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Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease

Abstract

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis with polyneuropathy (also known as familial amyloid polyneuropathy) is a condition with adult onset caused by mutation of transthyretin (TTR) and characterized by extracellular deposition of amyloid and destruction of the somatic and autonomic PNS, leading to loss of autonomy and death. This disease represents a model of the scientific and medical progress of the past 30 years. ATTRv amyloidosis is a worldwide disease with broad genetic and phenotypic heterogeneity that presents a diagnostic challenge for neurologists. The pathophysiology of the neuropathy is increasingly understood and includes instability and proteolysis of mutant TTR leading to deposition of amyloid with variable lengths of fibrils, microangiopathy and involvement of Schwann cells. Wild-type TTR is amyloidogenic in older individuals. The main symptoms are neuropathic, but the disease is systemic; neurologists should be aware of cardiac, eye and kidney involvement that justify a multidisciplinary approach to management. Infiltrative cardiomyopathy is usually latent but present in half of patients. Disease-modifying therapeutics that have been developed include liver transplantation and TTR stabilizers, both of which can slow progression of the disease and increase survival in the early stages. Most recently, gene-silencing drugs have been used to control disease in the more advanced stages and produce some degree of improvement.

Key points

  • Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is an autosomal dominant, adult-onset systemic disease that usually presents as a progressive peripheral neuropathy and is caused by point mutations in the gene that encodes transthyretin (TTR).

  • ATTRv amyloidosis was initially considered to be endemic to certain regions but is now known to occur worldwide; there are many variants of the TTR gene, which creates large genetic and phenotypic heterogeneity.

  • Dissociation of mutant TTR homotetramers, disruption of the blood–nerve barrier and misfolding and aggregation of TTR that causes endoneurial toxicity are major events in the pathogenesis of ATTRv amyloidosis.

  • Clinical presentation is diverse, including length-dependent small-fibre polyneuropathy, all-fibre polyneuropathy, pseudo-chronic inflammatory demyelinating polyneuropathy, upper-limb-onset neuropathy and motor neuropathy; half of patients also have cardiac amyloidosis.

  • Diagnosis is based on TTR gene sequencing to detect causal mutations and biopsy to detect amyloid deposits or scintigraphy to assess cardiac uptake of bone tracers when biopsy samples are negative.

  • Disease-modifying therapy includes liver transplantation, TTR stabilizers and TTR gene-silencing therapies; trials of RNA interference therapy have produced improvements in neuropathy and quality of life, suggesting reversal of the disease.

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Fig. 1: Sites of transthyretin production and sites affected by amyloid deposition and denervation in hereditary transthyretin amyloidosis.
Fig. 2: Mechanistic models of amyloid fibril formation and disease progression.
Fig. 3: Representative photographs of sural nerve biopsy specimens from patients with hereditary transthyretin amyloidosis.
Fig. 4: Strategy for diagnosis of hereditary transthyretin amyloidosis with polyneuropathy.
Fig. 5: Overall management of hereditary transthyretin amyloidosis with polyneuropathy.
Fig. 6: Overview of therapeutic strategies in hereditary transthyretin amyloidosis with polyneuropathy.

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D.A. has received grants and personal fees (consulting, advisory board fees, travel fees and grants) from Alnylam Pharmaceuticals and personal fees (advisory board fees and travel fees) from Pfizer. H.K. has received personal fees (consulting fees and travel fees) from Pfizer. M.S. has received grants and personal fees (consulting fees, advisory board fees, travel fees and grants) from Alnylam Pharmaceuticals and personal fees (advisory board fees and travel fees) from Pfizer. T.C. has received financial support to attend scientific meetings and honoraria for lectures from Alnylam, Biogen, Glaxo, Ionis and Pfizer.

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Glossary

Penetrance

The proportion of mutation carriers who will express the associated disease phenotype.

Holter monitoring

Continuous electrocardiogram recording using a portable device for the assessment of patients with suspected cardiac arrhythmias.

Strain imaging

Echocardiographic technique used to measure myocardial regional or global deformation during cardiac contraction.

Scintigraphy

Imaging of the heart at the molecular level using radiolabelled ligands.

Schirmer test

A test to determine whether the eye produces enough tears or whether a patient has dry eye.

QRS complex

Electrical activity of the ventricles, as recorded by electrocardiogram.

Cryptic epitope

Epitopes that are not exposed for presentation to the immune system under normal conditions.

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Adams, D., Koike, H., Slama, M. et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol 15, 387–404 (2019). https://doi.org/10.1038/s41582-019-0210-4

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