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

Abstract

Background: Hereditary 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. Methods: We 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. Results: Two 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 wellknown cases of the same mutation in the literature. Conclusions: In 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.

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features

“…ATTRIle107Val was considered as a mixed-phenotype mutation in a review in 2013 [6], but ATTRHis88Arg was recognized only in 2019 as a pathogenic mutation in ATTRv guidelines [25]. ATTRIle107Val was reported in many countries: for example, in Japan [26,27], France [28][29][30], Brazil [31], and Germany [32], although in a recent review of ATTRv, only 11 individuals were identified with ATTRIle107Val in Western Europe [33]. Data showed that the phenotype associated with ATTRIle107Val ATTRv is mixed: cardiac and neurologic features are both present, although the heart is predominantly involved [6,25].…”