Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis

Abstract

Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.

Keywords: amyloid; neuropathy.

Figure 1

(A) Clinical features and genotype–phenotype correlations. (A) ATTRv a multisystem disease with a variety of clinical features. The most frequent phenotypes include ATTR polyneuropathy (ATTRv-PN), ATTR cardiomyopathy (ATTRv-CM) and ATTR leptomeningeal amyloidosis (ATTRv-LA). (B) To date, 140 mutations in the ATTR gene (TTR) have been reported that lead to ATTRv. The Val30Met is the most frequent mutation, reported globally and in endemic regions. While mutations may give proclivity to specific phenotypes, a poor correlation between phenotype and genotype has been reported. For example, ATTRv Val30Met may be associated with early-onset and late-onset ATTRv-PN, with a paucity of cardiomyopathy in the former. ATTRwt is predominantly associated with ATTR-CM, with relative absence of neuropathy, although carpal tunnel is a common feature. (B) Modified with permission from Castaño and colleagues. ATTR, transthyretin amyloidosis; ATTR-PN, transthyretin amyloidosis–polyneuropathy; ATTRv, hereditary transthyretin amyloidosis; ATTRv-CM, hereditary transthyretin amyloidosis–cardiomyopathy; ATTRv-LA, hereditary transthyretin leptomeningeal amyloidosis; ATTRv-PN, hereditary transthyretin amyloidosis–polyneuropathy; ATTRwt, wild-type transthyretin amyloidosis; TTR, transthyretin.

Figure 2

Investigation findings in ATTR. Sural nerve biopsy demonstrating typical features of amyloidosis. (A) Severe reduction in myelinated and unmyelinated nerve fibre density with evidence of active degeneration (black arrowheads); amyloid deposition is observed in endoneural blood vessels, resulting in thickened vessels walls (black arrow), toluidine blue; scale bar=0.05 mm; (B, C) Amyloid deposits in the endoneurial blood vessel wall (blue arrowheads), Congo red-stained frozen sections. (B) Immunofluorescence with Texas red filter and (C) transmitted light. Scale bars=0.1 mm. (D, E) Technetium-99m-pyrophosphate scintigraphy in hereditary transthyretin demonstrating cardiac uptake compared with surrounding tissues with a heart to contralateral lung ratio of 2.1 (normal <1.5). ATTR, transthyretin amyloidosis.

Figure 3

Diagnostic algorithm for ATTR polyneuropathy. Tissue biopsy may include a target organ such as nerve, heart, bone marrow or skin, or an ‘off-target’ biopsy such as salivary gland or abdominal fat pad aspirate. ^$Depending on availability; IHC and LD-MS are important for amyloid fibril typing. Bone scintigraphy may be semiquantitatively graded relative to rib uptake with the following grades: grade 0, no uptake and normal bone scan; grade 1, uptake less than rib uptake; grade 2, uptake equal to rib uptake; and grade 3, uptake greater than rib uptake with mild or absent rib uptake abnormalities. Echo and CMR are important investigations for detecting cardiac amyloid disease. ATTR, transthyretin amyloidosis; ATTR-PN, transthyretin amyloidosis–polyneuropathy; CMR, cardiac MRI; CTS, carpal tunnel syndrome; Echo, echocardiogram; IHC, immunohistochemistry; LD-MS, laser dissection–mass spectrometry; MGUS, monoclonal gammopathy of uncertain significance; TTR, transthyretin.

Figure 4

Mechanisms by which TTR mutants exert pathogenesis and therapeutic strategies for ATTRv. TTR is predominantly produced by the liver. The conversion of TTR tetramer into insoluble amyloid fibrils is a multistep dynamic process, with dissociation of TTR tetramers into misfolded monomers being the rate-limiting step for the formation of amyloid fibrils. TTR gene mutations destabilise quaternary and tertiary TTR structures and induce thermodynamic instability, resulting in the formation of misfolded monomers. Amyloid fibril formation occurs by nucleation-dependent polymerisation and is influenced by a variety of physiological factors. Therapeutic strategies aimed at different stages of amyloid formation have shown efficacy in ATTRv. ATTRv, hereditary transthyretin amyloidosis; TTR, transthyretin.