AB-656. Pathologic and electrophysiologic features of late-onset transthyretin familial amyloid polyneuropathy based on the background of the Glu61Lys mutation in the transthyretin gene

Transthyretin (TTR) amyloidosis is a protein misfolding disease characterized by amyloid fibril deposition in vital organs, leading to cardiomyopathy (ATTR-CM). Early diagnosis of ATTR-CM remains challenging due to lack of sensitive, rapid screening methods. Here, we report cryo-EM structures of TTR amyloid fibrils extracted from minimally invasive abdominal fat-pad biopsies of three living Ala97Ser ATTR-CM patients. The adipose-derived fibril structures closely mirror those from diseased post-mortem cardiac tissues, validating the use of fat-pad biopsies to investigate the atomic structure of TTR fibrils in living patients. Furthermore, we determined cryo-EM structures of TTR fibrils in complex with two amyloid-binding dyes, Congo Red (CR) and Thioflavin S (ThS), which are widely used in the clinical diagnosis of ATTR-CM. Both CR and ThS predominantly bind to a specific surface arginine site on the TTR fibril via electrostatic interactions. These findings provide structural insights into how small-molecule dyes bind TTR fibrils, offering a molecular foundation for the rational design of TTR-specific tracers to enable early and accurate diagnosis of TTR amyloidosis.

RNA interference is an ancient biological defense mechanism against external invasions. Mechanistically, small interfering RNA (siRNA) can specifically bind to any target gene, according to the principle of complementary base pairing, to exert silencing effects. Therefore, siRNA has the potential to serve as an efficient therapeutic agent for various diseases. However, due to their susceptibility to nucleases, off-target effects, and low cellular uptake, the development of siRNA-based drugs remains challenging. Fortunately, with the advancement in chemical modifications and delivery systems, patisiran, the first siRNA therapeutic, was approved for the treatment of hereditary transthyretin amyloidosis by the United States Food and Drug Administration (FDA) in 2018, which represents a crucial milestone in the field of siRNA research. Subsequently, seven other siRNA drugs were introduced to the market. Thus, siRNA drugs are on their way to becoming standard pharmacotherapy tools. This review presents the mechanisms of action, delivery barriers, chemical modifications, and delivery platforms of siRNA. Furthermore, it also summarizes commercialized siRNA drugs and some clinical trials, thereby providing a comprehensive knowledge map of siRNA drug modifications, delivery strategies, action mechanisms, and updated clinical trials.

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform nonbinding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses vutrisiran (Amvuttra), 25 mg/0.5 mL, prefilled syringe, subcutaneous injection. Indication: Proposed for the treatment of cardiomyopathy in adult patients with wild-type or hereditary transthyretin-mediated amyloidosis.

Cascade genetic screening in hereditary transthyretin amyloidosis: when early diagnosis becomes survival.

Hereditary transthyretin amyloidosis (ATTRv) is a genetic disorder caused by more than 100 autosomal dominant mutations in the TTR gene. Owing to its marked clinical heterogeneity-particularly in its cardiac manifestations-ATTRv is frequently underdiagnosed and requires comprehensive clinical evaluation. The disease commonly presents as a progressive axonal sensorimotor polyneuropathy with autonomic involvement. Despite advances in disease-modifying therapies, including the availability of Tafamidis, delayed diagnosis remains a major challenge, contributing to increased morbidity and mortality. Therefore, the identification of reliable biomarkers for early detection, disease staging, and therapeutic monitoring is essential. One promising candidate is neurofilament light chain (NfL), a structural axonal protein released into the circulation following neuronal injury, which has been proposed as a biomarker of neuroaxonal damage in ATTRv in other populations. The present study aimed to evaluate plasma NfL (pNfL) levels in Brazilian patients with ATTRv and to investigate their association with neuropathy severity. Symptomatic and asymptomatic patients with genetically confirmed ATTRv followed at a specialized university reference center were included, along with healthy volunteer controls. A subgroup of symptomatic patients was receiving Tafamidis therapy. Clinical and demographic data were collected during routine visits, and neuropathy severity was assessed using validated instruments, including the Neuropathy Impairment Score (NIS) and the Polyneuropathy Disability (PND) score. Plasma NfL concentrations were measured using the ultrasensitive SIMOA SR-X platform. Statistical analyses were performed to compare pNfL levels across groups and to assess correlations with clinical parameters. Symptomatic patients not receiving Tafamidis exhibited significantly higher pNfL levels compared with treated symptomatic patients, asymptomatic mutation carriers, and healthy controls. Moreover, pNfL concentrations showed a positive correlation with NIS scores, indicating increasing axonal damage with disease progression. Z-score analyses further supported the ability of pNfL to discriminate between disease stages. In conclusion, plasma NfL emerges as a promising biomarker for assessing disease severity, progression, and treatment response in ATTRv, supporting its potential utility in Brazilian clinical practice.

The aim of this study was to describe a case of vitreous amyloidosis as a rare aetiology of vitreous opacities and to show diagnostic value of vitreous biopsy in the diagnostic process as well as show a potiential new non-invasive diagnostic for vitreous amyloidosis. Retrospective case report with presentation of medical record data, clinical imaging, and pathological work-up. A 82-year-old man underwent diagnostic vitrectomy due to dense vitreous opacities in the right eye. While visual acuity did not improve much due to an underlying advanced fibrotic age related macular degeneration, pathology confirmed amyloid material in the vitreous. The patient was diagnosed with hereditary amyloid transthyretin amyloidosis (ATTRv) and offered a transthyretin stabilising therapy (tafamidis, vindaqel®). While vitreous opacities are a common usually benign phenomenon, it is important to recognise atypical presentation. Diagnostic work-up may include diagnostic vitrectomy, which can aid in diagnosing relevant underlying systemic disease such as ATTRv amyloidosis. While pathologic work-up of vitreous material is the current gold standard, there may be novel non-invasive imaging techniques to aid in diagnosis of vitreous amyloidosis.

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disease with variable penetrance. Cascade genetic screening may enable earlier diagnosis and intervention, but its prognostic impact remains unclear. This study retrospectively analysed 967 individuals from 431 families between 2004 and 2024 across 15 Italian referral centres. Participants were categorized as ATTRv index cases, symptomatic carriers (genotype-positive/phenotype-positive [G+/P+]), or asymptomatic carriers (genotype-positive/phenotype-negative [G+/P-]). Clinical characteristics, disease conversion, and survival were evaluated. Following identification of 398 index cases, genetic screening of 1243 relatives identified 569 carriers (461 G+/P-, 108 G+/P+). Among the 461 G+/P-, over a median follow-up of 5.3 [1.7-9.8] years, 77 (16.7%) patients developed a clinical diagnosis of ATTRv: Glu89Gln (42.2%, 95% confidence interval [CI] 28.8-56.9), Phe64Leu (24.7%, 95% CI 16.1-35.8), Val30Met (13.1%, 95% CI 7.4-22.1), Ile68Leu (7.3%, 95% CI 4.1-12.8), and Val122Ile (5.1%, 95% CI 1.3-18.3), other variants 22.9% (95% CI 14.5-34.1). Notably, 11/62 (17.7%) carriers converted >10 years earlier than the predicted age of disease onset. G + P+ patients had better survival than index (hazard ratio [HR] 0.43, 95% CI 0.24-0.79), and mixed phenotype showed worse outcomes than cardiac presentations. Disease-modifying therapy was independently associated with lower mortality (HR 0.11, 95% CI 0.01-0.17). Cascade genetic screening facilitated earlier diagnosis and was associated with improved survival, likely related to identification at an earlier stage of disease and timely treatment initiation. Variant-specific follow-up is essential, as some carriers convert earlier than predicted. Systematic, genotype-informed surveillance in ATTRv is key to optimize outcomes.

Multidimensional care in transthyretin cardiac amyloidosis: Integrating extracardiac organ involvement and comorbidity management.

Disease Prognosis and Progression in Transthyretin Amyloidosis: JACC: CardioOncology State-of-the-Art Review.

Transthyretin (TTR) is a tetrameric transporter of retinol and thyroxine that aggregates in the central and peripheral nervous system upon a severe pathology known as transthyretin amyloidosis. Although small molecular weight drugs can stabilize TTR preventing its aggregation, molecular mechanisms of transthyretin amyloidosis remain poorly understood. Accumulating evidence indicates that lipids can alter TTR stability by facilitating protein aggregation into toxic oligomers and fibrils. Consequently, pathological changes in the lipid composition of plasma membranes can be responsible for the onset and progression of transthyretin amyloidosis. In this study, we investigated the role of concentration-dependent changes in phosphatidylcholine (PC), one of the most abundant phospholipids in the plasma membrane, on the rate of TTR aggregation. For this, TTR was exposed to large unilamellar vesicles (LUVs) composed of 30%, 35%, and 40% PC. We found that a decrease in the concentration of PC from 40% to 35% drastically accelerated TTR aggregation. We also observed an increase in the cytotoxicity of TTR aggregates formed in the presence of 35% PC compared to TTR fibrils grown in the presence of LUVs with 40% PC. These results indicate that changes in the concentration of PC in the plasma membrane could trigger amyloid formation that leads to transthyretin amyloidosis.

Cardiac remodeling and arterial stiffness progression in wild-type vs hereditary transthyretin amyloidosis in Crete.

Acquired transthyretin (ATTR) amyloidosis is a rare iatrogenic complication of domino liver transplantation (DLT), in which mutant transthyretin (TTR) continues to be produced by the graft, leading to systemic amyloid deposition in recipients. Liver retransplantation has been proposed as a potential therapeutic strategy, but its clinical benefit remains uncertain. This case series aims to describe the clinical evolution of three patients with acquired ATTR amyloidosis who underwent liver retransplantation and assess the impact of the procedure on disease progression. We retrospectively reviewed three male patients diagnosed with acquired ATTR amyloidosis after DLT and followed at a national referral center. Clinical data were extracted from medical records, including neurological findings, autonomic and systemic involvement, timing of symptom onset, and outcomes after retransplantation. All patients underwent electrodiagnostic studies and tissue biopsy confirming ATTR amyloidosis. All three patients developed neuropathic symptoms approximately nine years after DLT. Two had advanced disease at the time of retransplantation, with marked autonomic and cardiac involvement. These two patients showed continued neurological and systemic deterioration after retransplantation. The third patient, who underwent earlier retransplantation and had a milder phenotype, demonstrated clinical stabilization over two years of follow-up. Liver retransplantation appears to offer limited benefit in halting disease progression in acquired ATTR amyloidosis, particularly when performed at advanced stages. Earlier intervention, before the establishment of significant systemic involvement, may improve outcomes. These findings highlight the need for timely diagnosis and individualized management in this underrecognized condition.

This exploratory analysis of the NEURO-TTRansform Phase 3 trial evaluated the efficacy of eplontersen in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy by genetic variant. Changes from baseline in NEURO-TTRansform primary endpoints serum transthyretin (TTR) at Week 65, modified Neuropathy Impairment Score+7 (mNIS+7) composite score, and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score at Week 66 were evaluated in patients with early-onset (aged < 50 years) and late-onset (aged ≥ 50 years) Val30Met (p.Val50Met) or non-Val30Met ATTRv amyloidosis with polyneuropathy. Secondary endpoints from NEURO-TTRansform were also evaluated by genetic variant. In total, 144 patients with early-onset (n = 54) or late-onset (n = 31) Val30Met or non-Val30Met (n = 59), ATTRv amyloidosis with polyneuropathy were randomized to eplontersen. A further 60 patients from NEURO-TTR with early-onset (n = 16) or late-onset (n = 17) Val30Met or non-Val30Met (n = 27), served as a historical placebo group. The mean percentage difference (95% confidence interval) in serum TTR was -79.9 (-87.8, -72.0), -85.0 (-93.3, -76.6), and -70.6 (-77.7, -63.5) with eplontersen versus placebo in the early- and late-onset Val30Met, and non-Val30Met groups, respectively. Across subgroups, the change from baseline to Week 66 in mNIS+7 composite score was generally well maintained, and the Norfolk QoL-DN total score improved with eplontersen versus worsening with placebo. The Polyneuropathy Disability score was maintained in most patients. From baseline to Week 65, the modified body mass index was maintained with eplontersen compared to a marked reduction (worsening) for placebo. Findings were suggestive of consistent benefits in reducing neuropathy impairment and improving QoL with eplontersen versus historical placebo, across TTR variants. ClinicalTrials.gov: NCT04136184, NCT01737398.

26-A-17094-ACC ATRIAL FIBRILLATION IS ASSOCIATED WITH POOR SURVIVAL IN PATIENTS WITH WILD-TYPE TRANSTHYRETIN AMYLOID CARDIOMYOPATHY

Redefining therapeutics in vATTR: Evaluation of response predictors to tafamidis and patisiran treatment in a non-endemic area. A proposal for a novel individualised therapeutic approach.

Identifying Subclinical Transthyretin Cardiac Amyloidosis in V142I TTR Carriers: Design, Rationale, and Methods of the VISTA (Variant Imaging of Subclinical Transthyretin Amyloidosis) Study.

Ocular manifestations of transthyretin amyloidosis and their diagnostic value in cardiology: A comprehensive review.

Background Disease-modifying therapies for hereditary transthyretin (ATTRv) amyloidosis necessitate sensitive, multi-organ assessment tools capturing early disease manifestations across heterogeneous phenotypes. We developed and validated the modified-comprehensive Kumamoto Score (mKS). Methods This prospective validation study enrolled 76 genetically confirmed ATTRv amyloidosis patients. The mKS comprises four organ-specific subscales: peripheral neuropathy (mKS-PN, 0–258), cardiomyopathy (mKS-CM, 0–195), eye (mKS-E, 0–60) and central nervous system (CNS) involvement (mKS-CNS, 0–45); total range 0–558. Construct validity was primarily assessed through Spearman’s correlations with established clinical scores, objective biomarkers and patient-reported quality of life. Results The median patient age was 56.2 years; 60.5% had Val30Met (p.Val50Met) mutations. The mKS demonstrated strong validity with established scores (Kumamoto Score (KS): ρ = 0.798; Neuropathy Impairment Score (NIS): ρ = 0.791; both p < .001) and quality of life (EuroQol 5-Dimension 5-Level (EQ-5D-5L): ρ = −0.731, p < .001). Organ-specific subscales demonstrated strong construct validity: mKS-PN correlated strongly with NIS (ρ = 0.906) and neurophysiological parameters (peroneal CMAP (compound muscle action potential): ρ = −0.819; tibial CMAP: ρ = −0.801); mKS-CM correlated strongly with cardiac biomarkers (B-type natriuretic peptide, BNP: ρ = 0.776; high-sensitivity troponin T (hs-TnT): ρ = 0.712) and imaging parameters (extracellular volume fraction (ECV): ρ = 0.743; interventricular septum thickness in diastole (IVSTd): ρ = 0.716). Subscale intercorrelations were weak (ρ = 0.155–0.381), confirming independent organ assessment. Conclusions The mKS provides a validated comprehensive assessment tool for ATTRv amyloidosis with enhanced early-stage sensitivity and independent organ-specific subscales, addressing critical unmet needs in the era of disease-modifying therapies.

Among cardiac storage diseases, amyloidosis has emerged as a common cause of heart failure (HF), particularly in older people: it is diagnosed in up to 13-19% of patients with heart failure and preserved ejection fraction. Current treatments for transthyretin amyloidosis (ATTR) focus on stopping the misfolding of the TTR protein or reducing TTR production and treating the symptoms with cardiac medication, while systemic chemotherapy is the focus for light-chain amyloidosis (AL). New fibril clearance agents and gene therapies are currently in development. In addition to clinical and laboratory observations, multimodal imaging is essential for the monitoring of the effects of treatment on the progression of heart disease, but it is not yet included in established staging systems. This narrative review collects current multimodal imaging parameters that have been evaluated in clinical trials to assess the progression of cardiac amyloidosis and used in phase III intervention studies. These evolving findings are compared with current consensus recommendations to identify gaps in knowledge for specific imaging modalities, particularly cardiac MRI. Ultimately, the goal should be to standardize imaging of disease progression in cardiac amyloidosis so that the therapeutic effects of new pharmacological treatment options can be compared with the current standard of care.