Mutations In TTR Gene Research Articles

The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism.

Transthyretin (TTR) is a homotetrameric protein mainly synthesised by the liver and the choroid plexus whose function is to carry the thyroid hormone thyroxine and the retinol-binding protein bound to retinol in plasma and cerebrospinal fluid. When the stability of the tetrameric structure is lost, it breaks down, paving the way for the aggregation of TTR monomers into insoluble fibrils leading to transthyretin (ATTR) amyloidosis, a progressive disorder mainly affecting the heart and nervous system. Several TTR gene mutations have been characterised as destabilisers of TTR structure and are associated with hereditary forms of ATTR amyloidosis. The reason why also the wild-type TTR is intrinsically amyloidogenic in some subjects is largely unknown. The aim of the review is to give an overview of the TTR biological life cycle which is largely unknown. For this purpose, the current knowledge on TTR physiological metabolism, from its synthesis to its catabolism, is described. Furthermore, a large section of the review is dedicated to examining in depth the role of mutations and physiological ligands on the stability of TTR tetramers.

P288 PREVALENCE OF AMYLOID TRANSTHYRETIN CARDIOMYOPATHY IN ELDERLY SUBJECTS FROM THE GENERAL POPULATION: FIRST RESULTS FROM THE CATCH STUDY

Abstract Background Amyloid transthyretin cardiomyopathy (ATTR–CM) has become treatable. Wild–type ATTR–CM is an age–related disorder. Establishing the exact prevalence of ATTR–CM in elderly subjects from the general population may be useful for healthcare providers and policy makers. Methods The Characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners in a part of Tuscany (Italy) where there is no cluster of variant ATTR. The study started on March 12, 2021 and is ongoing. Patients with 1) any clinical red flag of amyloidosis, 2) interventricular septal thickness ≥12 mm or other echocardiographic red flags, and/or 3) hs–troponin T > 14 ng/L are referred to diphosphonate scintigraphy and search for a monoclonal protein. Results As of October 13, 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n = 132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR–CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR–CM in the elderly population can be calculated as 2/266=0.8%. Conclusions The CATCH study is expected to enroll at least 1,000 subjects and will provide the first data on the epidemiology of ATTR–CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR–CM.

Skin amyloid deposits and nerve fiber loss as markers of neuropathy onset and progression in hereditary transthyretin amyloidosis.

This study was undertaken to assess skin biopsy as a marker of disease onset and severity in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), a treatable disease. In this single center retrospective study, skin Congo red staining and intraepidermal nerve fiber density (IENFD) were evaluated in symptomatic ATTRv-PN patients and asymptomatic TTR gene mutation carriers between 2012 and 2019. Non-ATTRv subjects with suspected small fiber neuropathy who underwent skin biopsy during the same timespan were used as controls. One hundred eighty-three symptomatic ATTRv-PN patients, 36 asymptomatic carriers, and 537 non-ATTRv patients were included. Skin biopsy demonstrated amyloid depositions in 80% of the 183 symptomatic cases. Skin amyloid deposits were found in 75% of early stage ATTRv-PN patients, and in 14% of asymptomatic carriers. All 183 symptomatic and 34 of 36 asymptomatic patients displayed decreased ankle IENFD with a proximal-distal gradient distribution, and reduced IEFND correlated with disease severity and duration. Our study demonstrates skin amyloid deposits are a marker of ATTRv-PN disease onset, and decreased IENFD a marker of disease progression. These results are of major importance for the early identification of ATTRv-PN patients in need of disease-modifying treatments.

172 Two mutations, one patient: which phenotype?

Abstract Methods and results Woman, 55 years old, she has as comorbidity high blood pressure and mild obesity. She came at our attention to perform screening cardiological exams after her brother, who was affected by amyloidotic TTR-related cardiomyopathy with Val30Met mutation, died for sudden cardiac death. At the first evaluation the patient is completely asymptomatic, she has not angor, dyspnoea and heartbeat. The ECG and echocardiography were negative for amyloidotic signs of heart involvement. The Tc-99-DPD scintigraphy showed no cardiac uptake (visual score = 0). To complete the diagnostic path the patient had been evaluated by a neurologist with electromyography, which was negative, and genetic test, which confirmed the presence of Val30Met mutation of TTR-gene. For this last outcome we decided to follow the patient at our clinics. In the following years the patient developed a progressive reduction of exercise tolerance and symmetric negative T waves in anterolateral and inferior lead at ECG. The echocardiogram showed a progressive medio-apical septal hypertrophy. To exclude an ischaemic cause the patient made a stress myocardial scintigraphy, which was negative for ischaemic signs, and she underwent to cardiac MRI which showed a septal thickness of 16 mm without amyloidotic radiological signs in T1-weighted and LGE sequences. For this reason, we suspected that the patient had a hypertrophic cardiomyopathy and she had been undergone another time to genetic test which confirmed the Val30Met TTR-mutation and MYBPC3 mutation. Usually, this last gene mutation for myosin binding protein C is associated with late-onset hypertrophic cardiomyopathy. Into account the new diagnosis and her sudden cardiac death family history we calculated the patient’s HCM-risk score which was under 4%, so that we did not undergo the patient to ICD implantation. Conclusions The case report is a rare example of coexistence of the transthyretin gene mutation and myosin binding protein C in the same patient. In this case to perform a correct diagnosis, it is crucial use an integrated multimodal approach including ECG, echocardiography and cardiac MRI.

541 Prevalence of amyloid transthyretin cardiomyopathy in elderly subjects from the general population: first results from the catch study

Abstract Aims Amyloid transthyretin cardiomyopathy (ATTR-CM) has become treatable. Wild-type ATTR-CM is an age-related disorder. Establishing the exact prevalence of ATTR-CM in elderly subjects from the general population may be useful for healthcare providers and policy makers alike. Methods and results The characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners working at the Casa della Salute in Terricciola, in an area of Tuscany where there is no cluster of variant ATTR. The study started on 12 March 2021 and is ongoing. The first step of the evaluation includes clinical history and physical examination, electrocardiogram, transthoracic echocardiogram, and blood sampling with measurement of N-terminal pro-B-type natriuretic peptide and high-sensitivity (hs) troponin T. The following elements are searched: (i) any clinical red flag of amyloidosis (history of carpal tunnel syndrome, lumbar spine stenosis, etc.), (ii) interventricular septal thickness ≥12 mm or other echocardiographic red flags, and (iii) hs-troponin T higher than the upper reference limit (14 ng/l). Patients with any of these elements are referred to a second step including diphosphonate scintigraphy and the search for a monoclonal protein in the serum and urine. The standard diagnostic workup for CA is then followed until the diagnosis is confirmed or discarded. As of 31 October 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n = 132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy, and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR-CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnoea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR-CM in the elderly population can be calculated as 2/266 = 0.8% (Figure). Conclusions The CATCH study is expected to enroll at least 1000 subjects and will provide the first data on the epidemiology of ATTR-CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR-CM.

Diagnosis of Cardiac Transthyretin Amyloidosis by Technetium-99m Pyrophosphate Heart Scan, Confirmed by Genetic Mutations: Case Report

Amyloid deposition in the myocardium can cause clinically significant heart failure, which is very difficult to diagnose. The present case reported presented a patient with heart failure, with suspected cause of cardiac amyloidosis, but abdominal fat pad and endomyocardial with Congo red stain biopsies were negative. Due to high suspicion of cardiac amyloidosis, a technetium-99m pyrophosphate (Tc-99m PYP) heart scan was done, which was revealed as strongly suggestive for cardiac transthyretin amyloidosis. So, the patient was sent for genetic testing, and a TTR gene mutation [c.148G>A (p.Val50Met)] was found. Keywords: Cardiac amyloidosis; Endomyocardial biopsy (EMB); Technetium-99m pyrophosphate (Tc-99m PYP) heart scan; Transthyretin amyloidosis (TTR)

RV free wall longitudinal strain as an independent predictor of survival in wtATTR-CA patients

Abstract Background Wild type transthyretin cardiac amyloidosis (wtATTR-CA) is increasingly recognized as a cause of heart failure with preserved ejection fraction (HFpEF) but prognosis is often limited due to late or misdiagnosis.Longitudinal left ventricular strain and biomarkers are established as markers of disease severity, but the role of RV free wall strain, reflecting RV contractility, is less well understood. Purpose We sought to determine whether RV free wall strain might add incremental prognostic value in wtATTR-CA. Methods Consecutive patients diagnosed with wtATTR-CA with tissue confirmation at Mayo clinic between 2013 and 2015 were included. Patients with TTR gene mutations were excluded. Baseline characteristics and transthoracic echocardiography measurements were obtained from the medical records. Speckle tracking RV free wall longitudinal 2D strain and peak LA longitudinal 2D strain were measured using Tom Tec Imaging System. Survival was determined using Kaplan Meier estimates and using the cox proportional hazard ratio, univariate and multivariable analysis were performed to identify predictors of mortality in patients with wtATTR. Results The study group comprised 139 patients (mean age 74.9±8.6, 92.8% male), of which 102 had adequate image quality for RV strain, and 99 for LA strain. Amongst these, 102 (73.3%) had AF and 118 patients (84.8%) had HF. During 3.23±2.0 years of follow up, 66 patients died. Both mean RV and LA strain were impaired at baseline: RV free wall strain was −14.7±4.9, and peak atrial longitudinal strain (PALS) was 13.2±8.8%. Using ROC analysis, RV strain of −16.8% was an independent predictor of all-cause mortality. In univariate modeling, higher levels of NT-proBNP (HR: 1.1 per 1000 pg.ml; 95%, CI 1.05–1.15, p<0.001) and Troponin T (HR: 2.0 per 0.1ng/ml; 95% CI 1.49–2.61, p<0.001) were associated with increased all-cause mortality. In addition, LV GLS (HR: 1.13 per 1%; 95% CI1.04–1.24, p=0.003), RV free wall LS (HR: 2.16 per 5%; 95%, CI 1.57–3.03, p<0.0001), and PALS (HR: 0.91 per1%; 95% CI 0.85–0.96, p<0.0001) were univariate predictors of all-cause mortality. In multivariate analysis using a stepwise regression model, RV free wall longitudinal strain (HR: 1.81; 95% CI 1.29–2.62, p<0.001) and Troponin T (HR: 1.7; 95% CI 1.25–2.26, p=0.001) remained independent predictors. Kaplan-Meier survival analysis demonstrated a higher mortality rate above −16.8 RV strain cut-off (Wilcoxon <0.0001). All stages were divided into two groups by −16.8% RV strain, and survival in individual stages analyzed. Stage 1 and 2 with <−16.8 RV free wall strain value had higher mortality than ≤-16.8% RV strain (Stage 1: Wilcoxon = 0.0041 and Stage 2: Wilcoxon = 0.023). However, there was not a survival difference between two RV strain groups in stage3 (Wilcoxon = 0.34) Conclusion RV free wall strain is an independent predictor of survival in wtATTR patients and may add incremental prognostic value to NT-proBNP and Troponin. Funding Acknowledgement Type of funding sources: None. Kaplan-Meier curve of all patientsKaplan-Meier curve of stages

Clinical and apparative investigation of large and small nerve fiber impairment in mixed cohort of ATTR-amyloidosis: impact on patient management and new insights in wild-type

Introduction Neuropathy in transthyretin (ATTR) amyloidosis is frequently underdiagnosed, delaying effective treatment. Early detection of large- and small-nerve fiber damage via a comprehensive diagnostic algorithm impacts on clinical management. Methods A mixed cohort of patients with ATTR amyloidosis (wild type-wt, hereditary-v and TTR gene mutation carriers) of the Interdisciplinary Amyloidosis Centre of Northern Bavaria underwent clinical examination, nerve conduction studies (NCS), quantitative sensory testing (QST), sympathetic skin response (SSR), quantitative sudomotor axon reflex testing (QSART), and skin punch biopsies. Results Out of 30 study participants (7 ATTRv/asymptomatic gene carriers, 23 ATTRwt) large-fiber neuropathy was found in 43% patients with ATTRv and 70% with ATTRwt. QST revealed a mixed small and large fiber impairment in all ATTRv/asymptomatic gene carriers and in 78% of ATTRwt. Autonomic tests were pathological in the majority of ATTRv and over 50% of ATTRwt patients. Skin biopsies (sampled from 19 patients) showed reduced intraepidermal nerve fiber density (IENFD) in all ATTRv/asymptomatic gene carriers and over 80% of ATTRwt. Two ATTRwt patients had a pure small fiber neuropathy. After reviewing for relevant co-morbidities, 44% of ATTRwt patients exhibited neuropathy (large and/or small fiber) without evidence of any other underlying cause. Disease manifestation in the peripheral nervous system was newly diagnosed in three ATTR gene mutation carriers, thereby influencing clinical management. Conclusion This comprehensive test program gives new insights regarding the presence of neuropathy in ATTRv and ATTRwt, which impact on patient management.

Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation

BackgroundTo determine the capability of 99mTc-DPD scintigraphy to detect early cardiac involvement and predict clinical worsening in transthyretin (TTR) gene mutation patients. MethodsEleven mutated subjects with normal interventricular septum (IVS) thickness, NT-proBNP level and no cardiac symptoms underwent three seriate 99mTc-DPD scans (visually and semiquantitatively analyzed), and was followed-up for 5-8-years. ResultsSix patients showed no myocardial accumulation in all scans. Increased IVS thickness occurring in one patient 4 years after the last scan was the only abnormal finding in these patients; no cardiac symptoms developed during the follow-up. In three patients, cardiac radiotracer uptake was found at enrollment; other laboratory/instrumental abnormal findings occurred later and cardiac symptoms developed during the follow-up period. Two patients had a negative 99mTc-DPD scan at enrollment and showed cardiac uptake in the following scans. Increased mean left-ventricular (LV) wall thickness was found 3 years after positive scintigraphy; NT-proBNP increased later in one patient. These patients developed cardiac symptoms during the follow-up period. Conclusions99mTc-DPD scan detects cardiac involvement in subjects with TTR gene mutation earlier than ECG, echocardiography and biochemical markers, occurring some years before the fulfillment of current diagnostic criteria for cardiac amyloidosis. A positive 99mTc-DPD scan predicts cardiac symptoms onset.

Prevalence of transthyretin amyloid cardiomyopathy in male patients who underwent bilateral carpal tunnel surgery: The ACTUAL study

IntroductionBilateral carpal tunnel syndrome (CTS), particularly in male individuals with left ventricular hypertrophy (LVH), has been recognized as a red flag for transthyretin cardiac amyloidosis (TTR-CA). Nonetheless, the opportunity of screening CTS patients for TTR has yet to be determined. MethodsMedical records of 1689 CTS surgeries performed at our institution between 2008 and 2018 were reviewed. Eighty-three males who underwent bilateral CTS surgery were considered eligible for the study, and offered a screening examination including electrocardiography and echocardiography. Individuals with LVH (diastolic septal wall thickness > 12 mm) were offered second-line diagnostic testing including blood testing and bone scintigraphy. ResultsStudy population consisted of 53 bilateral CTS male patients, with median age of 73 years. LVH was found in 6 (11%) individuals. None of them had monoclonal gammopathy or reported CTS occupational risk factors. Two declined to undergo further testing, whereas 2 had negative and 2 had positive bone scintigraphy (both Perugini 2 uptake) and tested negative for TTR gene mutations (wild-type TTR-CA). ConclusionsPrevalence of TTR-CA in the entire study population was 4%, but among bilateral CTS patients with LVH peaked at 33%. In this latter population, screening for TTR-CA appeared feasible and effective.

Challenges in Diagnosis and Treatment of Systemic Amyloidosis: 10 Years of Experience in a Public Brazilian University Center

Systemic Amyloidosis (SA) results from tissue deposition of insoluble protein fibrils leading to organ dysfunction. Considering the scarcity of data from Latin America, a retrospective study was conducted by reviewing medical records of patients with biopsy proven SA diagnosed from 2009 to 2018 at a public tertiary center to assess clinical, laboratory and therapeutic features. Confirmed SA subtype was established if causative protein was identified on tissue biopsies by immunohistochemistry (IHC), indirect immunofluorescence (IIF), mass spectrometry (MS) or in the presence of pathogenic gene mutation related to SA. Probable cases were classified as light chain SA (AL) if evidence of monoclonal gammopathy (MG), transthyretin SA (ATTR) if moderate/strong cardiac uptake in 99mTc-pyrophosphate scintigraphy (99mTc-PYP), classical neurological symptoms with familial history or previous liver transplant from a donor with hereditary ATTR (hATTR), and secondary SA (AA) in the context of underlying chronic inflammatory disease. Inconclusive cases had ≥2 concomitant features suggestive of different subtypes. Primary endpoint was overall survival (OS). From 198 cases revised, 110 met the eligibility criteria. Median age was 60 years, 56% were male. Before diagnosis 53% were seen by ≥3 physicians: 65% general practitioners, 45% nephrologists, 42% cardiologists. Median time from onset of symptoms to diagnosis was 11.3 months. In 79% of patients ECOG was ≤2. Clinical presentations were: 54% renal disorders, 43% heart disease, 36% consumptive syndrome, 26% gastrointestinal symptoms, 25% neuropathy, 19% fatigue, 12% skin lesions, 9% hepatic disorders. The mean number of biopsies performed per patient was 2.3 and 60% had a method to subtype amyloid on biopsy: 67% IIF, 36% IHC and MS in 1 case. Mean number of affected organs was 2.6 (19% 1 organ, 38% 2 and 43% ≥ 3). Main organs were: 75% heart, 55% kidney, 43% soft tissue, 37% peripheral nervous system. Dialysis patients were 12%. Positive familial history was seen in 7% and 17% were tested for genetic mutations: 63% for transthyretin, 21% fibrinogen, 5% lysozyme, 16% MEFV gene. MG screening was assessed in 97% of patients, amyloid protein A in 4 and 99m Tc-PYP performed in 11. SA subtypes were confirmed in 32% of patients, probable in 59% and inconclusive in 9%. Frequency of subtypes were 68% AL, 12% ATTR, 6% AA, 4% fibrinogen amyloidosis (AFib), 1% lysozyme amyloidosis (ALys). Most of AL were λ (75%) and 34% had coexisting multiple myeloma. Standard Mayo Clinic Staging (MCS) was evaluated in 56% (59% stage III, 31% II, 10% I). Stage III were assessed by European staging (32% IIIa, 48% IIIb, 20% IIIc). Revised MCS was available in 21% (25% each I to IV). Renal staging showed 81% stages I/II, 19% stage III. Among ATTR patients 1 was wild type and 69% had mutation in TTR gene: 44% V30M, 33% V122I, 11% G89L. In 11% genetic data were not assessed. Mutated ATTR was presumed in 2 domino liver transplant recipients from hATTR donors. Inflammatory diseases in AA were: 43% Familial Mediterranean Fever (FMF), rheumatoid arthritis, vasculitis, immunoglobulin G4-related disease, combined polymyositis/primary biliary cholangitis (14% each). Treatments in AL were: 81% chemotherapy (CT) (54% melphalan, 18% thalidomide, 10% bortezomib), 12% stem cell transplant, 12% supportive measures (SM), 4% doxycycline, 1 kidney transplantation. Responses were available in 40 cases: 30% PR, 13% VGPR, 18% CR, 25% no response, 15% progression. ATTR was treated with: 31% liver transplantation, 54% SM, 8% tafamidis, 8% doxycycline. AA related to FMF treatments were anti-IL1 and colchicine and other AA received immunosuppressive therapy for underlying diseases. ALys was treated with SM. CT was given to 1 AFib patient before proper diagnosis, the others received SM. Inconclusive cases were managed 90% with SM, 1 received empirical CT. Median follow-up time of survivors was 66.3 months. At 5 years, estimated OS was 33%. Median OS in AL and non-AL were 18 and 74.4 months respectively (p < 0.001). In conclusion, the broad clinical spectrum of SA and the complex diagnostic approach lead to late diagnoses in advanced stages. Medical awareness of the disease, early suspicion, establishment of reference centers, better diagnostic tools, multidisciplinary team, a SA registry and access to disease-modifying drugs may result in early diagnosis and prompt intervention, improving outcomes in Brazil and Latin America. Disclosures No relevant conflicts of interest to declare.

Cardiac sympathetic denervation in wild-type transthyretin amyloidosis

Abstract Background Tissue accumulation of misfolded transthyretin (TTR) may occur because of TTR gene mutations (variant amyloid TTR amyloidosis, ATTRv), or as an age-related phenomenon (wild-type ATTR, ATTRwt). Cardiac sympathetic denervation has been reported in ATTRv, but has never been investigated in ATTRwt. Methods Fifteen consecutive patients with ATTRwt cardiomyopathy (81% men, median age 82 years, no one with prior myocardial infarction) underwent Cadmium Zinc Telluride tomographic imaging for amyloid burden (99mTc-hydroxymethylene diphosphonate - 99mTc-HMDP), innervation (123I-metaiodobenzylguanidine – 123I-MIBG), and perfusion (99mTc-tetrofosmin). Results Median summed 99mTc-HMDP score was 60 (58–62), denoting a severe and diffuse amyloid burden. Planar 123I-MIBG examination showed decreased early and late H/M ratios (late H/M ratio: 1.5 [1.3–1.6], range 1.2–1.9, reference value ≥2.0). Summed 123I-MIBG score was 12 (6–22), with the most prominent denervation in the infero-septal, inferior, and infero-lateral regions; summed rest score was 7 (5–11), with lowest degrees of myocardial perfusion in the inferior and infero-septal regions. The correlation between amyloid burden (as relative 99mTc-HMDP uptake) and innervation (as relative 123I-MIBG uptake) did not achieve statistical significance at both segmental (p=0.252) and regional level (p=0.251). Nevertheless, denervation tended to worsen in parallel with the amyloid burden, and 123I-MIBG scores increased with 99mTc-HMDP scores. Segments and regions with more prominent hypoperfusion were those showing the more intense denervation (r=0.500 and 0.591, respectively; both p<0.001). Conclusions Patients with ATTRwt cardiomyopathy display cardiac sympathetic denervation, particularly in the inferior and septal myocardial wall. Myocardial hypoperfusion has a similar regional pattern, while the amyloid burden is more extensive. Funding Acknowledgement Type of funding source: None

Nerve ultrasound in hereditary transthyretin amyloidosis: red flags and possible progression biomarkers

BackgroundDiagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers.MethodsPatients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers.ResultsSixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity (r = − 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p < 0.001).ConclusionsThe present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

Clinical, pathological, and proteomic characteristics of newly diagnosed amyloidosis patients: Experience from a single referral center in Japan

AbstractNovel therapies have recently been used for different amyloidoses including hereditary transthyretin (ATTR, ATTRv) amyloidosis, wild‐type ATTR (ATTRwt) amyloidosis, immunoglobulin light chain (AL)amyloidosis, and amyloid A (AA) amyloidosis. Early, accurate diagnosis is important for improved prognosis and cure. However, early intervention with early diagnosis is often difficult, because these diseases are frequently difficult to identify given their phenotypic heterogeneity. This study aimed to analyze characteristics of patients with amyloidosis that was diagnosed at the Amyloidosis Medical Practice Center, Kumamoto University Hospital, which, as an amyloidosis center in Japan, conducts histopathological, proteomic, and genetic analyses of amyloidosis. We analyzed diagnostic results and disease manifestations of patients diagnosed during April 2012 and March 2019. This study reviewed 1937 consecutive consultations that provided clinical information. The patients’ average age was 65.9 (median 69) years. Of all patients, 66.6% were male. Diagnoses included ATTRv: 13.4%, ATTRwt: 14.3%, ATTR (no genetic analysis consultation requested): 4.6%, ALλ: 19.7%, ALκ: 8.8%, AA: 3.0%, β2‐microglobulin (dialysis‐related): 0.8%, and others: 1.9%, no TTR gene mutation (no histopathological analysis consultation requested): 23.2% (including duplicate consultations). ATTRv amyloidosis cases included V30M in endemic areas: 7.4%, V30M in non‐endemic areas: 51.2%, and non‐V30M: 41.4%. Sixty‐six cases required laser microdissection and liquid chromatography‐tandem mass spectrometry. Initial manifestations included polyneuropathy: 13.2%, carpal tunnel syndrome: 5.6%, autonomic dysfunction: 2.7%, heart failure: 28.4%, cardiac hypertrophy: 2.2%, arrhythmia: 5.0%, renal impairment: 11.1%, and stroke: 1.8%. Amyloidosis types and manifestations were diverse. For early diagnosis and appropriate interventions, improved diagnostic systems are needed.

TTRMDB: A database for structural and functional analysis on the impact of SNPs over transthyretin (TTR) using bioinformatic tools

Hereditary Transthyretin-associated amyloidosis (ATTR) is an autosomal dominant protein-folding disorder with adult-onset caused by mutation of transthyretin (TTR). TTR is characterized by extracellular deposition of amyloid, leading to loss of autonomy and finally, death. More than 100 distinct mutations in TTR gene have been reported from variable age of onset, clinical expression and penetrance data. Besides, the cure for the disease remains still obscure. Further, the prioritizing of mutations concerning the characteristic features governing the stability and pathogenicity of TTR mutant proteins remains unanswered, to date and thus, a complex state of study for researchers. Herein, we provide a full report encompassing the effects of every reported mutant model of TTR protein about the stability, functionality and pathogenicity using various computational tools. In addition, the results obtained from our study were used to create TTRMDB (Transthyretin mutant database), which could be easy access to researchers at http://vit.ac.in/ttrmdb.

PREVALENCE AND CHARACTERISTICS OF WILD TYPE TRANSTHYRETIN AMYLOID CARDIOMYOPATHY IN HOSPITALIZED PATIENTS REFERRED FOR TC-99M PYROPHOSPHATE (PYP) SCAN

Understanding the characteristics of patients with a final diagnosis of wild type ATTR cardiomyopathy (ATTR-CA wt) may help optimally triage patients for Tc-99m PYP scanning. We evaluated hospitalized patients who had a positive PYP scan with no TTR gene mutation and negative serum AL studies (ATTR

Hereditary transthyretin amyloidosis

Hereditary transthyretin amyloidosis is described in this review, including the TTR gene structure and mutation spectrum, the transthyretin protein structure and functions, the main clinical manifestations of transthyretin amyloidosis. Also the problems of differential diagnosis are discussed, the history of the spread of the disease among various ethnic groups is examined, information is provided on the current possibilities of pathogenetic and etiological treatment of the disease.

P2732Prevalence of electrocardiographic abnormalities in patients with cardiac amyloidosis

Abstract Background Electrocardiographic (ECG) abnormalities are common in patients presenting with Light-Chain (AL) or Transthyretin (ATTR) related Cardiac Amyloidosis (CA). Type of amyloid may differently affect electrical properties of the heart being responsible for variable patterns of ECG anomalies at presentation. Purpose In this retrospective, observational study we sought to compare prevalence of ECG abnormalities between AL and ATTR patients with CA. Methods Clinical files from two Referral Centres were reviewed; ECG recordings were analysed by trained cardiologists and relevant findings were reported about rhythm (sinus vs atrial fibrillation [AF]), grade I or grade II atrio-ventricular (AV) delays, intra-ventricular (IV) conduction abnormalities, low-voltage QRS and pseudo-necrosis pattern. Presence of pace-maker (PM) and stimulated QRS were regarded to as clinical equivalents for AV block, after review of indications to implantation. Results Two hundred and fifty-one patients were identified (127 ATTR vs 124 AL; among ATTR, 27 patients had mutation in TTR gene: 10 Val142Ile, 11 Ile88Leu, 6 other). As expected, most ATTR patients were male (89% vs 56% in AL, p: &lt;0.001), and AL patients were younger (mean age 64 [53–70] vs 79 [73–83]; p: &lt;0.001). Pathological ECG findings were common in both subgroups, involving more than three-quarters of the overall population (82% in ATTR, vs 72% in AL, p: 0.06). Atrial fibrillation was more common in ATTR, prevailing in 39% vs 5.6% (p: &lt;0.001). ATTR had a higher burden of AV block (53% vs 13%, p: &lt;0.001) and IV conduction delays (43% vs 21%, p: &lt;0.001), and consistently presented a higher prevalence of PMs (24 patients vs 1). Low-voltage QRS was more prevalent in AL patients (52% vs 28%, p: &lt;0.001), while no significant difference was found in prevalence of pseudo-necrosis patterns (ATTR: 29%, AL: 40%; p: ns). Due to imbalance in age and gender and relative possible confounding effect on rhythm disturbances, adjusted odds ratios (OR) were calculated. It resulted that ATTR was independently associated with a higher prevalence of AF and AV conduction delays when compared to AL (adjusted OR: 4 [95% CI: 1.4–11.2], p: 0.008, and 6.2 [95% CI: 2.6–14.9], p: &lt;0.001; respectively), while being inversely associated with low-voltage QRS (adjusted OR: 0.4 [95% CI: 0.2–0.9], p: 0.026). Conclusions ECG abnormalities are common in CA. Rhythm disturbances are more prevalent in ATTR, while AL more often results in low-voltage QRS. Such differences remain relevant after adjustment for age and gender imbalance, thus suggesting an aetiology-specific link.

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

ABSTRACTIntroduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body.Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms ‘inotersen,’ ‘AG10,’ ‘antisense oligonucleotide,’ ‘hereditary transthyretin amyloidosis,’ ‘familial amyloid polyneuropathy,’ and ‘familial amyloid cardiomyopathy’ was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance.Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia.

P71-S Transthyretin familial amyloid polyneuropathy (TTR-FAP). Neurophysiological assessment in asymptomatic carriers

Background Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare hereditary disorder caused by mutations in the TTR gene. Unless treated, its course is very severe and death occurs after 7–10 years of symptoms onset. Genetic counseling is crucial in the detection of asymptomatic carriers, and scientific societies recommend a thorough examination and follow-up to detect the onset of the disease and indication of treatment. The aim of the study is to evaluate the usefulness of neurophysiological tests to detect the onset of polyneuropathy in asymptomatic carriers of the TTR mutation. Material and methods Asymptomatic carriers of the TTR mutation were selected. Clinical and neurophysiological evaluation were performed every 12 months. Motor and sensory nerve conduction studies (NCS) were used to evaluate thick nerve fiber in upper and lower limbs. The study of fine nerve fiber included the variation of the RR interval, cutaneous sympathetic response (SSR) by electrical stimulation, Sudoscan, and the study of thermal and algic thresholds by quantitative sensory test (QST) in the hands and feet. Results Nineteen asymptomatic carriers of the TTR mutation have been included (13 men and 6 women) and followed for an average of 5 years. Four of them developed some abnormality in the QST, 4 developed carpal tunnel syndrome, and 5 showed some abnormality of SSR and QST of uncertain significance. The sudoscan test provided greater sensitivity than the SSR. Conclusion The neurophysiological study of fine nerve fiber is a useful method in the follow-up of asymptomatic patients carrying TTR mutation.