Hereditary transthyretin amyloidosis overview

Abstract

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient’s monitoring and treatment, and from presymptomatic testing to management of carriers.

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

“…FAP is a heterogeneous disorder with a clinical presentation that varies based on the genotype and geographic origin [69,70]. To date, more than 40 TTR mutations have been identified and associated with different patterns of organ involvement, age of onset and disease progression [71,72]. The most common type of mutation is a substitution of valine for methionine at position 30 (ATTRV30M) [73].…”

The neuropathy in hereditary transthyretin amyloidosis: A narrative review

“…1 Mutations in TTR gene result in an unstable tetramer that disassociates in misfolded monomers that accumulate in extracellular spaces forming oligomers and ultimately aggregating into amyloid fibrils with the typical structure of cross β-sheets. 2 This conformation allows TTR fibrils to be marked as apple green birefringence deposits under polarized light after Congo red staining. 3 On the other hand, extracellular deposition of TTR-oligomers before fibril aggregation may be visualized using eosinophilic staining and typed by anti-prealbumin antibodies.…”

In Silico Modeling of the Influence of Environment on Amyloid Folding Using FOD-M Model

“…Of course, the presence of amyloid transformation may also be alleged in vivo for both IgG light chain [110] and transthyretin [111,112]. However, they are often associated with the presence of mutations [113,114].…”