Background Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers.
Methods We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy.
Results We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%).
Conclusions Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.
Data availability statement
Data are available upon reasonable request. Data are available upon request.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant disease (ATTRv). The available disease-modifying ATTRv treatments are more effective if initiated early.
WHAT THIS STUDY ADDS
Amyloidosis was detected in 16.9% of mutation carriers with normal nerve conduction studies.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of disease-modifying ATTRv treatments.
Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease due to pathogenic TTR gene variants that mostly affects the peripheral nerves and heart.1 The most frequent mutation, Val30Met, provokes two main neurological phenotypes: an early-onset (before 50 years of age) length-dependent neuropathy beginning with small-fibre involvement and including cardiac dysautonomia, “EOVal30Met”,2 and a late-onset form, “LOVal30Met”, in which large-fibre sensorimotor neuropathy and cardiomyopathy predominate but dysautonomia is less common.3 4 Penetrance is high, reaching 80% at 50 years for EOVal30Met or at 80 years for LOVal30Met and other variants,5 except in Sweden.6
Patient prognosis and management have been transformed by the emergence of five disease-modifying treatments (DMTs) that slow or stop disease progression in most patients. These five DMTs are liver transplantation and four molecules with marketing authorisation: the TTR stabiliser tafamidis,7 and three TTR gene silencers—the antisense oligonucleotide inotersen8 and two interfering RNAs, patisiran9 and vutrisiran.10 Earlier treatment administration is associated with greater efficacy against progression of the neuropathy11–13 for reducing mortality14 15 and against cardiomyopathy for tafamidis.16
Genetic counselling is available, with the screening of TTR gene mutation carriers at baseline and periodic monitoring with several tests and investigations to ensure the earliest possible detection of disease onset.17 Carriers are currently considered to become ‘patients’ when they display clinical symptoms associated with markers of denervation and amyloid deposition,18 but this transition can be gradual and insidious, and the point at which the disease really begins may be unclear. Many techniques have been proposed for detecting early damage to peripheral nerves, including skin nerve pathology analyses,19 assessments of sudomotor function with Sudoscan20 and evaluations of heart rate variability (HRV), because changes in nerve conduction studies (NCS) results reflecting large-fibre axonal neuropathy occur quite late in ATTRv carriers.
The objective of this study was to develop a multimodal approach based on neurological and cardiac investigations, including the study of sensory and autonomic small fibres, cardiac biomarkers and searches for amyloid deposits in a cohort of ATTRv carriers with normal NCS results, to facilitate early diagnosis and the early initiation of DMT.
We conducted a retrospective single-centre study on clinical and paraclinical data for TTR gene mutation carriers after their genetic diagnosis through family screening and genetic counselling following the identification of a proband between 1 March 2015 and 31 January 2019 at the Bicetre National Reference Centre for Rare Peripheral Neuropathies and Familial Amyloid Neuropathy.
Carriers were included in this study if they fulfilled all the following criteria:
Proven pathogenic TTR gene mutation associated with ATTRv.
Normal NCS results according to the norms for our laboratory: sural and superficial fibular sensory nerve amplitudes >10 µV (antidromic) and radial nerve amplitude >15 µV (antidromic); common fibular motor nerve amplitude >3 mV and tibial, median and ulnar motor nerve amplitudes >6 mV. Carpal tunnel syndrome (CTS) and ulnar elbow compression were noted, when present, but were not exclusion criteria.
Subjects were excluded if:
They had another confounding cause of neuropathy.
They were already on anti-amyloid treatment.
We collected data for sex, age, the presence or absence of CTS and history of pacemaker implantation. The difference between the age of the proband in the family at symptom onset and the age of the subject was calculated (subject age – proband age). The ‘at-risk decade’ was defined as the 10 years preceding the age at which symptoms began in the proband. For the Val30Met mutation, the age of the proband at symptom onset was used to define early (<50 years old) and late (>50 years old) onset.
Clinical manifestations and standard explorations
All carriers underwent a standardised examination by a neurologist from our neuromuscular reference centre. A Lauria score21≥2 was considered abnormal (0–1: normal to 15: maximal impairment), reflecting symptoms of sensory or autonomic dysfunction. This score was preferred to the Small Fibre Neuropathy - Symptom Inventory Questionnaire22 (online supplemental data 1). A physical examination was performed to check for distal thermal or pain hypoesthesia of the lower limbs, Achilles areflexia and symptomatic orthostatic hypotension. The neurological physical examination was considered pathological if the findings for at least one of these four items were abnormal.
NCS were performed on a Keypoint G4 workstation (Natus). CTS was defined as a median motor distal latency >3.7 ms or median sensitive conduction velocity <40 m/s at the palm, and ulnar elbow compression by a slow-down velocity or a conduction block at the elbow. All raw results for NCS were reviewed to confirm inclusion of the patient.
Clinical signs and symptoms of heart failure were recorded and the New York Heart Association (NYHA) stage was determined. A surface ECG was performed to search for low-voltage, arrhythmia or conduction abnormalities. Biological test results were collected, including determinations of BNP (brain natriuretic peptide), NT-pro BNP and ultrasensitive troponin.
Small nerve fibre involvement
Punch biopsies were performed on the skin at the ankle, thigh and wrist, to assess both denervation with intra-epidermal small-fibre loss and infiltration with amyloid deposits, as described by Leonardi et al.23 Intra-epidermal nerve fibre density (IENFD, fibres/mm), evaluated on a skin biopsy specimen with double immunofluorescence labelling for PGP9.5 and col4, was adjusted for age and sex as described by Provitera et al.24
Impeto Medical’s EZSCAN machine was used to provide an accurate sweat assessment reflecting the function of small sweat gland fibres. We considered the fifth percentile in healthy subjects (56 μS for the hands, 70 μS for the feet25) to define the lower limit of the normal range for conductance measurements.
HRV, which reflects autonomous nervous system function, was studied on the Keypoint G4 workstation. The SD of the R-R interval and the root mean square of the SD of successive R-R intervals were assessed over a period of 60 s (six cycles) of deep breathing (DB-SDRR and DB-RMSSD). The Valsalva ratio was calculated during a 15-s Valsalva manoeuvre. The norms for our laboratory, established on the basis of data from 40 healthy subjects, were as follows: for individuals under the age of 40 years, DB-SDRR<0.05, DB-RMSSD<0.04 and Valsalva ratio<1.5; for individuals over the age of 40 years, DB-SDRR<0.03, DB-RMSSD<0.02, Valsalva ratio<1.4.
The SD of the N-N intervals (SDNN) was calculated on a 24-hour Holter ECG recording. We considered SDNN values >100 ms to be normal.26
The atropine test was used to evaluate parasympathetic cardiac tone according to a modified version of the protocol of Sutton et al.27 The variation of heart rate was monitored over a period of 15 min following the direct intravenous infusion of 0.04 mg/kg (maximum dose: 2 mg) atropine. An increase of 42±12 bpm from baseline HR to maximum HR was expected, and a change of less than 20 bpm was considered a sign of cardiac parasympathetic denervation.14
Sympathetic cardiac innervation was examined by the scintigraphy-based measurement of heart-to-mediastinum uptake ratio (H/M ratio) 4 hours after the injection of 3 MBq/kg f 123-I-MIBG, as described by Piekarski et al.28 A ratio <1.85 was considered suggestive of cardiac sympathetic denervation.14
The presence of intracutaneous amyloid deposition (ICAD) was evaluated by Congo red of skin punch biopsy specimens from the ankle, thigh, and wrist.23
Technetium-99m hydroxydiphosphonate bone scintigraphy
Static planar whole-body images were taken 2 hours after the injection of the radiotracer. Myocardial uptake was assessed visually according to the Perugini classification.29 Pathological cardiac DPD uptake was defined here as a Perugini score ≥1. This score has been shown to be correlated with histologically proven deposition.30
Evaluation of cardiac morphology
The following variables were studied on echocardiography: interventricular septum thickness (IVS), with an IVS ≥12 mm considered abnormal,31 percentage of the normal longitudinal strain, with a value < −18% considered abnormal,32 mitral E/e’ ratio evaluating left ventricular filling pressure, with a ratio >13 considered abnormal.28 Cardiac MRI (GE 450W) was used to detect morphological abnormalities, with late gadolinium contrast enhancement used as a means of detecting amyloid deposits indirectly.33
Not all tests were performed in all carriers (routine care).
Quantitative variables are described in terms of their position parameters (mean and median) and dispersion (SD and range), and qualitative variables are described in terms of frequency (percentage). X2 tests were used for comparisons of categorical variables (Fisher’s test if cell size <5) and Mann-Whitney tests were used for comparisons of quantitative variables (Kruskal-Wallis’s test if >2 groups). A p value <0.05 was considered statistically significant. Spearman’s correlation analyses were performed. The rho coefficient obtained indicated the direction (positive or negative) and strength (<0.3: weak, 0.3–0.5: moderate, >0.5: strong) of the association. Data were collected with Excel software (V.14.4.8) and statistical analyses were performed with JASP (V.0.16.2).
Demographic data and medical history
We analysed 130 mutation carriers (40.8% men, mean age 43.6±13.5 years) (table 1). At first evaluation, mean subject age-proband age was −12.8 years (±14.7; range −51 to +19) and 103/130 (79%) carriers were younger than the proband. There were 18 pathogenic variants of the TTR gene, with Val30Met accounting for 65% of the variants detected (2/3 LOVal30Met and 1/3 EOVal30Met). Thirty-two carriers (24.6%) had CTS, either noted in their medical history or detected on NCS.
One-third of the carriers had subjective neurological complaints (28.5% had a Lauria score ≥2), one-third had at least one abnormality on clinical examination (33.1%) (table 2) and 17 (13.1%) had both a clinical complaint and an abnormality on clinical examination.
Amyloid deposition: ICAD and cardiac DPD uptake
In total, 121 carriers underwent skin biopsy or bone scintigraphy, with 89 (74%) undergoing both investigations. ICAD was detected at one or more of the sites tested (ankle, thigh, wrist) in 11 of 115 carriers (9.6%), cardiac DPD uptake was observed on bone scintigraphy in 15 of 95 carriers (15.8%) (table 2). ICAD and/or cardiac DPD uptake was present in 22/130 carriers (16.9%). Eighteen of the 89 carriers undergoing both investigations (20%) had one of these abnormalities and 4 carriers had both abnormalities (4.5%) (table 3, details in online supplemental material 2). Two carriers had ICAD at the wrist only. One of these carriers displayed cardiac DPD uptake (Ser77Phe), whereas bone scintigraphy results were normal in the other carrier (Ala36Pro), who had no clinical symptoms. Fifteen carriers with amyloid infiltration (83.3%) had reached or passed their at-risk decade (data missing for four carriers).
ICAD was more frequent in the EOVal30Met group than in the LOVal30Met group or in carriers of other mutations (20.8% vs 6.6%, respectively; p=0.035) (table 4). In the EOVal30Met group, lower IENFD values at the ankle were associated with higher frequency of ICAD (2.6 /mm vs 8.4 /mm, p<0.05) (figure 1). In the LOVal30Met group, carriers with cardiac DPD uptake on bone scintigraphy had lower levels of sympathetic innervation, as shown by meta-iodo-benzyl-guanidine (mIBG) scintigraphy (1.9 vs 2.1, p<0.01).
Rate of skin denervation
In total, 115 carriers underwent skin biopsy. Sensory denervation was detected at the ankle in 102 (88.7%), with a median IENFD of 6.6 fibres/mm at the ankle, 9.2 /mm at the wrist and 10.0 /mm at the thigh, corresponding to a ‘length-dependent’ histological profile (table 2). The results for the three sampling sites were correlated (online supplemental material 3), but we found no significant association between intra-epidermal denervation and the presence of clinical symptoms (p=0.794).
Autonomic small-fibre involvement
Sudoscan revealed sudomotor denervation in the feet in 36.2% of carriers, with a correlation between the results for the feet and hands (online supplemental material 3).
Cardiac denervation was documented by measurements of 24-hour HRV in 21/68 carriers (30.9%) and by determination of the Valsalva ratio for short-term HRV in 26/113 (23.0%). The three short-term HRV variables (DB-RMSSD, DB-SDRR and Valsalva ratio) were significantly correlated (online supplemental material 2), as were 24-hour HRV and short-term HRV.
mIBG scintigraphy detected sympathetic cardiac denervation in 15 of 97 cases (15.5%) and atropine test results were abnormal in 3 of 71 tests (4.2%). The results of these two examinations were correlated (online supplemental material 3).
Cardiac morphological abnormalities
On echocardiography, only 8 of 108 (7.4%) carriers had an IVS≥12 mm, and 16 of 83 (19.3%) presented alterations to strain. Only one carrier (1.1%) had a high ventricular filling pressure. Twelve carriers (13.2%) displayed late gadolinium enhancement on cardiac MRI.
Classification of the carriers: overt ATTRv amyloidosis, weak signals with or without amyloidosis
Based on these results for 130 ATTRv carriers, we identified four groups of carriers with normal NCS results (table 3):
Nine carriers (6.9%) had overt amyloidosis: five with ATTRv small-fibre neuropathy (SFN) (Lauria≥2, low IENFD and amyloid deposition according to ICAD or cardiac DPD uptake results), and four with ATTRv cardiomyopathy (NYHA≥2 and cardiac DPD uptake). All but two of these carriers were treated after this first evaluation, the exceptions having Perugini score of 1 and disease that has not progressed during follow-up.
Thirteen carriers (10.0%) had asymptomatic ATTRv: they had no symptoms (Lauria<2, NYHA<2) but had amyloid deposits on ICAD and/or cardiac DPD evaluations and a low IENFD (11/13, 84.6%) or autonomic dysfunction (pathological HRV, Sudoscan and/or mIBG). Twelve (92.3%) were treated either immediately after this first evaluation (n=3), or during follow-up (n=9) due to the onset of symptoms occurring in a delay ranging from 1 and 5 years after the discovery of the deposit. One carrier is being followed at another centre.
In 105 carriers (80.8%), isolated abnormalities of unknown significance were observed, including a Lauria score≥2, low IENFD and short-term HRV abnormalities.
Only three carriers had no neurological or cardiac abnormality (2.3%).
We performed a comprehensive analysis of our series of 130 carriers of TTR gene mutations with normal nerve conduction studies, including multiple neurological and cardiac investigations and, for the first time, the detection of amyloidosis by combined punch biopsies of the skin and bone scintigraphy. Amyloidosis was detected in 16.9% of cases. We found signs of diffuse denervation with a low intra-epidermal nerve fibre density in 88.7% of cases, but also sudomotor or cardiovascular autonomic denervation at a lower frequency. One third of carriers had neurological complaints suggestive of SFN (Lauria≥2). We classified our carriers into four categories depending on the severity of the impairment: 9 carriers (6.9%) with overt ‘symptomatic’ amyloidosis (5 with SFN and 4 with cardiomyopathies); 13 asymptomatic carriers (10.0%) with amyloidosis associated with various abnormalities, including low IENFD and/or autonomic dysfunction; 105 carriers with isolated abnormalities of unknown significance (80.8%) without amyloid deposition; and 3 carriers (2.3%) without abnormalities. The systematic evaluation of these carriers led to the initiation of DMT in 19 of 22 carriers with amyloid deposits (86.4%).
High frequency of amyloid deposits
We used a comprehensive series of investigations, extending beyond clinical evaluation and NCS, to search actively for disease onset in both the peripheral nervous system and the heart, to justify the early initiation of treatment. Amyloidosis was detected in 22/130 carriers (16.9%) on the basis of ICAD and/or cardiac DPD uptake. The frequency of ICAD was 9.6%, consistent with the findings of two studies on about 10 asymptomatic carriers,34 but well below the incidence of 69% reported for 16 ATTR Val30Met carriers.35 Skin biopsy is the preferred technique for the detection of amyloid deposition, because it also allows evaluations of skin denervation, is easily repeatable and well tolerated, unlike biopsy of the labial salivary glands.23 We recommend at least lateral distal leg and distal thigh for detection of amyloid deposits. The addition of the wrist to the classically used sites for punch biopsies of the skin—the lateral distal leg, and distal thigh—improved the performance of this assessment.23 ICAD detection was accompanied by the cardiac uptake of DPD in 15.8% of carriers. We used a combination of skin punch biopsy and bone scintigraphy, for the first time, for the detection of amyloidosis. In total, 89 carriers underwent both skin biopsy and DPD scintigraphy. Amyloidosis was detected in 22 carriers (24.7%). Amyloid detection rate in skin biopsies was higher for EOVal30Met than in LOVal30Met and other mutations carriers, which supports that fibrils’ type B induces stronger Congo red staining (than fibrils type A)36 37 and that the method is less valuable for late onset forms. In some carriers, amyloid deposits were detected by one technique (skin biopsy or DPD scintigraphy) but not by the other, hence the interest of combining these techniques to maximise the chances of detecting amyloidosis especially in LOVal30Met and other mutations carriers.
We detected amyloidosis in 13 asymptomatic carriers presenting both sensory and autonomic dysfunction (HRV, Sudoscan). This finding highlights the need for annual follow-up in these individuals, without waiting for neurological or cardiac symptoms to appear before initiating DMT: treatment was initiated in 12 of these 13 (92.3%) carriers.
Denervation is frequent in TTRv mutation carriers
The frequency of sensory or autonomic small-fibre involvement was higher than that of amyloid deposition, suggesting that denervation probably becomes detectable before amyloid deposition. This finding is in line with the cytotoxicity of TTR in a prefibrillar stage before amyloid deposition detected by Congo red staining as described in 2001 by Mendes Sousa et al38 on sural nerve biopsies of asymptomatic TTR mutation carriers. Sensory small-fibre involvement was detected in almost all ATTRv carriers (88.7% with low IENFD) and was more frequent than autonomic involvement (found in one-third of carriers). The low IENFD found in almost all the carriers of our cohort is consistent with the findings of a limited study of 11 ‘asymptomatic carriers’.34 The ankle site seems to be the most informative for IENFD assessment for many reasons: (1) The standards have been validated on the ankle. (2) The ankle is where sensitivity is highest: IENFD reduction seems to follow a distal-proximal gradient (ankle>thigh).23 (3) The interest of IENFD lies in the repetition of skin biopsies over time in order to look for disease progression and therefore progressive denervation.
There was no correlation between low IENFD and the presence of clinical symptoms, unlike that found in symptomatic carriers.23 It could be explained by a lack of statistical power due to small numbers (13 carriers with normal IENFD). The second reason could be that Lauria score reflects both sensory and autonomic symptoms and not only sensory symptoms, whereas IENFD assesses only sensory fibres. This absence of correlation may also reflect a clinical–paraclinical discordance: progression of damage in low noise before really entering the symptomatic phase.
HRV tests exploring both the sympathetic and parasympathetic systems (SDNN, Valsalva) identified alterations more frequently than tests focusing exclusively on the sympathetic system (mIBG scintigraphy) or the parasympathetic system (DB-RMSSD or atropine test). Sudoscan revealed abnormalities in 36% of carriers, consistent with the 24% of asymptomatic carriers with low ESC and the 40% of paucisymptomatic ATTRv mutation carriers with low ESC previously reported.39
If our cohort is representative of the natural course of the disease in TTR gene mutation carriers, then clinical symptoms and abnormal NCS results should be considered the tip of the iceberg, with early denervation and progressive amyloid infiltration into target organs corresponding to the much larger, submerged part (figure 2).
Towards new recommendations?
One major issue for ATTRv carriers is the number and type of initial evaluations to be performed once genetic screening has detected an amyloidogenic TTR variant.
We think that both punch skin biopsy and DPD scintigraphy should be performed in the initial evaluation, to maximise the chances of detecting amyloid deposition. These two investigations are complementary to each other and to questionnaires and small-fibre investigations even in carriers with normal NCS results (figure 3).
The timing of the evaluation of TTRv mutation carriers is crucial. Our centre respects the majority of current guidelines40 recommending the initiation of evaluations 10 years before the age at disease onset of the proband in the family in EOVal30Met. For LOVal30Met and other mutation carriers, we detected disease onset before the at-risk decade in three LOVal30Met and other mutation carriers (13.6%). We thus recommend to initiate evaluations immediately after molecular diagnosis whatever the age at the disease onset of the proband in the family and to intensify the follow-up during the at-risk decade.
The lowest IENFD values at the ankle were associated with a higher risk of ICAD being detected in the EOVal30Met group; positive mIBG scintigraphy was associated with a higher risk of positive DPD scintigraphy in carriers of the LOVal30Met and other variants. We suggest that the evaluation of carriers of the EOVal30Met variant should include at least punch skin biopsy, whereas cardiac mIBG and DPD scintigraphy examinations are crucial for carriers with ATTRv leading to mixed phenotypes. Other innovative techniques for detecting early damage to the peripheral nerve are also being developed, including high-resolution magnetic resonance neurography,41 nerve ultrasound,42 quantitative sensory testing43 and analyses of emerging biomarkers, such as neurofilament chains.44
Strengths and limitations of our study
This cohort of 130 ATTRv carriers with 18 different TTR mutations and normal NCS findings is the largest to date to study both neurological and cardiac involvement and amyloid infiltration. Coelho and the THAOS investigators recently described 740 asymptomatic carriers in a multinational cohort, but they focused exclusively on clinical criteria,45 whereas we chose to combine clinical examination with other investigations in a multimodal approach, including techniques for amyloid detection, to make it possible to detect disease onset earlier in ATTRv carriers. Our study has limitations due to its design as a retrospective analysis of a single-centre cohort from a tertiary centre. Our tertiary centre has specific patient recruitment procedures and dedicated evaluations of ATTRv carriers adapted to the specialist technical platforms locally available. However, not all tests were performed in all carriers, reflecting usual routine care practices (cardiac MRI, atropine test, NT proBNP). This may have led to biases according to the mutation or the age of the carrier: more cardiac DPD uptake would be expected in a carrier of the Val122Ile mutation than in a carrier of the Val30Met mutation, for example. Similarly, more tests are performed in carriers close to the age at symptom onset in the proband of the family. The frequency of amyloid deposition should be confirmed in another prospective study.
Multimodal investigations of ATTRv carriers with normal NCS findings should include skin punch biopsy and DPD scintigraphy for the detection of amyloid deposits, to make it possible to classify carriers into one of four categories: overt amyloidosis, asymptomatic amyloidosis, asymptomatic denervation and disease-free. Early DMT can then be initiated immediately or during follow-up in the first two categories.
Data availability statement
Data are available upon reasonable request. Data are available upon request.
Patient consent for publication
This study was approved by the ethics committees of our institutions and was performed in accordance with the ethics guidelines of our institutions for clinical studies and the Helsinki Declaration. Data collection was declared in accordance with the General Data Protection Regulation (no. 20190403113200), as required for the retrospective collection of routine care data.
The authors wish to thank: the carriers and their families, the team of the Referral Center for Familial Amyloid Polyneuropathy and other rare peripheral neuropathies (CERAMIC) for their help in the care of patients, the French association of amyloidosis (Association Française Contre l’Amylose) which provided a grant to the referral centre for the work of DB, Olivier Morassi for the information he gave us on laboratory techniques and histology, Julie Sappa for proofreading the English version and Agathe Bicart-Sée for the figure of the iceberg.
VA and GB contributed equally.
Contributors GB, CL, DA, CC, BF, MSS, VA and DB contributed to the conception and design of the study. All authors contributed to the acquisition and analysis of data. GB, DA, CL, AEL, VA, MSS and DB contributed to drafting a significant portion of the manuscript or figures. GB is the guarantor of the study.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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