Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Sep;30(3):e70043.
doi: 10.1111/jns.70043.

Etiologic Diagnosis of Neuropathies Based on First-Line Screening of TTR Gene Mutations

Armelle Magot  1 , Maud Lepetit  2 , Steeve Genestet  3 , Jean-Baptiste Noury  3 , Yolaine Ollivier  4 , Pascal Lejeune  5 , Lucie Metzger  6 , Stephane Beltran  7 , Julien Cassereau  8 , Morgane Pihan  9 , Ivan Kolev  10 , Benoit Pegat  11 , Karine Boyer  12 , Alexandra Stancu  13 , Clément Baron  13 , Faycal Dahimène  13 , Caroline Perrault  14 , Anne-Sophie Martineau  14 , Morgane Péré  15 , Stéphane Bézieau  16 , Florence Kyndt  17 , Yann Péréon  1
Affiliations
Clinical Trial

Etiologic Diagnosis of Neuropathies Based on First-Line Screening of TTR Gene Mutations

Armelle Magot et al. J Peripher Nerv Syst. 2025 Sep.

Abstract

Background: Hereditary amyloid transthyretin (ATTRv) is caused by TTR gene mutations, which lead to multisystem amyloid deposits. A misdiagnosis is common, which delays treatment. We assessed the prevalence of TTR mutations in patients with neuropathy of unknown cause at the first stage of assessment.

Methods: This prospective study, conducted in western France, assessed patients with neuropathy aged 18-90 years. We excluded individuals with known causes or prior screening of TTR mutations. Genetic analyses of TTR mutations were done using Sanger sequencing. Clinical, biochemical, and electrophysiological data were collected. Statistical analyses estimated the prevalence of TTR amyloidosis in this cohort.

Results: Among 400 patients, four (1%) were identified as having a heterozygous TTR mutation. The mean age of these patients with a TTR mutation was 75 years, with a mean duration of neuropathy of 2.5 years. The initial symptoms varied, with one patient experiencing mixed sensory impairment, another with motor and sensory issues, one with purely motor symptoms, and one with small-fiber sensory impairment. Notably, none had cardiological or renal impairments, and all exhibited sensorimotor neuropathy upon electromyography. Three patients had an axonal profile, and one showed demyelinating neuropathy, which highlighted the diagnostic challenges.

Interpretation: We identified a 1% prevalence of TTR mutations, which is lower than that reported previously, and highlights the influence of selective inclusion criteria on such estimates. Our data emphasize the need for early detection because patients frequently lack red-flag symptoms. Ultimately, early screening allows for prompt management and minimizes long-term complications in individuals with unexplained neuropathy.

Trial registration: ClinicalTrials.Gov Identifier: NCT03190577.

Keywords: ATTRv; diagnostic challenge; prevalence; unknown neuropathy.

PubMed Disclaimer

References

    1. P. Coutinho, A. Martins da Silva, and L. J. Lopas, “Forty Years of Experience With Type 1 Amyloid Neuropathy. Review of 483 Cases,” in Amyloid and Amyloidosis (Excerpta Medica, 1980), 88–98.
    1. H. Koike, F. Tanaka, R. Hashimoto, et al., “Natural History of Transthyretin Val30Met Familial Amyloid Polyneuropathy: Analysis of Late‐Onset Cases From Non‐Endemic Areas,” Journal of Neurology, Neurosurgery, and Psychiatry 83, no. 2 (2012): 152–158, https://doi.org/10.1136/jnnp‐2011‐301299.
    1. M. Inês, T. Coelho, I. Conceição, F. Duarte‐Ramos, M. de Carvalho, and J. Costa, “Epidemiology of Transthyretin Familial Amyloid Polyneuropathy in Portugal: A Nationwide Study,” Neuroepidemiology 51, no. 3–4 (2018): 177–182, https://doi.org/10.1159/000490553.
    1. G. Holmgren, P. M. Costa, C. Andersson, et al., “Geographical Distribution of TTR met30 Carriers in Northern Sweden: Discrepancy Between Carrier Frequency and Prevalence Rate,” Journal of Medical Genetics 31, no. 5 (1994): 351–354, https://doi.org/10.1136/jmg.31.5.351.
    1. F. Gorram, M. Olsson, F. Alarcon, G. Nuel, I. Anan, and V. Planté‐Bordeneuve, “New Data on the Genetic Profile and Penetrance of Hereditary Val30Met Transthyretin Amyloidosis in Sweden,” Amyloid 28, no. 2 (2021): 84–90, https://doi.org/10.1080/13506129.2020.1841623.

MeSH terms

Supplementary concepts

Associated data

Grants and funding