Improving early diagnostics in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN): biomarkers of transition to symptomatic disease.

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 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. Although awareness of ATTRv polyneuropathy (ATTRv-PN) among neurologists has increased, there remains significant delays in diagnosis, resulting in accrued disability for patients.

Therapeutic advances in ATTRv-PN have raised novel challenges, including the need to optimise diagnostic techniques and management approaches. Early treatment institution has proved essential to prevent morbidity in ATTRv-PN. However, the major bottleneck to commencement of effective treatment is the ability to identify transition from asymptomatic carrier states to early disease, where symptoms may be subtle.

As a result, the aim of this thesis is to identify and evaluate novel neurophysiological and serological biomarkers of transition to early disease in ATTRv-PN in order to improve diagnostic strategies for determining disease onset.

Collectively, this thesis makes a significant contribution to the understanding and development of early diagnostic strategies in ATTRv-PN. Novel specific biomarkers for axonal loss and remodelling in ATTRv-PN are provided and further clarity regarding the role and utility of serum NfL is confirmed in this cohort. Moving forward, our ability to optimise treatment initiation and improve patient outcomes will rely on the use of combinations of easily reproducible, sensitive and specific biomarkers, which permit the early recognition of transition to symptomatic disease in ATTRv-PN.