Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers

Abstract

Background: Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers.

Methods: We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy.

Results: We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%).

Conclusions: Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

Keywords: AMYLOID; EMG; NEUROPATHOLOGY; NEUROPATHY; NEUROPHYSIOLOGY.

Figure 1

Relationship between infiltration and denervation as a function of the variant group and organ analysed. H/M ratio, heart-to-mediastinum uptake ratio; ICAD, intracutaneous amyloid deposition; IENFD, intra-epidermal nerve fibre density; mIBG, meta-iodo-benzyl-guanidine.

Figure 2

The ‘iceberg’ hypothesis of ATTRv pathophysiology. BNP, brain natriuretic peptide; F-esc, foot electrochemical skin conductance; HRV, heart rate variability; ICAD, intracutaneous amyloid deposition; IVS, interventricular septum thickness; IENFD, intra-epidermal nerve fibre density; mIBG, meta-iodo-benzyl-guanidine; NCS, nerve conduction studies; NYHA, New York Heart Association; SDNN, standard deviation of NN intervals.

Figure 3

Criteria for disease onset and indications for DMT initiation. *Symptoms were classified by level of relatedness to ATTR amyloidosis based on the investigator’s designation on the clinical report form; symptoms marked ‘yes’ were considered definitely related to ATTR amyloidosis. DMT, disease-modifying treatment; HRV, heart rate variability; IENFD, intra-epidermal nerve fibre density; NCS, nerve conduction studies; NYHA, New York Heart Association.