Prevalence of hereditary transthyretin amyloid polyneuropathy in idiopathic progressive neuropathy in conurban areas

Andreas Thimm,Michael Fleischer,Christoph Kleinschnitz,Tienush Rassaf,Sebastian Wurthmann,Benjamin Stolte,Ken Herrmann,Lars Steinmüller-Magin,Christoph Rischpler,Andreas Totzeck,Alexander Carpinteiro,Tim Hagenacker,Maria Papathanasiou,Peter Luedike,Saskia Bolz

doi:10.1186/s42466-019-0035-z

Abstract

BackgroundHereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, genetically heterogenous, and clinically variable autosomal dominant disease that severely reduces life expectancy. As treatment options grow, a proper diagnostic approach is mandatory especially in non-endemic regions with diverse genetic backgrounds.MethodsWe examined 102 neuropathy patients at a German neuromuscular centre. Common causes of polyneuropathy were ruled out by medical history and extensive laboratory testing to define a cohort of patients with progressive polyneuropathy classified as idiopathic. Molecular genetic testing of the entire TTR gene was performed, and the detected amyloidogenic and non-amyloidogenic variants were associated with the observed clinical phenotypes and results of prior diagnostic testing.ResultsTwo of 102 patients tested positive for amyloidogenic mutations (p.Ile127Val and p.Glu81Lys), while a variant of unknown significance, p.Glu26Ser, was found in 10 cases. In both positive cases, previous negative biopsy results were proved by gene sequencing to be false negative. In case of the p.Glu81Lys mutation we detected clinical presentation (combination of severe polyneuropathy and cardiomyopathy), ethnic background (patient of polish origin, mutation only reported in Japanese families before), and disease course clearly differed from well-known cases of the same mutation in the literature.ConclusionsIn conclusion, transthyretin hereditary amyloid polyneuropathy (ATTR-PN) should be considered in cases of otherwise idiopathic polyneuropathy. Sequencing of the four exons of the TTR gene should be considered the key step in diagnosis, while tissue biopsy possibly leads to false negative results.

Highlights

Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, genetically heterogenous, and clinically variable autosomal dominant disease that severely reduces life expectancy
We collected data from a cohort of 102 patients, 65 with a sensorimotor neuropathy, four with a pure motor neuropathy, five with a pure sensory neuropathy, two with bilateral carpal tunnel syndrome (CTS), and 26 with a small fibre neuropathy confirmed by skin biopsy
Two of 102 patients tested positive for amyloidogenic mutations in the TTR gene, thereby confirming diagnosis of Transthyretin hereditary amyloid polyneuropathy (ATTR-PN)

Summary

Introduction

Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, genetically heterogenous, and clinically variable autosomal dominant disease that severely reduces life expectancy. TTR is a homotetrameric plasma protein transporting thyroxine and retinol binding protein-vitamin A complex [1] It is mainly synthesised in the liver and to a far lesser extent in the. Because of the severe natural course of ATTR-PN in endemic regions leading to disability and death within ten years, early diagnosis and treatment initiation are mandatory. This early diagnosis is of great importance in light of recent emerging treatment options apart from liver transplantation, which has been the standard therapeutic strategy since 1990. In 2011, the first transthyretin tetramer stabilising oral agent, Tafamidis, was approved in the European Union [17], while disease-modifying treatment by gene silencing emerged as another promising approach, with patisiran and inotersen being recently approved for ATTRPN treatment [18, 19]

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