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

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.