Hereditary transthyretin amyloidosis with polyneuropathy: results of multicenter screening of patients with carpal tunnel syndrome in Russia (LOCUS study)

Introduction. Hereditary transthyretin amyloid polyneuropathy (hATTR-PN) is a disabling, life-threatening systemic autosomal dominant disease associated with a pathogenic variant of the TTR gene and transthyretin protein misfolding.

The aim of the study was to determine the detection rate of hATTR-PN in a cohort of patients with bilateral carpal tunnel syndrome (CTS) in routine clinical practice in Russia and to assess their demographic and clinical characteristics, including genetic testing results.

Materials and methods. As part of the retrospective part of a multicenter observational study, data from adult patients with a confirmed diagnosis of bilateral CTS were analyzed to identify signs suggestive of probable hATTR-PN. If ≥ 1 sign of the disease (red flags) was present based on medical history, a comprehensive assessment of participants’ clinical characteristics, including neurological examination findings, was conducted during the prospective part. Molecular genetic testing via Sanger sequencing of the TTR gene was performed to confirm or exclude the hATTR-PN. The primary endpoint was the proportion of patients with genetically confirmed hATTR-PN diagnosis.

Results. Among 1,378 patients with carpal tunnel syndrome (CTS) included in the retrospective phase, 1,321 (95.9%) exhibited ≥ 1 feature of hATTR-PN. The most common manifestations were paresthesia and burning sensation in distal extremities without specific localization (89.6%), limb muscle hypotrophy/hypotonia and areflexia (16.1%), and left ventricular hypertrophy (15.4%). In the prospective cohort (n = 723; age 58.5 ± 12.0 years; 82.6% women), hATTR-PN diagnosis was confirmed in 1 patient (0.14%) — a 65-year-old woman with TTR p.Val50Met variant. The interval from CTS symptom onset to hATTR-PN diagnosis exceeded 20 months, with 4 red flags present: heart failure with preserved ejection fraction, ophthalmological abnormalities, paresthesias, and autonomic nervous system dysfunction (constipation). The proportion of hATTR-PN patients in the overall bilateral CTS cohort was 0.073%. Five participants carried other TTR variants with varying clinical significance: p.Ala101Val, p.His110Asn (n = 2), p.Arg5His, and c.[-61G>A].

Conclusion. The detection rate of hATTR-PN in Russian patients with bilateral CTS is 0.073%, reaching 0.076% when ≥ 1 disease feature is present. Considering the p.Arg5His variant classified as of uncertain significance but with published evidence of pathogenicity increases the frequency to 0.14% in bilateral CTS patients. Improvement of screening algorithms for selecting candidates for molecular genetic testing is required to verify diagnosis.