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

Published: Oct 05, 2023
Category
Scientific Articles
Key Information
Source
National Library of Medicine
Year
2023
summary/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.

Keywords: ATTRwt, ATTRv, amyloid, transthyretin, polyneuropathy

Introduction

Although hereditary transthyretin amyloidosis (ATTRv) is globally the most frequent form of familial amyloidosis, it is a rare disorder with a largely variable worldwide prevalence (–). It is caused by autosomal dominant mutations in the transthyretin (TTR) gene (TTR), located on chromosome 18 ().

TTR is a protein synthesized in the liver, pancreas, choroid plexus, and retinal pigment epitelium (, ). Its primary function is to transport the thyroid hormone thyroxine in the plasma and cerebrospinal fluid and the retinol-binding protein (RBP) bound to retinol in the plasma (, ). Pathological dysfunction of TTR protein is related to the aggregation of misfolded proteins causing extracellular deposition of amyloid-insoluble fibrils and local tissue damage (). While wild-type TTR amyloidosis (ATTRwt) is an acquired condition that mainly affects the heart, develops with age and commonly affects men over the age of 60, ATTRv provides a wide range of clinical presentations that differ for age of onset, organ involvement, and severity of disease (). It may present with infiltrative cardiomyopathy (hereditary transthyretin amyloidosis cardiomyopathy, or ATTRv-CM) and/or length-dependent sensory motor polyneuropathy (hereditary transthyretin amyloidosis polyneuropathy, or ATTRv-PN), variably associated with autonomic dysfunction (). However, ATTRv is a multisystem disorder, and clinicians should always investigate possible eye, kidney and gastrointestinal involvement (–). The heterogeneity in clinical presentations depends mostly on genotype and ethnicity (, ). Thanks to the institution of an online registry for mutations in ATTRv, awareness of genotype-phenotype correlation has been rising in the past decade (). Regarding global distribution, endemic and non-endemic areas have been described (–). Patients from endemic areas (e.g., Portugal, Sweden, Japan) usually present with early-onset involvement of small nerve fibers, while late-onset length-dependent sensory-motor polyneuropathy is frequent in non-endemic areas (–). In this review, we discuss the latest acquisitions into the pathology and clinical aspects of ATTRv, with a focus on ATTRv-PN and its management and treatment.

Epidemiology

The global prevalence of ATTRv is estimated to be around 10,186 people, with a range between 5,000 and 38,000 (). The so-called endemic clusters are described in Portugal, Sweden, Brazil and Japan where some specific endemic sub-regions (e.g., area of Póvoa do Varzim/Vila do Conde, Skellefteå, and Piteå, Nagano/Kumamoto/Ishikawa) were also reported (, –). Prevalence in endemic countries ranges from 0.9 to 204 (per 1 000 000 persons) countrywide, yet in endemic sub-regions, it may reach 1,631 (per 1 000 000 persons) ().

While smaller endemic foci were also reported in Cyprus and Mallorca (, ), in the rest of Europe, the incidence of ATTRv is highly variable with countrywide lower rates (, ). In Italy, the prevalence is around 4.33/million with regional clusters in Tuscany, Latium and mainly in Southern Italy as Sicily, Calabria, and Puglia (, ). However, data from the Italian Registry may be underestimated because of the voluntary participation and the high rate of unrelated patients, suggesting that relatives of affected ones did not always undergo familial segregation ().

In the last few years, an increasing number of ATTRv late-onset cases have been reported in many countries across Europe, the USA, China, and India (, ). With the growing awareness of the disease, the more frequent use of genetic testing, and the benefits of the currently available disease-modifying therapies, the incidence and prevalence of ATTRv are likely to increase over the years, especially in regions where it is not endemic.

The age of onset is usually between the 2nd and 5th decades of life in endemic areas, while late-onset cases (7–8th decade) are more often reported in non-endemic countries ().

ATTRv affects males and females usually with no significant gender prevalence, yet the parent-of-origin effect in carriers is hypothesized because maternal inheritance of the mutation seems to be related to a higher risk of disease (). However, in families with late-onset disease, a male predominance has been reported ().

Authors
Loris Poli, Beatrice Labella, Stefano Cotti Piccinelli, Filomena Caria, Barbara Risi, Simona Damioli, Alessandro Padovani and Massimiliano Filosto