Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy

Abstract

Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called “amyloid”. The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.

Non-Cardiac Amyloidosis Findings Are Not Increased in African American Carriers of TTR V142I with Heart Failure and/or Arrhythmia

“…The V142I TTR monomer that results can undergo a rapid partial denaturation, which allows for self-assembly into amyloid fibrils. The tissue specificity of the amyloid deposition may be related to the physico-chemical characteristics of the resulting fibrils [ 26 ].…”

Gene-based therapies for neuromuscular disorders

“…Mutations in the transthyretin gene (TTR) result in an amyloidogenic multisystemic disease (ATTRv) that affects mainly the peripheral nervous system (ATTRv-pn) and the heart (ATTRv-h). 65,66 Most of the TTR protein has liver production and circulates as a monotetramer, that transports thyroxin and vitamin A. 65,66 ATTRv is a fatal autosomal dominant disease of variable penetrance caused by the deposition of misfolded TTR fibrils whose prognosis changed enormously after liver transplantation.…”

“…65,66 Most of the TTR protein has liver production and circulates as a monotetramer, that transports thyroxin and vitamin A. 65,66 ATTRv is a fatal autosomal dominant disease of variable penetrance caused by the deposition of misfolded TTR fibrils whose prognosis changed enormously after liver transplantation. The natural history of the disease was also modified with the introduction of tafamidis, a small molecule that stabilizes the TTR tetramer, avoiding fibril formation.…”

“…The natural history of the disease was also modified with the introduction of tafamidis, a small molecule that stabilizes the TTR tetramer, avoiding fibril formation. 65,66 The possibility of interrupting TTR production through gene silencing became a clinical reality in the second half of the last decade with the use of two different technologies: antisense oligonucleotides (ASO) and small interfering RNAs (siRNA), both effectively suppressing TTR production acting at RNA level. 66 ASO selectively binds to the complementary RNA, preventing RNA translation and gene expression, which can also be modulated by siRNA which targets and cleaves complementary mRNAs.…”

“…Mutations in the transthyretin gene ( TTR ) result in an amyloidogenic multisystemic disease (ATTRv) that affects mainly the peripheral nervous system (ATTRv-pn) and the heart (ATTRv-h). 65 66 Most of the TTR protein has liver production and circulates as a monotetramer, that transports thyroxin and vitamin A. 65 66 …”