Neurological manifestations of hereditary transthyretin amyloidosis: a focus on diagnostic delays

Abstract

Background

The recent availability of disease-modifying therapies for hereditary transthyretin amyloid (ATTRv) amyloidosis warrants urgency for earlier diagnosis and timely identification of active disease state among genetic carriers.

Methods

We reviewed clinical neurological data of all patients with ATTRv amyloidosis with initial visits at our amyloidosis centre between January 2016 and December 2018. We abstracted the signs and symptoms of neurological manifestations, as well as rates and patterns of diagnostic testing.

Results

Of 92 patients with 19 different transthyretin (TTR) mutations, 66 and 36% had symptoms attributed to large-fibre and small-fibre neuropathy, respectively, compared to 75 and 66% with corresponding examination findings. Thirty-six patients with V122I ATTR mutation had asymptomatic polyneuropathy identified on neurological examination, eight without concurrent cardiac disease. Seventy-three percent of patients had symptoms of carpal tunnel syndrome (CTS), while 26% had dysautonomia. The average delays between the onset of symptoms of large fibre neuropathy (LFN) or CTS to ATTRv amyloidosis diagnosis were 2.9 and 6.7 years, respectively.

Discussion

Our study found higher rates of polyneuropathy by examination than patient-reported symptoms, especially among those with V122I TTR amyloidosis, signalling asymptomatic polyneuropathy. Our findings suggest the need for routine neurological examinations and other testing for genetic carriers to achieve earlier identification of active disease state.

Keywords:

• Hereditary transthyretin amyloidosis
• carpal tunnel syndrome
• polyneuropathy
• dysautonomia

Disclosure statement

Michelle C. Kaku, Shivkumar Bhadola and K.H. Vincent Lau: Nothing to declare.

Lawreen Connors:

R01HL139671 (NIH/NHLBI);

The Wildflower Foundation (Foundation Grant);

R01 DK107604 (NIH/NIDDK);

Janssen Biotechnology, Inc. (Sponsored Research Agreement);

Charles J. Brown Research Professorship in Amyloidosis.

Vaishali Sanchorawala:

Research support: Takeda, Celgene, Janssen, Prothena, Caelum, Sorrento, Karyopharm, Oncopeptide;

Consultancy: Pfizer;

Scientific advisory board: Proclara, Caelum, Protego, Abbvie, Prothena, Regeneron.

John Berk:

Scientific advisor: Intellia Therapeutics, Corino Therapeutics;

Consultant: Eidos/BridgeBio;

Ad hoc Clinical Trial Advisor: IONIS.