligonucleotide; ATTRwt, wild-type transthyretin amyloidosis; BNP, brain natriuretic peptide; CADT, Compound Autonomic Dysfunction Test; CNS, central nervous system; COMPASS-31, Composite Autonomic Symptom Scale-31; CSF, cerebrospinal fluid; EGCG, epigallocatechin-3-gallate; eGFR, estimated glomerular filtration rate; EMA, European Medicines Agency; FAC, familial amyloid cardiomyopathy; FAP, familial amyloid polyneuropathy; FDA, Food and Drug Administration; GalNAc, N-acetylgalactosamine; hATTR, hereditary transthyretin amyloidosis; hATTR-CM, hereditary transthyretin amyloidosis with cardiomyopathy; hATTR-PN, hereditary transthyretin amyloidosis with polyneuropathy; LT, liver transplantation; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score +7; MRI, magnetic resonance imaging; NIS, Neuropathy Impairment Score; NIS+7, Neuropathy Impairment Score +7; NIS-LL, Neuropathy Impairment Score-Lower Limbs; Norfolk QoL-DN, Norfolk Quality of Life-Diabetic Neuropathy; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PND, Polyneuropathy Disability score; QoL, quality of life; RNAi, RNA interference; RNase H1, ribonuclease H1; R-ODS, Rasch-built Overall Disability Scale; siRNAs, small interfering RNAs; T4, thyroxine; TTR, transthyretin.

Disclosure

Dr Luigetti received financial grants (honoraria and speaking) from Akcea, Alnylam and Pfizer, and travel grants from Pfizer, Kedrion and Grifols; Dr Bisogni received financial grants (honoraria and speaking) from Alnylam, and travel grants from Pfizer, and Grifols; Dr Romano received travel grants from Akcea and Pfizer; Dr Di Paolantonio received travel grants from Akcea and Pfizer; Dr Sabatelli received financial grants (honoraria and speaking) from Akcea. The authors report no other conflicts of interest in this work.