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

Natalia A. Suponeva; Супонева Наталья Александровна; Maria S. Kazieva; Казиева Мария Сергеевна; Anton P. Soloviev; Соловьев Антон Павлович; Evgenia A. Zorina; Зорина Евгения Александровна; Shakir Sh. Abdullaev; Абдуллаев Ш. Ш.; Nadezhda V. Amosova; Амосова Н. В.; Elena A. Antipenko; Антипенко Е. А.; Oleg P. Artyukov; Артюков О. П.; Maria B. Arkhincheeva; Архинчеева М. Б.; Alisa I. Afanasyeva; Афанасьева А. И.; Marina Yu. Afanasyeva; Афанасьева М. Ю.; Alsu G. Akhunova; Ахунова А. Г.; Svetlana V. Balakleets; Балаклеец С. В.; Tatyana V. Balueva; Балуева Т. В.; Mariana A. Barabanova; Барабанова М. А.; Angelina I. Bondarenko; Бондаренко А. И.; Inga V. Vaskovskaya; Васьковская И. В.; Vladislav V. Vilov; Вилов В. В.; Tatyana G. Vstavskaya; Вставская Т. Г.; Timur R. Galiullin; Галиуллин Т. Р.; Olga V. Gilvanova; Гильванова О. В.; Alena A. Gindullina; Гиндуллина А. А.; Vitaly V. Goldobin; Голдобин В. В.; Ivan S. Goncharov; Гончаров И. С.; Zoya A. Goncharova; Гончарова З. А.; Valentina V. Gordeeva; Гордеева В. И.; Yulia V. Grigoryeva; Григорьева Ю. В.; Natalya A. Grishina; Гришина Н. А.; V. V. Gusev; Гусев В. В.; Rezeda I. Davletshina; Давлетшина Р. И.; Daniil A. Degterev; Дегтярев Д. А.; Indira I. Dulatova; Дулатова И. И.; Diana G. Erofeeva; Ерофеева Д. Г.; Ksenia A. Eruslanova; Ерусланова К. А.; Dmitriy S. Zharov; Жаров Д. С.; Pavel V. Zhuravlev; Журавлев П. В.; Maria I. Karpova; Карпова М. И.; Alsu R. Kafizova; Кафизова А. И.; Anastasia A. Kovaleva; Ковалева А. А.; Natalya S. Kovaleva; Ковалева Н. С.; Evgenia A. Koltsova; Кольцова Е. А.; Denis N. Kornilov; Корнилов Д. Н.; Ivan V. Korobeinikov; Коробейников И. В.; Daria G. Korotkova; Короткова Д. Г.; Elena E. Kudasheva; Кудашева Е. Е.; Nadezhda I. Kuznetsova; Кузнецова Н. И.; Elena A. Kuzmina; Кузьмина Е. А.; Mansur A. Kutlubaev; Кутлубаев М. А.; Stanislav S. Kucherenko; Кучеренко С. С.; Vitaly V. Lebedev; Лебедев В. В.; Venera V. Mayorova; Майорова В. В.; Elmira M. Maksudova; Максудова Э. М.; Irina P. Malaya; Малая И. П.; Margarita F. Mingalisheva; Мингалишева М. Ф.; Valentina A. Mikhailova; Михайлова В. А.; Evgenia I. Mokeeva; Мокеева Е. И.; Dmitry D. Molokov; Молоков Д. Д.; Alexandra D. Munasipova; Мунасипова А. Д.; Ekaterina S. Novikova; Новикова Е. С.; Irina A. Pakhomova; Пахомова И. А.; Anastasia V. Petrokovskaya; Петроковская А. В.; Sergey Yu. Pushkin; Пушкин С. Ю.; Elena V. Reznik; Резник Е. В.; Ekaterina A. Ruina; Руина Е. А.; Tatyana G. Sakovets; Саковец Т. Г.; Kirill A. Salimov; Салимов К. А.; Inna V. Svetlichnaya; Светличная И. В.; Ekaterina V. Sidorova; Сидорова Е. В.; Aleksey A. Titov; Титов А. А.; Olga N. Tkacheva; Ткачева О. Н.; Valentin L. Filippov; Филиппов В. Л.; Olga E. Furman; Фурман О. Э.; Nina M. Khasanova; Хасанова Н. М.; Tatyana V. Khlevchuk; Хлевчук Т. В.; Anastasia V. Chernobrivtseva; Чернобривцева А. В.; Ekaterina M. Chernykh; Черных Е. М.; Irina G. Chulovskaya; Чуловская И. Г.; Artem V. Shumov; Шумов А. В.

doi:10.17816/ACEN.1433

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

Authors: Suponeva N.A.¹, Kazieva M.S.¹, Soloviev A.P.², Zorina E.A.², Abdullaev S.S.³, Amosova N.V.⁴, Antipenko E.A.⁵, Artyukov O.P.⁶, Arkhincheeva M.B.⁷, Afanasyeva A.I.⁸, Afanasyeva M.Y.⁹^,10, Akhunova A.G.¹¹, Balakleets S.V.¹², Balueva T.V.¹³, Barabanova M.A.¹⁴, Bondarenko A.I.¹⁴, Vaskovskaya I.V.¹⁵, Vilov V.V.³, Vstavskaya T.G.⁹^,10, Galiullin T.R.¹⁶, Gilvanova O.V.¹⁷, Gindullina A.A.¹⁶, Goldobin V.V.¹⁰, Goncharov I.S.¹⁸, Goncharova Z.A.¹⁹, Gordeeva V.V.²⁰, Grigoryeva Y.V.⁷, Grishina N.A.¹⁹, Gusev V.V.¹³, Davletshina R.I.¹¹, Degterev D.A.¹⁷, Dulatova I.I.¹⁵, Erofeeva D.G.⁷, Eruslanova K.A.²¹, Zharov D.S.²¹, Zhuravlev P.V.⁴, Karpova M.I.²⁰, Kafizova A.R.¹², Kovaleva A.A.³, Kovaleva N.S.¹⁹, Koltsova E.A.³, Kornilov D.N.⁷, Korobeinikov I.V.⁷, Korotkova D.G.²⁰^,22, Kudasheva E.E.²³, Kuznetsova N.I.¹², Kuzmina E.A.⁷, Kutlubaev M.A.¹⁶, Kucherenko S.S.⁴, Lebedev V.V.¹⁷, Mayorova V.V.¹³, Maksudova E.M.¹⁵, Malaya I.P.²¹, Mingalisheva M.F.²³, Mikhailova V.A.¹⁷, Mokeeva E.I.⁷, Molokov D.D.⁷, Munasipova A.D.⁹, Novikova E.S.²⁴, Pakhomova I.A.²³, Petrokovskaya A.V.¹⁷, Pushkin S.Y.¹², Reznik E.V.³, Ruina E.A.⁵, Sakovets T.G.²⁵, Salimov K.A.¹⁸, Svetlichnaya I.V.⁴, Sidorova E.V.⁴, Titov A.A.²¹, Tkacheva O.N.²¹, Filippov V.L.²⁵, Furman O.E.²⁴, Khasanova N.M.²⁶, Khlevchuk T.V.¹⁸, Chernobrivtseva A.V.⁷, Chernykh E.M.²⁶, Chulovskaya I.G.²¹, Shumov A.V.⁷
Affiliations:
1. Russian Center for Neurology and Neurosciences
2. AstraZeneca Pharmaceuticals
3. Russian National Research Medical University named after N.I. Pirogov
4. North-Western District Scientific and Clinical Center named after L.G. Sokolov
5. Privolzhsky Research Medical University
6. University Clinical Hospital named after V.V. Vinogradov
7. Irkutsk Order of the Badge of Honour Regional Clinical Hospital
8. Profimed LLC
9. North-Western State Medical University named after I.I. Mechnikov
10. Peter the Great Regional Clinical Hospital of North-Western State Medical University named after I.I. Mechnikov
11. Republican Clinical Hospital, Kazan
12. Regional Clinical Hospital named after V.D. Seredavin
13. Central City Clinical Hospital No. 23, Yekaterinburg
14. Regional Clinical Hospital No. 1 named after Professor S.V. Ochapovsky
15. University Clinical Center named after V.V. Vinogradov, Peoples’ Friendship University of Russia named after Patrice Lumumba
16. Republican Clinical Hospital named after G.G. Kuvatov
17. Moscow Clinical Scientific Center named after A.S. Loginov
18. Сity Hospital named after A.K. Eramishantsev
19. Rostov State Medical University
20. Chelyabinsk Regional Clinical Hospital
21. Russian Gerontological Research and Clinical Center, Russian National Research Medical University named after N.I. Pirogov
22. South-Ural State Medical University
23. Medical Radiological Center Clinic
24. Moscow Regional Research and Clinical Institute named after M.F. Vladimirsky
25. Kazan State Medical University
26. Northern State Medical University
Issue: Vol 19, No 4 (2025)
Pages: 28-38
Section: Original articles
Submitted: 13.10.2025
Accepted: 17.11.2025
Published: 25.12.2025
URL: https://annaly-nevrologii.com/pathID/article/view/1433
DOI: https://doi.org/10.17816/ACEN.1433
EDN: https://elibrary.ru/XJYDMB
ID: 1433

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Abstract

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.

Keywords

transthyretin amyloidosis, amyloid polyneuropathy, carpal tunnel syndrome, screening

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Introduction

Hereditary transthyretin (TTR) amyloid polyneuropathy (hATTR-PN) is a disabling, life-threatening systemic autosomal dominant disease associated with a pathogenic variant in the TTR gene and transthyretin protein misfolding, leading to amyloid formation and deposition in the endoneurium, manifesting as progressive peripheral nerve damage [1–4].

Diagnosis of hATTR-PN may be delayed, particularly in the absence of family history due to variability in symptom presentation and onset timing, which is associated with reduced quality and length of patient survival, and may result in delayed initiation of effective treatment [3, 5–7]. It is estimated that there are approximately 10,000 patients with hATTR-PN worldwide, though epidemiological rates vary significantly not only between endemic and non-endemic regions but also within them [8, 9]. The true prevalence remains unknown due to underdiagnosis of hATTR-PN and variations in diagnostic approaches used [1, 11–15].

Over 200 pathogenic variants of the TTR gene associated with hereditary TTR amyloidosis have been reported [16]. The implementation of TTR gene sequencing and patient selection algorithms for individuals with idiopathic neuropathy at high risk of developing hATTR-PN in clinical practice serves as a valuable tool for confirming or excluding the diagnosis, thereby determining the need for modern disease-modifying therapy [2, 3, 11–15, 17].

Carpal tunnel syndrome (CTS) occurs in 3–6% of the population and may develop in hATTR-PN due to focal amyloid deposition in the wrist area, typically preceding involvement of other organs [13, 15, 18], predominantly in non-endemic regions [19]. This syndrome is included in most published diagnostic algorithms as one of the hallmarks of hATTR-PN [1, 3, 7, 13, 15, 20], particularly in cases of bilateral involvement and/or need for surgical intervention and/or concurrent occurrence in multiple family members [11, 12, 14, 15, 21].

To date, no observational studies have been conducted on the epidemiology of hATTR-PN in either the general Russian population or CTS patients. The aim of this study was to determine the prevalence of hATTR-PN in patients diagnosed with bilateral CTS in routine clinical practice in Russia, and to assess their demographic and clinical characteristics, including genetic testing results.

Materials and methods

A multicenter observational retrospective-prospective study of the prevalence and clinical characteristics of hATTR-PN in Russian patients with bilateral CTS in real clinical practice (LOCUS, ClinicalTrials.gov identifier NCT06414746) was conducted across 21 research centers in different regions of the Russian Federation.

During the retrospective analysis phase, patients diagnosed with bilateral CTS at age ≥18 years between January 01, 2021 and December 31, 2024 were consecutively selected for inclusion, regardless of prior surgical intervention history for this condition. Patients participating in interventional clinical trials after bilateral carpal tunnel involvement detection were excluded.

The retrospective phase involved selecting patients with increased risk of hATTR-PN based on documented disease markers (red flags) present either at diagnosis, during CTS surgery, or at the last comprehensive neurological examination in patients with CTS progression, using data from electronic or paper medical records.

The following clinical features were considered red flags:

Family history of polyneuropathy (PN) of unknown etiology or chronic inflammatory demyelinating PN;
Lumbar spinal stenosis;
Autonomic dysfunction, defined as ≥ 1 of:

- gastrointestinal symptoms (constipation/chronic diarrhea);

- erectile dysfunction;

- orthostatic hypotension;

Gait abnormalities;
Sudomotor disorders/anhidrosis;
Distal limb paresthesia and burning sensations;
Symmetric distal paresis;
Muscle atrophy/hypotonia, areflexia;
Biceps tendon rupture;
Aortic stenosis;
Heart failure with preserved ejection fraction (HFpEF);
Unexplained ≥ 5 kg weight loss post-CTS onset;
Left ventricular hypertrophy (ECG/echo criteria);
Arrhythmias;
Renal impairment determined as ≥ 1 of the following:

- chronic kidney disease diagnosis;

- eGFR < 60 mL/min/1.73 m²;

- elevated serum creatinine;

- albuminuria (≥ 30 mg/g creatinine or ≥ 30 mg/day);

- proteinuria on urinalysis;

Ophthalmologic findings determined as ≥ 1 of the following:

- vitreous opacities;

- glaucoma;

- pupillary dysfunction;

- prior vitrectomy.

Patients presenting with one or more of the aforementioned signs, and without a previously established diagnosis of hATTR-PN, were invited to participate in the second prospective phase of the study after providing written informed consent. Individuals who had previously undergone molecular genetic testing of the TTR gene, as well as those with confirmed vitamin B₁₂ deficiency and/or a history of alcohol abuse, were excluded from the prospective phase.

The prospective phase included documentation of anthropometric data, life history (health habits), hemodynamic parameters, disease history (including details of previous CTS surgeries and hospitalizations for renal failure), results of comprehensive neurological examinations with instrumental methods, laboratory parameters, and comorbidities. Additionally, patients underwent molecular genetic testing involving Sanger sequencing of the TTR gene using dried blood spots, performed at the Medical Genetic Research Center laboratory to confirm or exclude hATTR-PN. The duration of prospective follow-up for each patient depended on the availability of genetic test results and the ability to communicate them to the patient, ranging from 1 week to 3 months.

Statistical analysis and data processing were performed using the R software environment (R Foundation for Statistical Computing, version of February 28, 2025) with epidemiological methods. Qualitative characteristics are presented as absolute frequencies and/or percentages, while continuous (quantitative) parameters are shown as mean ± standard deviation for normally distributed real numbers, or median and interquartile range for data with non-normal distribution. The primary endpoint was the proportion of patients with genetically confirmed hATTR-PN, expressed as percentages with exact 95% confidence intervals (CI) among all patients with CTS, as well as among patients enrolled in the prospective study phase.

Results

Frequency of identifying signs and confirming diagnosis of hATTR-PN

The distribution of patients included in the study is presented in the Figure. Among 1,380 patients with bilateral CTS who underwent screening during retrospective data collection, 2 patients (0.14%) were excluded from further analysis due to protocol deviations; 57 participants (4.13%) showed no signs of hATTR-PN (red flags). The frequency of specific hATTR-PN manifestations in the remaining CST patients (n = 1,321) is presented in Table 1. The most frequently reported findings were paresthesia and burning sensations in distal extremities (89.6%), limb muscle hypotrophy and hypotonia with areflexia (16.1%), left ventricular hypertrophy (15.4%), distal symmetric paresis (13.0%), and gait disturbances (11.0%).

Flow chart of distribution of study participants.

Table 1. Frequency of identifying individual signs of hATTR-PN, n (%)

Red flag	Patients with bilateral CTS and red flags (n = 1321)	Patients followed up prospectively (n = 723)
Family history of polyneuropathy (PN) of unknown etiology or chronic inflammatory demyelinating PN	43 (3.26)	31 (4.29)
Lumbar spinal stenosis	81 (6.13)	50 (6.92)
Autonomic dysfunction	135 (10.20)	122 (16.90)
Gait abnormalities	145 (11.00)	101 (14.00)
Sudomotor disorders/anhidrosis	30 (2.27)	30 (4.15)
Distal limb paresthesia and burning sensations	1184 (89.60)	650 (89.90)
Symmetric distal paresis	172 (13.00)	98 (13.60)
Muscle atrophy/hypotonia, areflexia	212 (16.10)	133 (18.40)
Biceps tendon rupture	3 (0.23)	2 (0.28)
Aortic stenosis	13 (0.98)	8 (1.11)
HFpEF	82 (6.21)	60 (8.30)
Unexplained weight loss ≥ 5 kg	21 (1.59)	21 (2.90)
Left ventricular hypertrophy	203 (15.40)	150 (21.80)
Arrhythmias	111 (8.40)	51 (7.05)
Renal impairment	88 (6.66)	60 (8.30)
Ophthalmological disorders	117 (8.86)	85 (11.80)

The prospective part of the study included 723 patients (54.7%) with red flags of hATTR-PN who provided written informed consent. The proportions of patients with 1, 2, 3, and 4–5 signs of hATTR-PN were 38.8%, 23.2%, 20.8%, and 14.9% respectively, with the detection rate of most individual signs being higher than in all patients selected for the prospective phase (see Table 1). Seventeen patients (2.35%) had more than 5 red flags. Molecular genetic testing results were obtained for 712 participants (98.5%) in the prospective phase. The diagnosis of hATTR-PN was confirmed in 1 patient (0.14%, 95% CI 0–0.77%) included in the prospective part, while 5 other participants (0.69%) were found to have different TTR gene variants with varying clinical significance. The diagnosis of hATTR-PN was excluded in the remaining 706 patients (97.6%). Thus, the proportion of patients with hATTR-PN was 0.8% when calculated for patients with ≥ 4 signs (n = 125), or 0.073% (95% CI 0–0.40%) relative to the entire cohort. When considering the p.Arg5His variant, classified as a variant of uncertain significance but with published data confirming pathogenicity, the frequency becomes 0.14% (95% CI 0.02–0.52%) in the cohort of all patients with bilateral CTS and 0.28% (95% CI 0.03–1.00%) among patients in the prospective part.

Characteristics of patients included in the prospective study phase

Among patients prospectively followed, women predominated (597; 82.6%), with the vast majority being Caucasian (719; 99.5%). The mean age was 58.5 ± 12.0 years, and the mean body mass index (BMI) was 29.7 ± 6.1 kg/m². Unexplained weight loss (≥ 5 kg) during the period since CTS diagnosis was observed in 32 patients (4.43%). The proportion of participants with a family history of PN was 3.6%.

The mean age at onset of CTS symptoms was 55.0 ± 12.2 years, at PN symptom onset - 55.8 ± 14.0 years (n = 670), and at initial CTS diagnosis and detection of bilateral involvement — 57.3 ± 12.0 and 57.5 ± 12.0 years, respectively. A history of surgical intervention for CTS was present in 293 patients (40.5%), with 44 (15.0%) undergoing bilateral hand surgery. Eight participants (2.73%) each exhibited CTS recurrence and PN progression following surgical treatment. By study completion, 87 patients (12.0%) had undergone repeat surgical intervention for CTS.

Comorbidities were observed in 504 patients (69.7%), with the subgroup of participants showing ≥ 2 signs of hTTR-AP (n = 442) having a comorbidity rate of 81.9%. The most frequently identified comorbidities involved the cardiovascular (428; 60.7%) and musculoskeletal (232; 32.1%) systems, as well as metabolic and nutritional disorders (132; 18.3%). Concomitant pharmacotherapy was received by 238 patients (32.9%), including angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (~40%), β-blockers (~22%), diuretics (~18%), and antiplatelet agents (~30%).

Essential hypertension and HFpEF were present in 303 (41.9%) and 57 (7.88%) patients respectively. Among concomitant ophthalmological disorders, glaucoma (31; 4.29%), vitreous body inclusions/opacities (23; 3.18%), and cataract (16; 2.21%) were most frequently reported, while musculoskeletal disorders included osteochondrosis (72; 9.96%), osteoarthritis (68; 9.41%), and spinal canal stenosis (60; 8.30%). Chronic kidney disease was diagnosed in 63 cases (8.71%), though decreased estimated glomerular filtration rate was only observed in 32 patients (4.43%). Specific peripheral neurological manifestations were assessed in 652 patients (90.2%), with paresthesias and dysesthesias (likely associated with CTS) found in 522 participants (80.1%), while neuropathic pain and progressive sensory loss were present in 328 (50.3%) and 284 (43.6%) respectively. Localization of PN or CTS symptoms was documented in 620 participants (85.8%). Four-limb involvement was recorded in 275 patients (44.4%). Among remaining patients, 267 participants (43.1%) showed bilateral upper limb involvement without lower extremity involvement.

Autonomic neurological disorders were assessed in 648 (89.6%) patients and were identified in 128 (19.8%) participants, with the most common being constipation (69; 10.6%), diarrhea (26; 4.01%), and orthostatic hypotension (23; 3.55%).

Nerve conduction study (NCS) was performed in 377 (52.1%) patients. Due to the observational nature of the study, the scope and parameters of NCS assessment were not standardized and were determined by the investigators. The evaluation of measurement deviations obtained during NCS from normal values was conducted at the research center level as part of routine clinical practice using local reference ranges. For data collection purposes in this study, only the results of such evaluation based on primary documentation were considered. Table 2 presents the results of this study: 312 (82.8%) and 181 (48.0%) patients were characterized by reduced conduction velocity in ≥ 1 peripheral sensory and motor nerve sites, respectively. The amplitude of the sensory action potential was decreased or absent in at least one investigated site in 240 (63.7%) patients, and that of the distal M-response in 135 (36.8%).

Table 2. NCS parameter values of participants in the prospective phase (n = 723)

Parameter	Nerve	Values (M ± SD)	Missing data, n (%)
Conduction velocity in sensory fibers of peripheral nerves, m/sec	Left median	37.32 ± 10.10	459 (63.5)
	Right median	37.69 ± 10.72	470 (65.0)
	Left ulnar	55.44 ± 7.30	459 (63.5)
	Right ulnar	55.72 ± 8.40	453 (62.7)
	Left sural	44.11 ± 10.22	596 (82.4)
	Right sural	44.19 ± 11.19	595 (82.3)
Conduction velocity in motor fibers of peripheral nerves, m/sec	Left median	52.23 ± 8.92	442 (61.1)
	Right median	51.76 ± 9.77	443 (61.3)
	Left ulnar	59.27 ± 9.37	458 (63.3)
	Right ulnar	59.72 ± 9.00	455 (62.9)
	Left tibial	46.06 ± 6.66	589 (81.5)
	Right tibial	46.49 ± 6.61	588 (81.3)
	Left peroneal	45.82 ± 6.98	589 (81.5)
	Right peroneal	45.40 ± 7.40	587 (81.2)
Sensory action potential amplitude, μV	Left median	6.82 ± 6.25	478 (66.1)
	Right median	6.92 ± 6.12	492 (68.0)
	Left ulnar	11.50 ± 8.81	472 (65.3)
	Right ulnar	11.73 ± 8.53	468 (64.7)
	Left sural	5.77 ± 3.89	598 (82.7)
	Right sural	6.26 ± 3.99	597 (82.6)
Distal motor response amplitude, mV	Left median	5.89 ± 2.56	496 (68.6)
	Right median	5.87 ± 2.40	496 (68.6)
	Left ulnar	6.58 ± 2.01	505 (69.8)
	Right ulnar	6.91 ± 2.19	502 (69.4)
	Left tibial	6.10 ± 3.25	596 (82.4)
	Right tibial	6.09 ± 3.54	596 (82.4)
	Left peroneal	3.24 ± 2.21	595 (82.3)
	Right peroneal	3.03 ± 1.89	595 (82.3)
Proximal motor response amplitude, mV	Left median	5.22 ± 2.55	505 (69.8)
	Right median	5.08 ± 2.32	504 (69.7)
	Left ulnar	6.07 ± 1.97	511 (70.7)
	Right ulnar	6.86 ± 4.06	508 (70.3)
	Left tibial	5.33 ± 3.14	600 (83.0)
	Right tibial	5.30 ± 3.19	600 (83.0)
	Left peroneal	2.83 ± 2.08	600 (83.0)
	Right peroneal	2.74 ± 2.03	599 (82.8)

¹Clinical practice guidelines project “Transthyretin familial amyloid polyneuropathy. Amyloid polyneuropathy (Portuguese type)”. 2022. URL: https://neuromuscular.ru/wp-content/uploads/2023/01/KR-amiloidoz-2022.pdf (accessed on: 08.10.2025).

Assessment of pain sensitivity was performed in 620 participants (85.8%) during the prospective phase. Decreased or absent pain sensitivity limited to both feet was observed in 183 patients (29.5%). Impaired pain sensitivity in the fingers of both hands was recorded in 484 patients (78.1%), while impairment in all four limbs was found in 142 participants (22.9%). Mild (2 points), moderate (3 points), and severe (4 points) disability according to the modified Rankin Scale criteria were present in 85 (11.8%), 15 (2.07%), and 1 (0.14%) participants, respectively.

Clinical characteristics of a female patient with confirmed hATTR-PN

A 65-year-old woman (Russian, BMI = 27.3 kg/m²) with overweight, who previously underwent surgical intervention for CTS in the right hand without subsequent procedures or symptom progression, was found to have a pathogenic variant of the p.Val50Met mutation in the TTR gene. Clinical examination revealed reduced pain sensitivity in the fingers of both hands. Four red flags were present: HFpEF, ophthalmological disorders (bilateral glaucoma, cataracts, and vitreous opacities), paresthesia and burning sensation in the distal extremities, and autonomic nervous system dysfunction (constipation). Additionally, during the prospective visit, the patient exhibited progressive sensory disturbances in the extremities. NCS showed reduced sensory impulse velocity in the left and right median nerves (30 m/s and 34 m/s, respectively), confirming bilateral CTS diagnosis. Medical documentation indicated PN, though sensory potentials in the lower limbs were not investigated. The patient scored 1 point on the Rankin scale (no significant disability). Stage 0 was established on the PND scale, with 1 point on the INCAT scale for upper limbs and 0 points for lower limbs. Subsequent scintigraphy confirmed TTR amyloid deposition in the myocardium. The time from initial CTS symptom onset to hATTR-PN diagnosis exceeded 20 months.

Description of patients with TTR gene variants not definitively pathogenic

Patient 1. A 66-year-old male (Russian, normal body weight, BMI = 25.0 kg/m²), who previously underwent two surgical interventions for CTS (first on the right hand, then on the left) without symptom recurrence, was found to have the TTR p.Ala101Val gene variant. Two red flags were present: HFpEF and cardiac arrhythmia (permanent atrial fibrillation with tachyarrhythmia). The patient also had chronic gastritis, cholecystitis, pancreatitis, and diverticular disease of the large intestine. Clinical examination revealed bilateral reduction of Achilles reflexes and impaired proprioception in the toes of the right foot. The patient scored 1 point on the Rankin scale (no significant disability). NCS of the lower extremities was not performed. Thus, no evidence of PN was found in the available data.

Patient 2. A 60-year-old woman (Tatar, with grade 2 obesity — BMI = 39.0 kg/m²) was found to have the TTR p.His110Asn gene variant. There was 1 red flag: paresthesia and burning sensation of the skin in the distal extremities. Clinical examination revealed decreased pain sensitivity and proprioception in the fingers of both hands, manifesting as bilateral CTS. The patient scored 1 point on the Rankin scale (no significant disability). NCS of the lower extremities was not performed. Thus, no evidence of PN was found in the available data.

Patient 3. A 61-year-old woman (Azerbaijani, with grade 2 obesity — BMI = 36.1 kg/m²) with previously diagnosed type 2 diabetes mellitus and diabetic PN was found to have the TTR p.His110Asn gene variant. The patient had 5 red flags: HFpEF, glaucoma, stage C3b chronic kidney disease, distal extremity paresthesias, and autonomic nervous system dysfunction (orthostatic hypotension, constipation). Additionally, comorbidities included osteoarthritis and cataracts; neuropathic pain was noted. Clinical examination showed decreased Achilles, knee, elbow, biceps, and brachioradialis reflexes bilaterally. Clinically evident PN symptoms of undetermined etiology (most likely diabetic PN) were observed. The patient scored 1 point on the Rankin scale (no significant disability). The patient died during the study for unknown reasons.

Patient 4. A 62-year-old woman (Russian, overweight — BMI = 26.1 kg/m²) was found to have the TTR Arg5His gene variant. There was 1 red flag: paresthesias without specified localization. Neuropathic pain was noted. Medical history included essential hypertension and type 2 diabetes mellitus. NCS showed sensory impulse conduction velocities of 30 m/s in the left median nerve and 34 m/s in the right median nerve. Exact sensory action potential values were not documented in the patient’s registration record. Additional findings included reduced motor fiber conduction velocity (45.3 m/s) in the right median nerve at the forearm level. Thus, NCS confirmed bilateral CTS.

Sensory impulse conduction velocities in the left and right ulnar nerves were reduced to 46.8 m/s and 48.7 m/s, respectively. Sensory action potential amplitudes measured 5.4 μV (reduced) in the left ulnar nerve and 5.0 μV (below normal) in the right ulnar nerve. Motor impulse conduction velocities remained within normal limits: left median nerve (56.7 m/sec), left ulnar nerve (58.1 m/sec), right ulnar nerve (51.1 m/sec), left tibial nerve (41.5 m/sec), right tibial nerve (44.0 m/sec), left peroneal nerve (40.1 m/s), and right tibial nerve (41.7 m/sec). Lower extremity sensory potentials were not recorded.

Clinical examination revealed diminished Achilles reflexes, impaired toe proprioception, and reduced pain sensitivity with impaired finger proprioception bilaterally. Therefore, the patient demonstrated clinical signs but lacked sufficient neurophysiological evidence for PN. Upper limb assessment using the INCAT scale yielded 1 point; lower limbs were not evaluated.

Patient 5. A 38-year-old male (Russian, with grade 1 obesity — BMI = 30.1 kg/m²) was identified with the TTR gene variant c.[-61G>A]. One red flag was present: paresthesias without specified localization. Essential arterial hypertension was also documented. NCS revealed decreased sensory impulse conduction velocities in the left and right median nerves (46.7 m/sec and 45.3 m/sec respectively), with reduced sensory action potential (SAP) amplitudes of 5.7 μV and 9.6 μV for the left and right median nerves correspondingly. Motor conduction velocities in the left median nerve (54.5 m/sec) and right median nerve (58.4 m/sec) remained within normal ranges; M-wave amplitudes of the median nerves were not recorded. These electrophysiological findings confirmed bilateral carpal tunnel syndrome.

Sensory conduction velocities in the left and right ulnar nerves were preserved at 57.5 m/s and 52.9 m/sec respectively. SAP amplitudes in the left ulnar nerve (68.2 m/sec) and right ulnar nerve (62.5 m/sec) were within normal limits. Sensory impulse conduction velocities in the left ulnar nerve (68.2 m/sec) and right ulnar nerve (62.5 m/sec) were within normal limits. NCS results confirmed PN. Upper limb assessment using the INCAT scale yielded 1 point; lower limbs were not evaluated.

Discussion

Our findings indicate a low frequency of hATTR-PN in the cohort of patients with bilateral CTS in Russia — the proportion of patients with confirmed diagnosis was 0.073% among all participants and 0.076% in patients presenting with ≥ 1 disease sign. This low prevalence pattern is characteristic of non-endemic regions where, as in our study, most cases lack family history [22–24]. This highlights both the importance and complexity of early diagnosis, as exemplified by a female hATTR-PN patient identified in our study who received confirmation more than 1.5 years after initial neurological symptom onset.

Patients with hATTR-PN are frequently misdiagnosed with idiopathic CTS at initial presentation. In many cases, only neurological symptom progression or lack of postoperative improvement following carpal tunnel release surgery prompts diagnostic reevaluation [12, 25]. A retrospective observational study of 76 Italian patients with TTR gene variants demonstrated CTS as the first manifestation in 33% of cases, preceding other clinical signs by an average of 4.6–5.6 years [26].

According to the literature, the CTS prevalence in patients with TTR amyloidosis, including hereditary TTR amyloidosis and wild-type TTR amyloidosis, ranges from 0.5% to 80% [27], while the prevalence of TTR amyloidosis in patients with CTS and/or a history of median nerve decompression surgery in the carpal tunnel ranges from 0.9% to 38% [27–29]. However, published prevalence rates cannot be directly compared due to heterogeneity in study methodologies and diagnostic approaches used.

Notably, the prevalence of CTS among patients with hATTR-PN in the PRIMER study was also significantly lower than in foreign sources, amounting to 19%. Thus, the results of this study regarding the association between CTS and ATTR-PN are consistent with the findings of the PRIMER study. The issue of the low predictive value for CTS in screening for hATTR-PN in the Russian population requires further investigation [30].

In a German retrospective study, TTR amyloidosis was detected in 1.4% of 699 patients who underwent CTS surgery, using histological examination as the diagnostic method [31]. Our study did not include patients with unilateral CTS, which might have led to some overestimation of hATTR-PN prevalence. Conversely, the proportion of patients with this diagnosis could have been higher if surgical treatment of CTS had been used as an inclusion criterion, particularly when only including patients with persistent median nerve symptoms postoperatively [1, 25].

The diagnostic approach used in this study to identify patients with CTS requiring confirmation or exclusion of hATTR-PN is not the only valid one. Most expert groups agree on the necessity of considering red flags before performing specific diagnostic tests. However, specific recommendations regarding the list and number of signs sufficient to establish a high suspicion of hATTR-PN vary across different sources [1, 3, 11–14, 21, 32].

In the only female patient in our study with confirmed hATTR-PN, the pathogenic Val50Met gene variant was identified, which is the most common genetic variant associated with hereditary TTR amyloidosis both in endemic regions and beyond. As in our patient, this variant is predominantly associated with manifestations from the peripheral nervous system, as well as the cardiovascular system and visual organs [3, 15, 33]. The medical documentation indicated PN, with complaints including paresthesia and burning sensations in the distal extremities. However, a complete examination required to confirm PN had not been performed at that time. This clinical case also presented with amyloidosis-related symptoms affecting the visual organs and gastrointestinal tract motility. Based on the available data, the patient has symptomatic PN caused by hereditary TTR amyloidosis, necessitating the initiation of pathogenetic therapy for her underlying disease.

In the presence of a pathogenic variant such as Val50Met, histological examination is not mandatory¹; however, its absence prevented confirmation of amyloidosis etiological role in the CTS and PN in 5 patients with other TTR gene variants that are not definitively pathogenic [3]. The c.[-61G>A] variant (patient 5) was classified as a variant of uncertain clinical significance (VUS), which precludes definitive attribution of amyloidosis as the cause of neurological manifestations in the upper extremities of a young male in our study [33] and indicates the necessity of biopsy of affected tissues. The p.Ala101Val variant (patient 1) demonstrates conflicting pathogenicity interpretations: various sources have classified it as pathogenic, likely pathogenic, or VUS. Given the cardiac manifestations present, myocardial scintigraphy may be indicated for such patients to identify cardiac involvement and verify the diagnosis [3, 33].

The p.His110Asn variant, identified in two female patients, was more frequently considered benign [33]. Thus, the younger patient likely had isolated CTS, while in the deceased participant with multiple comorbidities, PN was a consequence of severe diabetes. Finally, the Arg5His variant (patient 4) has been previously described in detail as clinically significant with confirmed amyloid deposition [34]. In the literature, it has also been mentioned as a VUS or likely benign [33]. Despite existing data on the pathogenicity of this variant, for differential diagnosis with diabetic PN, particularly in cases of progressing neurological symptoms or involvement of other organ systems, morphological diagnosis of amyloidosis should also be considered.

The low detection rate of hATTR-PN in our study might be influenced by the absence of progressive sensorimotor axonal PN or chronic inflammatory demyelinating PN as mandatory inclusion criteria [1, 3, 11]. The consideration of numerous red flags helped minimize the likelihood of hATTR-PN underdiagnosis and enabled genetic testing for all eligible patients. However, the low proportion of hATTR-PN patients among participants with ≥ 1 red flag indicates their limited specificity, which represents one of the recognized challenges in diagnosing this condition. Notably, had the inclusion criterion required > 2 red flags, 4 out of 6 identified variants would not have qualified for the prospective phase and could not have been detected within this study framework.

Other study limitations include missing data (e.g., NCS findings) for a substantial proportion of patients, and potential inaccuracies inherent to non-interventional study designs. Furthermore, the study design excluded patients with previously diagnosed hATTR-PN, which might have led to underestimation of disease prevalence. Since molecular genetic testing served as the primary diagnostic method, wild-type TTR amyloidosis cases [31, 35] were not accounted for, though identifying such cases was not among this study aims.

Nevertheless, the study nationwide scale involving clinical centers across Russia enabled precise estimation of hATTR-PN prevalence among patients with bilateral CTS in the Russian Federation. The obtained epidemiological and clinical data can facilitate further refinement of diagnostic algorithms to optimize healthcare resource allocation, enable timely disease detection, and permit early initiation of disease-modifying therapy that may improve prognosis in hATTR-PN patients.

Conclusion

The prevalence of hTTR-PN in the cohort of Russian patients with bilateral CTS is 0.073%, increasing to 0.076% when ≥ 1 red flag indicating possible hTTR-PN is present. The high prevalence and/or overdiagnosis of several conditions classified as red flags makes it insufficiently reliable to identify patients with the highest suspicion of hTTR-PN. The applicability of CTS as one of the key red flags for detecting patients at increased risk of hTTR-PN in Russia also remains open. There is a need to improve algorithms and develop alternative screening approaches for selecting candidates for molecular genetic testing to verify the diagnosis.

Additional materials for the article:

Appendix 1. List of LOCUS investigators

Appendix 2. Information about the LOCUS investigators

About the authors

Natalia A. Suponeva

Russian Center for Neurology and Neurosciences

Email: suponeva@neurology.ru
ORCID iD: 0000-0003-3956-6362
SPIN-code: 3223-6006
https://www.neurology.ru/expert/suponeva-natalya-aleksandrovna

Dr. Sci. (Med.), Corr. Member of RAS, Director, Institute of Neurorehabilitation and Recovery Technologies

Russian Federation, Moscow

Maria S. Kazieva

Russian Center for Neurology and Neurosciences

Email: suponeva@neurology.ru
ORCID iD: 0009-0007-5683-0934

neurologist

Russian Federation, Moscow

Anton P. Soloviev

AstraZeneca Pharmaceuticals

Email: suponeva@neurology.ru
ORCID iD: 0009-0001-3407-7220

medical advisor

Russian Federation, Moscow

Evgenia A. Zorina

AstraZeneca Pharmaceuticals

Email: suponeva@neurology.ru
ORCID iD: 0009-0004-9283-5714

Head, Therapeutic direction

Russian Federation, Moscow

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