Amyloid-Journal of Protein Folding Disorders最新文献

{"title":"RNA-based full length immunoglobulin light chain sequencing reveals lambda constant domain mutations with potential implications for thermodynamic stability in light chain amyloidosis.","authors":"Eyad Naser, Sara Oubari, Josefine Jakob, Björn Häupl, Bettina Budeus, Bernd Walkenfort, Melanie Nowakowski, Gabriele Hessler, Claudine Kühn, Mike Hasenberg, Thomas Oellerich, Hans Christian Reinhardt, Alexander Carpinteiro","doi":"10.1080/13506129.2026.2679153","DOIUrl":"10.1080/13506129.2026.2679153","url":null,"abstract":"<p><strong>Background: </strong>Systemic light chain amyloidosis is a protein misfolding disorder characterized by deposition of clonal immunoglobulin light chains in vital organs. To date, little is known about the contribution of light chain constant domain mutations in thermodynamic stability and amyloidogenicity.</p><p><strong>Methods: </strong>In 89 patients, RNA-based full-length light chain repertoire sequencing with Oxford Nanopore was performed, in addition to Illumina sequencing and mass spectrometric detection of light chain protein in serum and amyloid deposits. Computational methods for conservation, free energy calculation and molecular dynamics simulations were applied to investigate the thermodynamic stability.</p><p><strong>Results: </strong>Monoclonal light chain detection rate was 95.4%, and sequences showed 100% identity with Illumina in all patients. Light chain protein was specifically detectable by mass spectrometry in serum and amyloid deposits. Lambda constant domain mutations were present in 10%, while no kappa constant domain mutations were detected. Fold free energy change and molecular dynamics simulations indicate potential light chain stabilizing or destabilizing effects of detected constant domain mutations.</p><p><strong>Conclusion: </strong>Current findings highlight the importance of routinely implementing full-length light chain sequencing in plasma cell dyscrasias, particularly light chain amyloidosis to account for the potential impact of constant domain mutations on light chain stability and amyloidogenicity.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"381-395"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term efficacy and safety of vutrisiran in hereditary transthyretin amyloidosis with polyneuropathy: final analysis of the HELIOS-A randomized treatment extension.","authors":"Cécile Cauquil, David Adams, Julian Gillmore, Alejandra Gonzalez-Duarte, Michelle Mezei, Laura Obici, Yoshiki Sekijima, Weizhi Zhao, Katherine Boyle, Prajakta Badri, Marianne Sweetser, Colleen Moffitt, Márcia Waddington-Cruz","doi":"10.1080/13506129.2026.2685666","DOIUrl":"10.1080/13506129.2026.2685666","url":null,"abstract":"<p><strong>Background: </strong>The long-term efficacy and safety of vutrisiran in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) were assessed in the HELIOS-A randomized treatment extension (RTE).</p><p><strong>Methods: </strong>Patients who completed the 18-month, phase 3, open-label HELIOS-A study could enter an open-label RTE with re-randomization 1:1 to vutrisiran 25 mg every 3 months (Q3M) or 50 mg every 6 months (Q6M; transitioned to 25 mg Q3M following an amendment) for up to 42 months (RTE M18 efficacy assessment; RTE M42 safety and transthyretin (TTR) levels).</p><p><strong>Results: </strong>In the RTE, 149 patients were re-randomized to vutrisiran (25 mg Q3M [<i>n</i> = 76]; 50 mg Q6M [<i>n</i> = 73]). Mean serum TTR reduction from study baseline at RTE M42 for the total vutrisiran group was 84.5%. Efficacy was sustained from RTE baseline through RTE M18 in modified Neuropathy Impairment Score +7, Norfolk Quality of Life-Diabetic Neuropathy score, 10-meter walk test, Rasch-built Overall Disability Scale and modified body mass index (mBMI); most patients (67.8%) had stable polyneuropathy disability scores. Most AEs were mild/moderate in severity with no new safety concerns.</p><p><strong>Conclusions: </strong>Results from the HELIOS-A RTE demonstrate relative stability with only modest changes in disease activity, sustained serum TTR reductions, and an acceptable safety profile with long-term vutrisiran treatment in patients with ATTRv-PN.</p><p><p>ClinicalTrials.gov: NCT03759379.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"356-367"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148254339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the yield index of genetic counselling for first-degree relatives of patients with hereditary transthyretin cardiac amyloidosis.","authors":"Bérénice Hébrard, Francois Sauer, Julie Pompougnac, Ariane Lunati-Rozie, Silvia Oghina, Arnault Galat, Amira Zaroui, Mounira Kharoubi, Marina Konyukh, Pascale Fanen, Sophie Mallet, Benoit Funalot, Thibaud Damy","doi":"10.1080/13506129.2026.2669751","DOIUrl":"10.1080/13506129.2026.2669751","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"426-430"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147950221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient focal neurological episodes in hereditary transthyretin-related amyloidosis treated with liver transplantation: electroencephalographic insights and clinical features.","authors":"Gonçalo Videira, João Moura, Joel Freitas, Cristina Alves, Márcio Neves Cardoso, Ana Paula Sousa, Miguel Mendonça Pinto, Diogo Pereira, Luísa Sousa, Sara Cavaco, Teresa Coelho","doi":"10.1080/13506129.2026.2676845","DOIUrl":"10.1080/13506129.2026.2676845","url":null,"abstract":"<p><strong>Background: </strong>Hereditary transthyretin-related (ATTRv) amyloidosis may involve the central nervous system (CNS) years after liver transplantation, causing transient focal neurological episodes (TFNEs). Their mechanisms and electrophysiological correlates remain unclear.</p><p><strong>Methods: </strong>We retrospectively analyzed 155 patients with ATTRV30M (p.V50M) amyloidosis patients who underwent liver transplantation and had at least one electroencephalogram (EEG). TFNEs were categorized into five clinical subtypes. EEGs from outpatient and hospital settings were included.</p><p><strong>Results: </strong>TFNEs occurred in 76.8% of patients, most commonly as seizure-like (37.0%), transient ischemic attack-like (25.2%) or migraine-like (24.4%) episodes. Stroke-like TFNEs and bilateral tonic-clonic seizures were rarely the initial presentation (13.4%). Anti-seizure medications were prescribed to 77.3% of patients with TFNEs and 26.9% required two or more drugs. Focal slow EEG activity was detected in 40.0% of patients and was associated with TFNEs (OR = 2.91) and reduced survival (HR = 2.18). During acute TFNEs, focal slowing predominated, whereas epileptiform patterns were infrequent (19.5%). Cognitive impairment correlated with posterior dominant rhythm slowing and focal slow activity, particularly in language and executive domains.</p><p><strong>Conclusions: </strong>TFNEs are common after liver transplantation in ATTRv amyloidosis. Focal slow EEG activity may indicate advanced CNS amyloid deposition, cognitive impairment and poorer prognosis.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"337-348"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of the modified-comprehensive Kumamoto Score: a multi-organ assessment tool for hereditary transthyretin amyloidosis.","authors":"Shiori Yamakawa, Toshiya Nomura, Yohei Misumi, Tomoaki Taguchi, Keiichi Nakahara, Masayoshi Tasaki, Naoto Kuyama, Hiroki Usuku, Yasuhiro Izumiya, Yuji Takihara, Emre Aldinc, Konen Obayashi, Toshihiro Inoue, Kenichi Tsujita, Yukio Ando, Mitsuharu Ueda","doi":"10.1080/13506129.2026.2649884","DOIUrl":"10.1080/13506129.2026.2649884","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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): <i>ρ</i> = 0.798; Neuropathy Impairment Score (NIS): <i>ρ</i> = 0.791; both <i>p</i> < .001) and quality of life (EuroQol 5-Dimension 5-Level (EQ-5D-5L): <i>ρ</i> = -0.731, <i>p</i> < .001). Organ-specific subscales demonstrated strong construct validity: mKS-PN correlated strongly with NIS (<i>ρ</i> = 0.906) and neurophysiological parameters (peroneal CMAP (compound muscle action potential): <i>ρ</i> = -0.819; tibial CMAP: <i>ρ</i> = -0.801); mKS-CM correlated strongly with cardiac biomarkers (B-type natriuretic peptide, BNP: <i>ρ</i> = 0.776; high-sensitivity troponin T (hs-TnT): <i>ρ</i> = 0.712) and imaging parameters (extracellular volume fraction (ECV): <i>ρ</i> = 0.743; interventricular septum thickness in diastole (IVSTd): <i>ρ</i> = 0.716). Subscale intercorrelations were weak (<i>ρ</i> = 0.155-0.381), confirming independent organ assessment.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"309-319"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147596129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical impact of lilac-colored aggregates on may-Grünwald-Giemsa-stained bone marrow smears in patients with amyloid light-chain amyloidosis.","authors":"Ayaka Kodama, Ritsuko Nakagoshi, Ryuto Oshita, Suzuho Onagi, Satoshi Fujimura, Yuka Takezawa, Nagaaki Katoh, Yoshiki Sekijima, Masahide Yazaki, Yumiko Higuchi","doi":"10.1080/13506129.2026.2639830","DOIUrl":"10.1080/13506129.2026.2639830","url":null,"abstract":"<p><strong>Background: </strong>Lilac-colored aggregates (LicAGs) are often observed on bone marrow (BM) aspirate smears stained with May-Grünwald-Giemsa (MG) in patients with amyloid light-chain (AL) amyloidosis. However, the clinicopathological features of LicAGs observed on MG-stained BM smears remain poorly understood.</p><p><strong>Methods: </strong>We examined MG-stained BM aspirate smears and clinical data from 103 patients with AL amyloidosis. To determine whether LicAGs represented amyloid, LicAG-positive specimens were decolorized, re-stained with Congo red, and examined under polarized light. Patients were grouped based on the presence or absence of LicAGs, and their clinical characteristics were compared. Serial changes in LicAG counts following therapy were assessed in two cases.</p><p><strong>Results: </strong>Of the 103 patients, 20 showed LicAGs (BM[+] group), confirmed as amyloid fibrils using Congo red staining. Compared to the BM(-) group, the BM(+) group had higher proportions of κ-type amyloid, liver and tongue involvement, and negative monoclonal immunoglobulin on immunofixation electrophoresis. LicAG counts decreased on serial BM examinations in two patients after treatment.</p><p><strong>Conclusions: </strong>LicAGs are amyloid fibrils, indicating their potential significance in AL amyloidosis, especially when monoclonal immunoglobulins are undetectable. They may also serve as indicators of organ involvement and as surrogate markers for treatment response.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"299-308"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidelines for the management of hereditary ATTR amyloidosis 2026.","authors":"Yoshiki Sekijima, Mitsuharu Ueda, John L Berk, Laura Obici, Ronald M Witteles, Violaine Planté-Bordeneuve, Markus Weiler, Marianna Fontana, Márcia Waddington Cruz, Teresa Coelho, Bo-Göran Ericzon, Pablo Garcia-Pavia, João Beirão, Jonas Wixner, Luísa Lobato, Yukio Ando, Giampaolo Merlini, Mathew S Maurer","doi":"10.1080/13506129.2026.2695368","DOIUrl":"10.1080/13506129.2026.2695368","url":null,"abstract":"<p><p>The pathogenesis of hereditary ATTR (ATTRv) amyloidosis has been elucidated, and disease-modifying drugs with multiple mechanisms of action are used clinically. The International Society of Amyloidosis (ISA) guidelines strongly recommend treating ATTRv amyloidosis patients with transthyretin (TTR) tetramer stabilizers or <i>TTR</i> gene silencers (e.g. small-interfering RNA, antisense oligonucleotide). Tafamidis and vutrisiran are indicated for both polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTR-CM), patisiran, eplontersen and diflunisal are for ATTRv-PN only, and acoramidis is for ATTR-CM only. Eligibility for treatment varies by country and is heterogeneous. These disease-modifying drugs are most effective before significant end-organ dysfunction has ensued, making early diagnosis of ATTRv amyloidosis essential. With multiple treatment options existing, it is important to accumulate evidence regarding treatment selection, switching and combination therapy. The currently available disease-modifying therapeutics have a limited effect on central nervous system (CNS) and ocular manifestations since they target either blood circulating TTR from the liver or ATTR amyloid fibrils misfolding in the blood and depositing in systemic (non-CNS, non-ocular) tissues. Development of disease-modifying therapies for CNS and ocular ATTR amyloidosis is an urgent unmet medical need.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"247-272"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of diflunisal for hereditary transthyretin amyloidosis: the Swedish real-world experience.","authors":"John L Berk, Kevin J Carroll, Jorge Mejia Baranda, Björn Pilebro, Kristin Samuelsson, Per Eldhagen, Jonas Wixner","doi":"10.1080/13506129.2026.2678340","DOIUrl":"10.1080/13506129.2026.2678340","url":null,"abstract":"<p><strong>Background: </strong>Diflunisal has been shown to slow the progression of hereditary transthyretin (ATTRv) amyloidosis. We examined the efficacy of diflunisal using data from SveATTR, a longitudinal Swedish registry open for patients with ATTR amyloidosis.</p><p><strong>Methods: </strong>Data from diflunisal treated patients registered in SveATTR through Dec 2022 were included. Available data on Kumamoto score, PND score/FAP stage, mBMI, NYHA classification and Karnofsky performance status were analyzed using random coefficients mixed effects modeling, and the results were combined with those of the pivotal diflunisal trial.</p><p><strong>Results: </strong>In total, 118 registry subjects were included. Estimated mean time of diflunisal therapy was 3.4 (range 0.1 to 10.2) years. Random coefficients mixed effects modeling demonstrated gradual progression of disease over time by upward trend of Kumamoto score, PND score and FAP stage, and downward trend in Karnofsky score and mBMI while NYHA class score remained unchanged. A Bayesian augmentation analysis was undertaken using registry data and pivotal trial data. After 24 months, the probability of superiority for diflunisal over placebo was 99.6% and 97.2% for Kumamoto score and mBMI, respectively.</p><p><strong>Conclusions: </strong>SveATTR registry data align with the results of the pivotal trial, providing long-term real-world evidence that confirm the efficacy of diflunisal for ATTRv amyloidosis.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"349-355"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148152217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerated apolipoprotein A-II senile amyloidosis in a plasminogen activator inhibitor-1 knock-out model.","authors":"Gilles R Codo, Pauline Duchatelet, Gemma Martinez-Rivas, Alessio Lampis, Karolina Weronika Świderska, Emilie Pinault, Camille Cohen, Magali Colombat, Sebastien Bender, Christophe Sirac","doi":"10.1080/13506129.2026.2661603","DOIUrl":"10.1080/13506129.2026.2661603","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"439-443"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Left atrial strain identifies early cardiac involvement in variant transthyretin amyloidosis.","authors":"Matteo Serenelli, Elisa Gardini, Stefania Marazia, Alessandro Barbarossa, Alberto Cipriani, Anna Cantone, Beatrice Dal Passo, Federico Sanguettoli, Rita Pavasini, Matteo Arzenton, Gianluca Campo, Andrea Zaccaro, Emiliano Rossi, Gioele Fabbri, Enrico Monti, Carmine Pizzi, Erika Pedio, Federico Guerra, Giulio Sinigiani, Alberto Aimo, Michele Emdin, Francesco Cappelli, Federica Colio, Simone Longhi","doi":"10.1080/13506129.2026.2663922","DOIUrl":"10.1080/13506129.2026.2663922","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"421-425"},"PeriodicalIF":5.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}