Prevalence of hereditary transthyretin amyloidosis in CIDP patients with red flags: a multicenter genetic screening and misdiagnosis analysis
- PMID: 40670759
- DOI: 10.1007/s00415-025-13218-6
Prevalence of hereditary transthyretin amyloidosis in CIDP patients with red flags: a multicenter genetic screening and misdiagnosis analysis
Abstract
Background: Hereditary transthyretin amyloidosis (ATTRv) is a rare, multisystemic disorder often presenting with peripheral neuropathy and can be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), especially in non-endemic areas. While clinical red flags have been proposed to aid diagnosis, their predictive value remains uncertain. This study prospectively assessed the prevalence of TTR variants in CIDP patients with red flags for ATTRv and retrospectively analyzed features of genetically confirmed ATTRv cases initially misdiagnosed as CIDP.
Methods: Thirteen Italian tertiary neuromuscular centers consecutively screened CIDP patients with at least one red flag for TTR gene variants. A retrospective analysis was also conducted on ATTRv patients initially misdiagnosed as CIDP, comparing clinical, electrophysiological, and treatment response features to confirmed CIDP cases.
Results: No TTR variants were identified among 124 screened CIDP patients despite 65% presenting with ≥ 2 red flags and 14% not responding to standard therapies. Among 17 retrospectively identified ATTRv patients, 5 (29%) met electrodiagnostic criteria for CIDP. In nearly half, CIDP was diagnosed without fulfilling electrodiagnostic criteria or obtaining appropriate supportive investigations. Compared to confirmed CIDP patients, ATTRv cases exhibited significantly more red flags, later onset, more insidious and distal presentations, a progressive course, lower rates of demyelination criteria fulfillment, and no response to immunomodulatory therapy.
Conclusions: Red flags alone have limited predictive value in specialized settings. However, ATTRv should be considered in distal, progressive, treatment-resistant neuropathies, especially with multisystem features. Greater diagnostic rigor and increased awareness in non-specialist settings is essential to reduce misdiagnosis and improve access to therapy.
Keywords: ATTR; Amyloidosis; CIDP; Chronic inflammatory demyelinating polyradiculoneuropathy; Diagnosis; Misdiagnosis.
© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.
Conflict of interest statement
Declarations. Conflict of interest: Pietro Emiliano Doneddu reports personal fees for Advisory from ArgenX, and received travel grants to attend scientific meetings from CSL Behring, and Kedrion. Giuseppe Cosentino has received travel grants to attend scientific meetings from CSL Behring, and Kedrion. Massimiliano Filosto has served on scientific advisory boards for CSL Behring, Sanofi, and Amicus, and has received travel grants from Sanofi, Biogen, Kedrion, and CSL Behring to attend scientific meeting. Anna Mazzeo has received travel grants from Kedrion, and CSL Behring to attend scientific meeting. Maurizio Inghilleri has received travel grants to attend scientific meetings from CSL Behring, ArgenX, and Alexion. Federica Moret has received travel grants to attend scientific meetings from CSL Behring, ArgenX, and Alexion. Eduardo Nobile-Orazio reports personal fees for Advisory or Scientific Board from ArgenX – Belgium, Takeda – Italy and USA, CSL-Behring—Italy and USA, Janssen – USA, Kedrion – Italy, LFB – France, Roche– Switzerland, Sanofi—USA. The authors declare that they have no conflict of interest. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of each participating center and was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent: Informed consent was obtained from all individual participants included in the study.
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