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Pillai AA, Frishman WH, Aronow WS. Antibody ALXN2220 (Formerly NI006) for the Treatment of Transthyretin Cardiac Amyloidosis. Cardiol Rev 2025:00045415-990000000-00472. [PMID: 40262023 DOI: 10.1097/crd.0000000000000934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
Transthyretin cardiac amyloidosis is an increasingly recognized infiltrative cardiomyopathy that is implicated in a growing number of cases of heart failure. Although it was once considered a disease without a cure, there have been rapid advances in pharmacotherapy over recent decades. The agents currently approved by the United States Food and Drug Administration-tafamidis and acoramidis-are transthyretin stabilizers that prevent the breakdown of the physiologic transthyretin tetramer into fibril-forming monomers. While these agents help prevent disease progression, they do not reverse existing disease. ALXN2220 (previously called NI006) addresses this unmet need. A recombinant human IgG1 monoclonal antibody with high specificity for transthyretin monomers and amyloid fibrils, ALXN2220 stimulates macrophage-mediated phagocytosis of deposited amyloid fibrils. Phase 1 studies have demonstrated the tolerability of doses ranging from 0.3 to 60 mg/kg/month. At doses higher than 10 mg/kg/month, ALXN2220 has demonstrated the ability to decrease cardiac tracer uptake on scintigraphy and decrease the extracellular volume on cardiac magnetic resonance imaging at 4 and 12 months when compared with placebo. These imaging parameters are known surrogates for the burden of cardiac amyloid deposition. In addition, significant reductions in levels of n-terminal proBNP and troponin T, as well as improvements in Kansas City Cardiomyopathy Questionnaire scores were also noted. The adverse effect and immunogenicity profiles were encouraging as well. A multinational, placebo-controlled phase 3 trial (DepleTTR-CM) is ongoing to assess long-term efficacy, functional outcomes, and survival impact. These results are expected to provide critical real-world evidence on ALXN2220's role in transthyretin cardiac amyloidosis management.
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Affiliation(s)
- Ashwin A Pillai
- From the Department of Medicine, University of Connecticut School of Medicine, Hartford, CT
| | | | - Wilbert S Aronow
- Departments of Cardiology and Medicine, Westchester Medical Center, and New York Medical College, Valhalla, NY
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Yek J, Chan S, Tay SM, Tan S. Dilemmas and Challenges in the Anesthetic Management of Liver Transplantation for Transthyretin Amyloidosis in the Asian Context: A Case Report. Cureus 2025; 17:e82784. [PMID: 40406766 PMCID: PMC12097723 DOI: 10.7759/cureus.82784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2025] [Indexed: 05/26/2025] Open
Abstract
Transthyretin (TTR) amyloidosis is a progressive, debilitating, and eventually fatal disease that is under-recognized and underdiagnosed in Asian patients. Liver transplantation is performed in patients with hereditary transthyretin amyloidosis to remove the source of abnormal transthyretin production to slow disease progression. There is uncertainty about the risk-benefit ratio due to the less favourable five-year survival of liver transplantation for Asian patients with non-Val30Met transthyretin amyloidosis, as the heterogeneity of non-Val30Met mutations and the potential for disease progression despite transplantation can make transplant outcomes unpredictable. Additionally, limited access and the prohibitive costs of disease-modifying therapies may influence the decision-making process with regard to liver transplantation. We present a case of a 57-year-old male with Ala117Ser TTR amyloidosis and clinical manifestations of polyneuropathy, cardiac amyloidosis, and autonomic neuropathy. He received a living-related liver transplant. We describe the dilemmas and challenges in the anesthetic planning and management of this patient. Along with limited scientific data on liver transplantation for non-Val30Met TTR amyloidosis patients, we faced challenges in the management of intraoperative tachyarrhythmias, which eventually necessitated the use of a relatively contraindicated drug, verapamil, to achieve rate control. The lack of specific data meant that we had to base some decisions on practical wisdom.
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Affiliation(s)
- Jacklyn Yek
- Division of Anaesthesiology and Perioperative Medicine, Singapore General Hospital, Singapore, SGP
| | - Steffi Chan
- Division of Anaesthesiology and Perioperative Medicine, Singapore General Hospital, Singapore, SGP
| | - Sook Muay Tay
- Division of Anaesthesiology and Perioperative Medicine, Singapore General Hospital, Singapore, SGP
| | - Selene Tan
- Division of Anaesthesiology and Perioperative Medicine, Singapore General Hospital, Singapore, SGP
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Junqueira B, Mestre C. Iatrogenic Amyloid Polyneuropathy Following Domino Liver Transplantation: A Case Report. Cureus 2024; 16:e53605. [PMID: 38449948 PMCID: PMC10915902 DOI: 10.7759/cureus.53605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2024] [Indexed: 03/08/2024] Open
Abstract
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary disorder. In Portugal, it is mainly linked to transthyretin (TTR) mutation, and patients present with length-dependent sensory-motor polyneuropathy, often accompanied by autonomic dysfunction. Treatment options for FAP include liver transplant, and due to the lack of organs, FAP livers began being implanted in patients with severe liver disease in a process known as domino liver transplantation (DLT). We report a case of a 68-year-old Portuguese man, with post-hepatitis C-related cirrhosis liver transplantation, who presented to his family doctor with decreased sensitivity in both feet and weight loss, which were initially attributed to diabetic neuropathy and an adjustment in diabetic medication, respectively. Symptoms evolved to changes in both feet's thermal and painful sensitivity, reduced sensitivity in both hands, diarrhea, and progressive weight loss. At this time, the patient's disclosure of receiving a DLT prompted the correct diagnosis of iatrogenic amyloid polyneuropathy. This case underscores the challenges in diagnosing and managing iatrogenic amyloid polyneuropathy following DLT, highlighting the importance of prompt identification of DLT recipients, active vigilance of these patients via structured monitoring, and increased healthcare providers' awareness of this practice so that early signs of the disease may be recognized.
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Affiliation(s)
- Bárbara Junqueira
- Family Health Unit Cartaxo Terra Viva, Regional Health Administration of Lisbon and Tagus Valley, Cartaxo, PRT
| | - Carlos Mestre
- Family Health Unit Cartaxo Terra Viva, Regional Health Administration of Lisbon and Tagus Valley, Cartaxo, PRT
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Casasnovas C, Lladó L, Borrachero C, Pérez-Santamaría PV, Muñoz-Beamud F, Losada-López IA, Baliellas-Comellas MC, González-Moreno J. A narrative review and expert recommendations on the assessment of the clinical manifestations, follow-up, and management of post-OLT patients with ATTRv amyloidosis. Ther Adv Neurol Disord 2023; 16:17562864231191590. [PMID: 37655225 PMCID: PMC10467168 DOI: 10.1177/17562864231191590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 07/17/2023] [Indexed: 09/02/2023] Open
Abstract
Orthotopic liver transplantation (OLT) was the first treatment able to modify the natural course of hereditary transthyretin (ATTRv) amyloidosis, which is a rare and fatal disorder caused by the accumulation of misfolded transthyretin (TTR) variants in different organs and tissues and which leads to a progressive and multisystem dysfunction. Because the liver is the main source of TTR, OLT dramatically reduces the production of the pathogenic TTR variant, which should prevent amyloid formation and halt disease progression. However, amyloidosis progression may occur after OLT due to wild-type TTR deposition, especially in the nerves and heart. In this review, we discuss the disease features influencing OLT outcomes and the clinical manifestations of ATTRv amyloidosis progression post-OLT to improve our understanding of disease worsening after OLT and optimize the follow-up and clinical management of these patients. By conducting a literature review on the PubMed database, we identified patient characteristics that have been associated with worse post-OLT outcomes, including late-onset V50M and non-V50M variants, age >40 years, long disease duration, advanced neuropathy and autonomic dysfunction, and malnutrition. Regarding post-OLT mortality, deaths occurring within the first year after OLT were mainly associated with fatal graft complications and infectious diseases, whereas cardiovascular-related deaths usually occurred later. Considering the diverse clinical manifestations of ATTRv amyloidosis progression post-OLT, including worsening neuropathy and/or cardiomyopathy, autonomic dysfunction, and oculoleptomeningeal involvement, we present advice on the most relevant tests for assessing disease progression post-OLT. Finally, we discuss the use of new therapies based on TTR stabilizers and TTR mRNA silencers for the treatment of ATTRv amyloidosis patients post-OLT.
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Affiliation(s)
- Carlos Casasnovas
- Neuromuscular Unit, Department of Neurology, Bellvitge University Hospital-IDIBELL, C/ Feixa Llarga s/n, 08906 l’Hospitalet de Llobregat, Barcelona, Spain
| | - Laura Lladó
- Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, Barcelona, Spain
| | - Cristina Borrachero
- ATTRv Unit, Department of Internal Medicine, Juan Ramón Jiménez Hospital, Huelva, Spain
| | | | | | | | | | - Juan González-Moreno
- Department of Internal Medicine, Son Llàtzer University Hospital, Palma de Mallorca, Spain
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Wang S, Peng W, Pang M, Mao L, Peng D, Yu B, Wu S, Hu D, Yang Y, He J, Ouyang M. Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China. Front Cardiovasc Med 2022; 9:900313. [PMID: 35833187 PMCID: PMC9271707 DOI: 10.3389/fcvm.2022.900313] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 06/07/2022] [Indexed: 01/15/2023] Open
Abstract
Background Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is a genotypically heterogeneous disorder with a poor prognosis. There is limited literature describing the variants responsible for ATTRv in areas outside the United State, the United Kingdom and Europe. This study was performed to describe the clinical characteristics and genotypic profiles of this disease in South China. Methods This was a single-center retrospective study that evaluated 29 patients with a confirmed diagnosis of hereditary transthyretin amyloid cardiomyopathy enrolled from January 2016 to November 2021. Results 93.1% patients were male and the median age of symptom onset was 53 (46, 62.5) years old. The initial manifestations of ATTR-CM were cardiovascular symptoms (55.2%), neuropathy (41.4%) and vitreous opacity (3.4%). Phenotypes at diagnosis were mixed (82.8%), predominant cardiac (6.9%), neurological (6.9%) and ophthalmic (3.4%). Poor R-wave progression (41%), pseudo-infarct (31%) and low-voltage (31%) patterns were common findings on electrocardiogram. Unexplained increased wall thickness was observed in all 29 patients, with mean septal and posterior wall thicknesses of 14.25 ± 6.26 mm and 15.34 ± 2.84 mm, respectively. Diastolic dysfunction was also seen in all 29 patients, and 17 (58%) had a restrictive fill pattern at diagnosis. Nine different missense mutations of the TTR gene were found in 29 patients from 23 families, with c.349G>T (p.Ala117Ser) the most common mutation. The median survival time after diagnosis was 47.6 (95% CI 37.9-57.4) months, with 1, 3 and 5-year survival rates of 91.2%, 74% and 38% respectively. Patients with advanced heart failure (National Amyloidosis Staging stage II/III) had worse survival than stage I [Breslow (Generalized Wilcoxon), χ2 = 4.693, P = 0.03)]. Conclusions ATTR amyloidosis genotypes and phenotypes are highly heterogeneous. Advanced heart failure predicts a poor prognosis. Understanding the different clinical profiles of ATTR cardiac amyloidosis with different genotype is important to its early recognition.
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Affiliation(s)
- Shuai Wang
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Wenke Peng
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Min Pang
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling Mao
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Daoquan Peng
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Bilian Yu
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Sha Wu
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Die Hu
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yang Yang
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jia He
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
| | - Mingqi Ouyang
- Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China
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Clinical Implication of Genetic Testing in Dilated Cardiomyopathy. INTERNATIONAL JOURNAL OF HEART FAILURE 2022; 4:1-11. [PMID: 36262197 PMCID: PMC9383343 DOI: 10.36628/ijhf.2021.0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/29/2021] [Accepted: 10/15/2021] [Indexed: 11/18/2022]
Abstract
Dilated cardiomyopathy (DCM) is one of the important causes of heart failure (HF). With the rapidly evolving technologies for gene analysis and tremendous advances in knowledge of HF genetics, the importance of genetic testing in DCM is currently highlighted. Several genetic variants causing DCM have been identified and this information is used for diagnosis, risk stratification and family screening of DCM patients. However, there are still several challenges in applying genetic testing to real clinical practice. In this review, we will summarize recent understandings in DCM genetics and provide an evidence-based practical guide to the use of genetic testing for DCM patients.
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Capustin M, Frishman WH. Transthyretin Cardiac Amyloidosis and Novel Therapies to Treat This Not-so-rare Cause of Cardiomyopathy. Cardiol Rev 2021; 29:263-273. [PMID: 34397539 DOI: 10.1097/crd.0000000000000387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Transthyretin cardiac amyloidosis (ATTR-CA) is typically a late-onset disease caused by the deposit of transthyretin amyloid fibrils throughout the heart. When this occurs, various cardiac sequelae can develop, including hypotension, conduction abnormalities, and valvular lesions. The cardiomyopathy caused by ATTR-CA (ATTR-CM) has proven difficult to treat. Until recently, symptomatic management was the only therapeutic option, and many therapies used to treat congestive heart failure were ineffective or even detrimental to patients with ATTR-CM. In addition, treatment was limited to heart and liver transplantation. As a result, prognosis was poor. Recently, a few drug therapies have come to light as potential treatment modalities for ATTR-CM, most notably tafamidis, sold under the brand names Vyndaqel and Vyndamax. After the phase III Transthyretin Amyloidosis Cardiomyopathy trial displayed the drug's efficacy, it was given breakthrough therapy designation and was approved by the Food and Drug Administration on May 6, 2019, for the treatment of ATTR-CA. This novel therapy, as well as various other therapies in the pipeline, such as inotersen and patisiran, provide hope where, until recently, there was little. Unfortunately, the exorbitant cost of these new therapies may present a barrier to long-term treatment for some patients. However, by further improving diagnostic algorithms and incorporating these new treatments into our existing therapeutic modalities, patients with ATTR-CA should be able to live far longer than previously expected. Finally, further research combining these novel treatment modalities must be done, as they may prove to be additive or even synergistic in their treatment of ATTR amyloidosis.
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Affiliation(s)
- Matthew Capustin
- From the Department of Medicine, Zucker School of Medicine/Northwell Northshore-Long Island Jewish Medical Center, Manhasset, NY
| | - William H Frishman
- Department of Medicine and Cardiology, New York Medicine and Westchester Medical Center, Valhalla, NY
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Rahman MM, Schmuck B, Hansson H, Härd T, Westermark GT, Sandgren M. Enhanced detection of ATTR amyloid using a nanofibril-based assay. Amyloid 2021; 28:158-167. [PMID: 33583280 DOI: 10.1080/13506129.2021.1886072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
More than 30 proteins and peptides have been found to form amyloid fibrils in human diseases. Fibrils formed by transthyretin (TTR) are associated with ATTR amyloidosis, affecting many vital organs, including the heart and peripheral nervous system. Congo red staining is the gold standard method for detection of amyloid deposits in tissue. However, Congo red staining and amyloid typing methods such as immunofluorescence labelling are limited to relatively large deposits. Detection of small ATTR deposits present at an early stage of the disease could enable timely treatment and prevent severe tissue damage. In this study, we developed an enhanced ATTR amyloid detection method that uses functionalised protein nanofibrils. Using this method, we achieved sensitive detection of monomeric TTR in a microplate immunoassay and immunofluorescence labelling of ex vivo tissue from two patients containing ATTR aggregates. The system's utility was confirmed on sections from a patient with AA amyloidosis and liver sections from inflamed mouse. These results suggest that the detection system constitutes important new technology for highly sensitive detection of microscopic amounts of ATTR amyloid deposited in tissue.
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Affiliation(s)
- M Mahafuzur Rahman
- Department of Molecular Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala BioCenter, Uppsala, Sweden
| | - Benjamin Schmuck
- Department of Molecular Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala BioCenter, Uppsala, Sweden
| | - Henrik Hansson
- Department of Molecular Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala BioCenter, Uppsala, Sweden
| | - Torleif Härd
- Department of Molecular Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala BioCenter, Uppsala, Sweden
| | | | - Mats Sandgren
- Department of Molecular Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala BioCenter, Uppsala, Sweden
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Adam RD, Coriu D, Jercan A, Bădeliţă S, Popescu BA, Damy T, Jurcuţ R. Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature. ESC Heart Fail 2021; 8:2380-2396. [PMID: 34089308 PMCID: PMC8318516 DOI: 10.1002/ehf2.13443] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Cardiac amyloidosis is a restrictive cardiomyopathy determined by the accumulation of amyloid, which is represented by misfolded protein fragments in the cardiac extracellular space. The main classification of systemic amyloidosis is determined by the amyloid precursor proteins causing a very heterogeneous disease spectrum, but the main types of amyloidosis involving the heart are light chain (AL) and transthyretin amyloidosis (ATTR). AL, in which the amyloid precursor is represented by misfolded immunoglobulin light chains, can involve almost any system carrying the worst prognosis among amyloidosis patients. This has however dramatically improved in the last few years with the increased usage of the novel therapies such as proteasome inhibitors and haematopoietic cell transplantation, in the case of timely diagnosis and initiation of treatment. The treatment for AL is directed by the haematologist working closely with the cardiologist when there is a significant cardiac involvement. Transthyretin (TTR) is a protein that is produced by the liver and is involved in the transportation of thyroid hormones, especially thyroxine and retinol binding protein. ATTR results from the accumulation of transthyretin amyloid in the extracellular space of different organs and systems, especially the heart and the nervous system. Specific therapies for ATTR act at various levels of TTR, from synthesis to deposition: TTR tetramer stabilization, oligomer aggregation inhibition, genetic therapy, amyloid fibre degradation, antiserum amyloid P antibodies, and antiserum TTR antibodies. Treatment of systemic amyloidosis has dramatically evolved over the last few years in both AL and ATTR, improving disease prognosis. Moreover, recent studies revealed that timely treatment can lead to an improvement in clinical status and in a regression of amyloid myocardial infiltration showed by imaging, especially by cardiac magnetic resonance, in both AL and ATTR. However, treating cardiac amyloidosis is a complex task due to the frequent association between systemic congestion and low blood pressure, thrombo-embolic and haemorrhagic risk balance, patient frailty, and generally poor prognosis. The aim of this review is to describe the current state of knowledge regarding cardiac amyloidosis therapy in this constantly evolving field, classified as treatment of the cardiac complications of amyloidosis (heart failure, rhythm and conduction disturbances, and thrombo-embolic risk) and the disease-modifying therapy.
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Affiliation(s)
- Robert Daniel Adam
- Department of CardiologyEmergency Institute for Cardiovascular Diseases ‘Prof. Dr. C. C. Iliescu’3rd Cardiology Department, 258 Fundeni StreetBucharest022328Romania
- University of Medicine and Pharmacy ‘Carol Davila’BucharestRomania
| | - Daniel Coriu
- University of Medicine and Pharmacy ‘Carol Davila’BucharestRomania
- Department of HematologyFundeni Clinical InstituteBucharestRomania
| | - Andreea Jercan
- University of Medicine and Pharmacy ‘Carol Davila’BucharestRomania
| | - Sorina Bădeliţă
- Department of HematologyFundeni Clinical InstituteBucharestRomania
| | - Bogdan A. Popescu
- Department of CardiologyEmergency Institute for Cardiovascular Diseases ‘Prof. Dr. C. C. Iliescu’3rd Cardiology Department, 258 Fundeni StreetBucharest022328Romania
- University of Medicine and Pharmacy ‘Carol Davila’BucharestRomania
| | - Thibaud Damy
- French Referral Center for Cardiac AmyloidosisAmyloidosis Mondor NetworkCréteilFrance
- Department of CardiologyHenri Mondor Hospital/AP‐HPCréteilFrance
| | - Ruxandra Jurcuţ
- Department of CardiologyEmergency Institute for Cardiovascular Diseases ‘Prof. Dr. C. C. Iliescu’3rd Cardiology Department, 258 Fundeni StreetBucharest022328Romania
- University of Medicine and Pharmacy ‘Carol Davila’BucharestRomania
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Lopes A, Fonseca I, Sousa A, Rodrigues C, Branco M, Coelho T, Sequeiros J, Freitas P. Psychopathological dimensions in subjects with hereditary ATTR V30M amyloidosis and their relation with life events due to the disease. Amyloid 2018; 25:26-36. [PMID: 29357699 DOI: 10.1080/13506129.2018.1428795] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND Chronic physical illness has been associated with emotional distress. Chronic diseases may change usual family patterns with economic, social and family losses. Hereditary ATTR V30M amyloidosis is a rare, fatal inherited systemic amyloidosis, with chronic evolution and beginning in adulthood. AIMS AND METHODS To evaluate psychopathological dimensions and how they correlated with disease-related life events, 209 symptomatic and asymptomatic carriers, participated in the study. Sociodemographic and Family and Personal History Disease questionnaires and brief symptom inventory (BSI) were applied. RESULTS BSI indices, global severity index (GSI), positive symptom index (PSI) and positive symptom total (PST) scored higher than general population. Independent predictors for GSI >0.83 were female sex (OR = 3.46, p = .005) and being symptomatic carriers (OR = 3.03, p = .039). Independent predictors of a PST >26.99 were female sex (OR = 3.74, p = .012) symptomatic carrier (OR = 5.32, p = .025), age between 15 and 24 years at affected parent's death (OR = 5.26, p = .04). Independent predictors of a PSI >1.56 were being asymptomatic carrier (OR = 6.3, p = .036); to have children (OR = 3.19, p = .043) and have ≤14 years at parent's disease onset (OR = 6.39, p = .05). CONCLUSIONS Results point to an important vulnerability of this population for psychological distress and psychiatric disease. Early life events related to disease, being sick and sex are associated with psychopathological distress.
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Affiliation(s)
- Alice Lopes
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal.,b ICBAS - Instituto de Ciências Biomédicas Abel Salazar , Universidade do Porto , Porto , Portugal
| | - Isabel Fonseca
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal.,c EPIUnit , Instituto de Saúde Pública da Universidade do Porto (ISPUP) , Porto , Portugal
| | - Alexandra Sousa
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal
| | - Carla Rodrigues
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal
| | - Margarida Branco
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal
| | - Teresa Coelho
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal.,d Serviço de Neurofisiologia , Centro Hospitalar do Porto , Porto , Portugal
| | - Jorge Sequeiros
- b ICBAS - Instituto de Ciências Biomédicas Abel Salazar , Universidade do Porto , Porto , Portugal.,e IBMC - Institute for Molecular and Cell Biology and i3S , Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto , Portugal
| | - Paula Freitas
- a Serviço de Psiquiatria e Saúde Mental , Centro Hospitalar do Porto , Porto , Portugal.,b ICBAS - Instituto de Ciências Biomédicas Abel Salazar , Universidade do Porto , Porto , Portugal
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11
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Lopes A, Fonseca I, Sousa A, Branco M, Rodrigues C, Coelho T, Sequeiros J, Freitas P. Psychopathological Dimensions in Portuguese Subjects with Transthyretin Familial Amyloid Polyneuropathy. Biomed Hub 2017; 2:1-14. [PMID: 31988916 PMCID: PMC6945894 DOI: 10.1159/000485118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 11/09/2017] [Indexed: 11/21/2022] Open
Abstract
Background Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a fatal, chronic, progressive disease. It is a rare hereditary amyloidosis, which manifests as a sensorimotor neuropathy and autonomic dysfunction. It begins during adulthood. Aims and Methods Our aim is to evaluate psychopathological dimensions in a population attending a consultation center for TTR-FAP. Two hundred and nine subjects (symptomatic and asymptomatic carriers), 84 men and 127, women participated in the study. Most subjects were married (67.1%) and most of them were still working; 33% were retired from work or on a sick leave. A sociodemographic questionnaire and The Brief Symptom Inventory (BSI) were applied. Statistical analysis was performed (descriptive analysis, Mann-Whitney, Wilcoxon, and Spearman tests). Results The Global Symptom Index (GSI) was significantly higher in patients (p = 0.001). Considering GSI, 32.7% of total subjects were above the median for general population. When subgroups were evaluated, 25.6% of symptomatic carriers, 26.3% of subjects without established diagnosis, and 39.1% of patients were above median. GSI was significantly higher in patients (p = 0.001). Some BSI dimensions were also significantly higher in the patient group (somatization, depression, anxiety, and psychoticism) when compared with carriers. Women scored higher than men. Sick women scored higher for all dimensions except somatization. Asymptomatic carriers scored statistically higher for phobic anxiety (p = 0.01), interpersonal sensitivity, anxiety, and depression. In patients, most dimensions and GSI (rho = 0.33, p = 0.002) had positive correlations with years of disease. Conclusions TTR-FAP patients and carriers are a very vulnerable group for psychological distress and psychopathological problems. Women and patients are at higher risk.
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Affiliation(s)
- Alice Lopes
- Unidade Corino de Andrade, Serviço de Psiquiatria e Saúde Mental, Centro Hospitalar do Porto, Porto, Portugal.,ICBAS - Instituto de Ciências Biomédicos Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Isabel Fonseca
- Unidade Corino de Andrade, Centro Hospitalar do Porto, Porto, Portugal.,EPIUnit and Instituto de Saúde Pública da Universidade do Porto (ISPUP), Porto, Portugal
| | - Alexandra Sousa
- Unidade Corino de Andrade, Centro Hospitalar do Porto, Porto, Portugal
| | - Margarida Branco
- Unidade Corino de Andrade, Serviço de Psiquiatria e Saúde Mental, Centro Hospitalar do Porto, Porto, Portugal
| | - Carla Rodrigues
- Unidade Corino de Andrade, Centro Hospitalar do Porto, Porto, Portugal
| | - Teresa Coelho
- Unidade Corino de Andrade, Serviço de Neurofisiologia, Centro Hospitalar do Porto, Porto, Portugal
| | - Jorge Sequeiros
- ICBAS - Instituto de Ciências Biomédicos Abel Salazar, Universidade do Porto, Porto, Portugal.,IBMC - Institute for Molecular and Cell Biology and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Paula Freitas
- ICBAS - Instituto de Ciências Biomédicos Abel Salazar, Universidade do Porto, Porto, Portugal
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12
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Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med 2017; 28:10-21. [PMID: 28739313 DOI: 10.1016/j.tcm.2017.07.004] [Citation(s) in RCA: 227] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 07/06/2017] [Accepted: 07/07/2017] [Indexed: 12/20/2022]
Abstract
The amyloidoses are a group of systemic diseases characterized by organ deposition of misfolded protein fragments of diverse origins. The natural history of the disease, involvement of other organs, and treatment options vary significantly based on the protein of origin. In AL amyloidosis, amyloid protein is derived from immunoglobulin light chains, and most often involves the kidneys and the heart. ATTR amyloidosis is categorized as mutant or wild-type depending on the genetic sequence of the transthyretin (TTR) protein produced by the liver. Wild-type ATTR amyloidosis mainly involves the heart, although the reported occurrence of bilateral carpal tunnel syndrome, spinal stenosis and biceps tendon rupture in these patients speaks to more generalized protein deposition. Mutant TTR is marked by cardiac and/or peripheral nervous system involvement. Cardiac involvement is associated with symptoms of heart failure, and dictates the clinical course of the disease. Cardiac amyloidosis can be diagnosed noninvasively by echocardiography, cardiac MRI, or nuclear scintigraphy. Endomyocardial biopsy may be needed in the case of equivocal imaging findings or discordant data. Treatment is aimed at relieving congestive symptoms and targeting the underlying amyloidogenic process. This includes anti-plasma cell therapy in AL amyloidosis, and stabilization of the TTR tetramer or inhibition of TTR protein production in ATTR amyloidosis. Cardiac transplantation can be considered in highly selected patients in tandem with therapy aimed at suppressing the amyloidogenic process, and appears associated with durable long-term survival.
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Affiliation(s)
- Omar K Siddiqi
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, 88 East Newton Street, Boston, MA; Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, MA
| | - Frederick L Ruberg
- Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, 88 East Newton Street, Boston, MA; Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, MA; Department of Radiology, Boston University School of Medicine, Boston Medical Center, Boston, MA.
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13
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Mnatsakanova D, Živković SA. Iatrogenic amyloid polyneuropathy after domino liver transplantation. World J Hepatol 2017; 9:126-130. [PMID: 28217248 PMCID: PMC5295145 DOI: 10.4254/wjh.v9.i3.126] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/04/2016] [Accepted: 12/09/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation has been used in treatment of transthyretin amyloidosis, and some patients undergo domino liver transplantation (DLT) with explanted liver being transplanted to another patient with liver failure as the liver is otherwise usually functionally normal. Until end of 2015, there were 1154 DLT performed worldwide. DLT for transthyretin amyloidosis is associated with the risk of developing de novo systemic amyloidosis and amyloid neuropathy, and the risk may be greater with some non-Val30Met mutations. De novo amyloid neuropathy has been described in up to 23% of transplant recipients. Neuropathy may be preceded by asymptomatic amyloid deposition in various tissues and symptoms of neuropathy started after a median of 7 years following DLT (5.7 ± 3.2 years; range 2 mo to 10 years). Typical initial symptoms include neuropathic pain and sensory loss, while dysautonomia usually starts later. Progression of neuropathy may necessitate liver re-transplantation, and subsequent improvement of neuropathy has been reported in some patients. Explant allograft recipients need close monitoring for signs of systemic amyloidosis, neuropathy and dysautonomia as progressive symptoms may require re-transplantation.
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14
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Carrera MT, Bogue EH, Schiano TD. Domino Liver Transplantation: A Practical Option in the Face of the Organ Shortage. Prog Transplant 2016; 13:151-3. [PMID: 12841523 DOI: 10.1177/152692480301300213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This case study describes a domino liver transplantation in which a patient with familial amyloid polyneuropathy received a cadaveric liver, and the explanted liver was in turn transplanted into a second recipient. Familial amyloid polyneuropathy is an autosomal dominant inherited disease associated with a mutant form of the protein transthyretin. Liver transplantation is the only definitive treatment for this disease. Transplantation removes the source of mutant transthyretin, halts the progression of this otherwise fatal disease, and significantly palliates many underlying symptoms. This case study illustrates that domino transplantation is a practical option to provide a liver transplant for a patient with this disease and a second listed patient from a single cadaveric liver organ, thus alleviating the organ donor shortage. Transplantation offers the only cure for the genetic defect that causes familial amyloid polyneuropathy, appears to result in subjective and objective improvement in neurological function, and eliminates the mortality associated with the disease. A signed informed consent was provided for publication of this case study.
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Affiliation(s)
- Maria T Carrera
- The Mount Sinai Hospital, Recanati/Miller Transplantation Institute, New York, NY, USA
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15
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Liver transplantation in transthyretin amyloidosis: Characteristics and management related to kidney disease. Transplant Rev (Orlando) 2016; 31:115-120. [PMID: 27671053 DOI: 10.1016/j.trre.2016.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 08/23/2016] [Accepted: 09/09/2016] [Indexed: 11/20/2022]
Abstract
Orthotopic liver transplantation (LT) was implemented as the inaugural disease-modifying therapy for hereditary transthyretin (ATTR) amyloidosis, a systemic amyloidosis mainly affecting the peripheral nervous system and heart. The first approach to pharmacologic therapy was focused on the stabilization of the TTR tetramer; following that new advent LT was assumed as the second step of treatment, for those patients whose neuropathy becomes worse after a course of pharmacologic therapy. The renal disease has been ignored in hereditary ATTR amyloidosis. The low level of proteinuria or slight renal impairment does not suppose such a heavy glomerular and vascular amyloid deposition. Moreover, severity of renal deposits does not consistently parallel that of myelinated nerve fiber loss. These are pitfalls that limit the success of LT and suggest troublesome criteria for pharmacological therapy or LT. An algorithm of evaluation concerning renal disease and treatment options is presented and some bridges-to-decision are exposed. In stage 4 or 5 kidney disease, the approach remains to deliver combined or sequential liver-kidney transplantation in eligible patients. However, in the majority, hemodialysis is the only option even in the presence of a well-functioning liver graft. In this review, we highlight useful information to aid the transplant hepatologist in the clinical practice.
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16
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Castaño A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 2015; 20:163-78. [PMID: 25408161 DOI: 10.1007/s10741-014-9462-7] [Citation(s) in RCA: 173] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.
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Affiliation(s)
- Adam Castaño
- Center for Advanced Cardiac Care, Columbia College of Physicians and Surgeons, New York City, NY, USA,
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17
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Novais SADL, Mendes FRP. Representation of illness in Familial Amyloidotic Polyneuropathy Portuguese Association newspaper: A documental study. Nurs Health Sci 2015; 18:85-90. [PMID: 26552610 DOI: 10.1111/nhs.12240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 07/06/2015] [Accepted: 07/09/2015] [Indexed: 01/02/2023]
Abstract
This study explores illness representations within Familial Amyloidotic Polyneuropathy Portuguese Association newspaper . A content analysis was performed of the issue data using provisional coding related to the conceptual framework of the study. All dimensions of illness representation in Leventhal's Common Sense Model of illness cognitions and behaviors are present in the data and reflect the experience of living with this disease. Understanding how a person living with an hereditary, rare, neurodegenerative illness is important for developing community nursing interventions. In conclusion, we suggest an integration of common sense knowledge with other approaches for designing an intervention program centered on people living with an hereditary neurodegenerative illness, such as familial amyloidotic polyneuropathy.
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18
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Nelson LM, Penninga L, Villadsen GE, Mølgaard H, Eiskjaer H, Hillingsø JG, Rasmussen A. Outcome in patients treated with isolated liver transplantation for familial transthyretin amyloidosis to prevent cardiomyopathy. Clin Transplant 2015; 29:1098-104. [PMID: 26361241 DOI: 10.1111/ctr.12633] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND Familial transthyretin (TTR) amyloidosis is caused by different TTR mutations resulting in different clinical phenotypes of the disease. The Leu111Met mutation causes severe restrictive cardiomyopathy. Liver transplantation (LTx) is an established treatment option for patients with TTR amyloidosis; however, information on outcome after isolated LTx in patients with Leu111Met mutation amyloidosis is limited. METHODS Between 2005 and 2012, six patients with TTR Leu111Met amyloidosis underwent isolated orthotopic LTx. None suffered from neuropathy. Prior to LTx, patients presented with echocardiographic manifestations of early cardiac amyloid involvement and in five endomyocardial biopsy was positive for TTR amyloid. RESULTS Median age at LTx was 45.5 yr (range 39-54), and four were male (67%). All patients were alive at a median follow-up of 56.6 months (range 18-104). No surgical complications occurred. Two patients (33%) underwent cardiac transplantation during follow-up due to progressive cardiomyopathy. The remaining four patients experienced no echocardiographic or clinical deterioration of cardiac function following LTx. CONCLUSION Isolated LTx appears to be a valuable treatment option for patients with familial TTR amyloidosis due to Leu111Met mutation. Appropriate timing of LTx is of utmost importance to avoid development of severe amyloid cardiomyopathy and the need for combined heart and liver transplantation.
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Affiliation(s)
- Laerke M Nelson
- Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Luit Penninga
- Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Gerda E Villadsen
- Department of Medicine, Hepatology and Gastroenterology V, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Mølgaard
- Department of Cardiology, Skejby, Aarhus University Hospital, Aarhus, Denmark
| | - Hans Eiskjaer
- Department of Cardiology, Skejby, Aarhus University Hospital, Aarhus, Denmark
| | - Jens G Hillingsø
- Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Allan Rasmussen
- Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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19
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Dubrey S, Ackermann E, Gillmore J. The transthyretin amyloidoses: advances in therapy. Postgrad Med J 2015; 91:439-48. [PMID: 26048914 DOI: 10.1136/postgradmedj-2014-133224] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 05/20/2015] [Indexed: 11/04/2022]
Abstract
There are two forms of transthyretin (TTR) amyloidosis: non-hereditary and hereditary. The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis. The hereditary form (ATTRm) is caused by variant TTR which results from a genetic mutation of TTR. The predominant effect of ATTRwt amyloidosis is on the heart, with patients having a greater left ventricular wall thickness at presentation than the devastating form which is light chain (AL) amyloidosis. ATTRm amyloidosis is broadly split into two categories: a type that predominantly affects the nervous system (often called familial amyloid polyneuropathy (FAP)) and one with a predilection for the heart (often called familial amyloid cardiomyopathy (FAC)). Approximately half of all TTR mutations known to express a clinical phenotype cause a cardiomyopathy. Since the introduction of orthotopic liver transplantation for ATTRm amyloidosis in 1991, several additional therapies have been developed. These therapies aim to provide a reduction or elimination of TTR from the plasma (through genetic approaches), stabilisation of the TTR molecule (to prevent deposition) and dissolution of the amyloid matrix. We describe the latest developments in these approaches to management, many of which are also applicable to wild-type amyloidosis.
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Affiliation(s)
- Simon Dubrey
- Department of Cardiology, Hillingdon & Mount Vernon Hospitals NHS Trust, Uxbridge, Middlesex, UK
| | | | - Julian Gillmore
- Division of Medicine, National Amyloidosis Centre, University College London, London, UK
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20
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Chen JJ, Genereux JC, Wiseman RL. Endoplasmic reticulum quality control and systemic amyloid disease: Impacting protein stability from the inside out. IUBMB Life 2015; 67:404-13. [PMID: 26018985 DOI: 10.1002/iub.1386] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/27/2015] [Indexed: 11/11/2022]
Abstract
The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking, and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them toward ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion, and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the unfolded protein response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease.
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Affiliation(s)
- John J Chen
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.,Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA
| | - Joseph C Genereux
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.,Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA
| | - R Luke Wiseman
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.,Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA
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21
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Marcacuzco Quinto AA, Manrique Municio A, Jimenez Romero LC, Loinaz Segurola C, Calvo Pulido J, Justo Alonso I, Garcia-Sesma Perez-F A, Abradelo de Usera M, Cambra Molero F, Caso M O, Moreno Gonzalez E. [Liver transplantation as treatment of familial amyloid polyneuropathy in patients older than 60 years]. Med Clin (Barc) 2015; 144:385-8. [PMID: 24746275 DOI: 10.1016/j.medcli.2014.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 02/20/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND AND OBJECTIVE Familial amyloid polyneuropathy (FAP) is the most prevalent type of hereditary systemic amyloidosis. It is an autosomal dominant disease characterized by the deposition of an abnormal variant transthyretin. It has a worldwide distribution, with localized endemic areas in Portugal, Sweden and Japan. In Spain there is an endemic focus, located in Mallorca. Liver transplantation is the only curative option for patients with FAP. The aim of this study was to describe the clinical and demographic characteristics of patients transplanted with a diagnosis of PAF. MATERIAL AND METHOD Six patients with PAF underwent liver transplantation between April 1986 and December 2012. RESULTS The mean age was 57.7+16 years, patients of Spanish origin were older than 60 years. All patients had progressive symptoms as mixed polyneuropathy. In 2 patients, combined heart-liver transplants sequentially were performed. Patient survival and graft was 80% at one, 3 and 5 years. CONCLUSIONS The only effective treatment for etiologic PAF is liver transplantation. Early detection is the key to the treatment and control, avoiding the irreversible organ damage.
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Affiliation(s)
- Alberto A Marcacuzco Quinto
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España.
| | - Alejandro Manrique Municio
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Luis C Jimenez Romero
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Carmelo Loinaz Segurola
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Jorge Calvo Pulido
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Iago Justo Alonso
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Alvaro Garcia-Sesma Perez-F
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Manuel Abradelo de Usera
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Felix Cambra Molero
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Oscar Caso M
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
| | - Enrique Moreno Gonzalez
- Servicio de Cirugía General C y Trasplante de Órganos Abdominales, Hospital Universitario 12 de Octubre, Madrid, España
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22
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Alshehri B, D'Souza DG, Lee JY, Petratos S, Richardson SJ. The diversity of mechanisms influenced by transthyretin in neurobiology: development, disease and endocrine disruption. J Neuroendocrinol 2015; 27:303-23. [PMID: 25737004 DOI: 10.1111/jne.12271] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 02/23/2015] [Accepted: 02/24/2015] [Indexed: 12/12/2022]
Abstract
Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs). TTR synthesised in the liver is secreted into the bloodstream and distributes THs around the body, whereas TTR synthesised in the choroid plexus is involved in movement of thyroxine from the blood into the cerebrospinal fluid and the distribution of THs in the brain. This is important because an adequate amount of TH is required for normal development of the brain. Nevertheless, there has been heated debate on the role of TTR synthesised by the choroid plexus during the past 20 years. We present both sides of the debate and how they can be reconciled by the discovery of TH transporters. New roles for TTR have been suggested, including the promotion of neuroregeneration, protection against neurodegeneration, and involvement in schizophrenia, behaviour, memory and learning. Recently, TTR synthesis was revealed in neurones and peripheral Schwann cells. Thus, the synthesis of TTR in the central nervous system (CNS) is more extensive than previously considered and bolsters the hypothesis that TTR may play wide roles in neurobiological function. Given the high conservation of TTR structure, function and tissue specificity and timing of gene expression, this implies that TTR has a fundamental role, during development and in the adult, across vertebrates. An alarming number of 'unnatural' chemicals can bind to TTR, thus potentially interfering with its functions in the brain. One role of TTR is delivery of THs throughout the CNS. Reduced TH availability during brain development results in a reduced IQ. The combination of the newly discovered sites of TTR synthesis in the CNS, the increasing number of neurological diseases being associated with TTR, the newly discovered functions of TTR and the awareness of the chemicals that can interfere with TTR biology render this a timely review on TTR in neurobiology.
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Affiliation(s)
- B Alshehri
- School of Medical Sciences, RMIT University, Bundoora, VIC, Australia
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23
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Carvalho A, Rocha A, Lobato L. Liver transplantation in transthyretin amyloidosis: issues and challenges. Liver Transpl 2015; 21:282-92. [PMID: 25482846 DOI: 10.1002/lt.24058] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 11/26/2014] [Indexed: 12/25/2022]
Abstract
Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin (TTR), which is usually derived from a single amino acid substitution in the TTR gene. More than 100 mutations have been described, with V30M being the most prevalent. Each variant has a different involvement, although peripheral neuropathy and cardiomyopathy are the most common. Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. In this review, we focus on the results and long-term outcomes of OLT for ATTR after more than 2063 procedures and 23 years of experience. After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses. The overall 5-year survival rate is approximately 100% for V30M patients and 59% for non-ATTR V30M patients. Cardiac-related death and septicemia are the main causes of mortality. Lower survival is related to malnutrition, a longer duration of disease, cardiomyopathy, and a later onset (particularly for males). Deposits, which are composed of a mixture of truncated and full-length TTR (type A) fibrils, have been associated with posttransplant myocardial dysfunction. A higher incidence of early hepatic artery thrombosis of the graft has also been documented for these patients. Liver-kidney/heart transplantation is an alternative for patients with advanced renal disease or heart failure. The sequential procedure, in which ATTR livers are reused in patients with liver disease, reveals that neuropathy in the recipient may appear as soon as 6 years after OLT, and ATTR deposits may appear even earlier. Long-term results of trials with amyloid protein stabilizers or disrupters, silencing RNA, and antisense oligonucleotides will highlight the value and limitations of liver transplantation.
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24
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Conejos-Sánchez I, Cardoso I, Oteo-Vives M, Romero-Sanz E, Paul A, Sauri AR, Morcillo MA, Saraiva MJ, Vicent MJ. Polymer-doxycycline conjugates as fibril disrupters: an approach towards the treatment of a rare amyloidotic disease. J Control Release 2014; 198:80-90. [PMID: 25481444 DOI: 10.1016/j.jconrel.2014.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/01/2014] [Accepted: 12/02/2014] [Indexed: 10/24/2022]
Abstract
The term amyloidosis describes neurological diseases where an abnormal protein is misfolded and accumulated as deposits in organs and tissues, known as amyloid, disrupting their normal function. In the most common familial amyloid polyneuropathy (FAP), transthyretin (TTR) displays this role primarily affecting the peripheral nervous system (PNS). Advanced stages of this inherited rare amyloidosis, present as fibril deposits that are responsible for disease progression. In order to stop disease progression, herein we designed an efficient family of nanoconjugates as fibril disrupters. These polymer conjugates are based on doxycycline (doxy), already in phase II trials for Alzheimer's disease, covalently linked to poly-l-glutamic acid (PGA). The conjugates were rationally designed, looking at drug loading and drug release rate by adequate linker design, always considering the physiological conditions at the molecular target site. Conjugation of doxycycline exhibited greater potential towards TTR fibril disaggregation in vitro compared to the parent drug. Exhaustive physico-chemical evaluation of these polymer-drug conjugates concluded that drug release was unnecessary for activity, highlighting the importance of an appropriate linker. Furthermore, biodistribution studies through optical imaging (OI) and the use of radiolabelled polymer-drug conjugates demonstrated conjugate safety profile and renal clearance route of the selected PGA-doxy candidate, settling the adequacy of our conjugate for future in vivo evaluation. Furthermore, preliminary studies in an FAP in vivo model at early stages of disease development showed non-organ toxicity evidences. This nanosized-system raises a promising treatment for advanced stages of this rare amyloidotic disease, and also presents a starting point for possible application within other amyloidosis-related diseases, such as Alzheimer's disease.
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Affiliation(s)
- Inmaculada Conejos-Sánchez
- Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain
| | - Isabel Cardoso
- Instituto de Biología Molecular e Celular (IBMC), Rua do Campo Alegre 823, Porto 4150-180, Portugal
| | - Marta Oteo-Vives
- Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT, Av. Complutense 40, Madrid 28040, Spain
| | - Eduardo Romero-Sanz
- Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT, Av. Complutense 40, Madrid 28040, Spain
| | - Alison Paul
- School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom
| | - Amparo Ruiz Sauri
- Pathology Department, University of Valencia, Blasco Ibáñez 15, Valencia 46010, Spain
| | - Miguel A Morcillo
- Biomedical Applications of Radioisotopes and Pharmacokinetics Unit, CIEMAT, Av. Complutense 40, Madrid 28040, Spain
| | - Maria J Saraiva
- Instituto de Biología Molecular e Celular (IBMC), Rua do Campo Alegre 823, Porto 4150-180, Portugal
| | - María J Vicent
- Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain.
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25
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Sher T, Gertz MA. Recent advances in the diagnosis and management of cardiac amyloidosis. Future Cardiol 2014; 10:131-46. [PMID: 24344669 DOI: 10.2217/fca.13.85] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The heart is commonly involved in various forms of amyloidosis and cardiomyopathy is a major cause of morbidity and mortality in these patients. Diagnosis of cardiac amyloidosis is often delayed due to nonspecific presenting symptoms and failure to recognize early signs of amyloid heart disease on routine cardiac imaging. Treatment of cardiac amyloidosis depends upon the type of amyloid protein. Systemic chemotherapy with or without stem cell transplantation is used to treat immunoglobulin-related amyloidosis and liver transplantation is used for familial transthyretin amyloidosis in select patients. Clinical trials with siRNA for the treatment of transthyretin amyloid cardiomyopathies and amyloid protein stabilizers are ongoing. Prognosis depends on the type of amyloid protein with poorer outcomes noted in immunoglobulin light-chain amyloidosis. Supportive care forms the cornerstone of management and advancements in cardiac imaging and proteomics are expected to positively impact our ability to diagnose, prognosticate and treat cardiac amyloidosis.
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Affiliation(s)
- Taimur Sher
- Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
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Wixner J, Mundayat R, Karayal ON, Anan I, Karling P, Suhr OB. THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease. Orphanet J Rare Dis 2014; 9:61. [PMID: 24767411 PMCID: PMC4005902 DOI: 10.1186/1750-1172-9-61] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 04/17/2014] [Indexed: 12/22/2022] Open
Abstract
Background Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients’ nutritional status and health-related quality of life (HRQoL). Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL. Results Data from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty-three percent of those with the hereditary form and 15% of those with the wild-type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p < 0.001) and gastrointestinal symptoms were more common in patients with the V30M mutation than in those with other mutations (p < 0.001). For patients with predominantly cardiac complications, the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population. Both upper and lower gastrointestinal symptoms were significant negative predictors of mBMI and the EQ-5D Index Score (p < 0.001 for all). Conclusions Gastrointestinal symptoms were common in patients with hereditary transthyretin amyloidosis and had a significant negative impact on their nutritional status and HRQoL. However, patients with wild-type transthyretin amyloidosis or transthyretin mutations associated with predominantly cardiac complications did not show an increased prevalence of gastrointestinal disturbances.
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Affiliation(s)
- Jonas Wixner
- Department of Public Health and Clinical Medicine, Umeå University, Umeå S-901 87, Sweden.
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Bolte FJ, Schmidt HHJ, Becker T, Braun F, Pascher A, Klempnauer J, Schmidt J, Nadalin S, Otto G, Barreiros AP. Evaluation of domino liver transplantations in Germany. Transpl Int 2013; 26:715-23. [PMID: 23668625 DOI: 10.1111/tri.12110] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 02/11/2013] [Accepted: 04/06/2013] [Indexed: 01/29/2023]
Abstract
A retrospective multicenter study has been conducted to evaluate domino liver transplantations (DLTs) in Germany. The study provides insight into survival and features having an impact on the assessment of neuropathy after DLT. In addition, a neurologic follow-up program with a scheme to estimate the likelihood of de novo amyloidosis is presented. A series of 61 DLTs at seven transplant centers in Germany was enrolled. The mean age of domino recipients at the time of transplantation was 58 years, 46 of them being men, and 15 being women. The median follow-up was 46 months. The overall 1-, 3-, and 5-year survival of domino recipients was 81.6%, 70.8% and 68.8%, respectively. Causes of death were primarily not related to familial amyloidosis. The main indication of DLT was hepatocellular carcinoma. Two of the reported domino recipients developed symptoms and signs of de novo amyloidosis within 10 years after transplantation. A total of 30 domino graft recipients (49.18%) presented with diabetes post transplantation. In conclusion, an advanced follow-up program is crucial to evaluate the risk of transmitting familial amyloidosis by DLT and to establish more strict selection criteria for domino recipients.
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Stoilova T, Colombo L, Forloni G, Tagliavini F, Salmona M. A new face for old antibiotics: tetracyclines in treatment of amyloidoses. J Med Chem 2013; 56:5987-6006. [PMID: 23611039 DOI: 10.1021/jm400161p] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The use of tetracyclines has declined because of the appearance of resistant bacterial strains. However, the indications of nonantimicrobial activities of these drugs have considerably raised interest and triggered clinical trials for a number of different pathologies. About 10 years ago we first reported that tetracyclines inhibited the aggregation of prion protein fragments and Alzheimer's β peptides, destabilizing their aggregates and promoting their degradation by proteases. On the basis of these observations, the antiamyloidogenic effects of tetracyclines on a variety of amyloidogenic proteins were studied and confirmed by independent research groups. In this review we comment on the data available on their antiamyloidogenic activity in preclinical and clinical studies. We also put forward that the beneficial effects of these drugs are a result of a peculiar pleiotropic action, comprising their interaction with oligomers and disruption of fibrils, as well as their antioxidant, anti-inflammatory, antiapoptotic, and matrix metalloproteinase inhibitory activities.
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Affiliation(s)
- Tatiana Stoilova
- IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156 Milano, Italy
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Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep 2013; 3:1279-92. [PMID: 23583182 DOI: 10.1016/j.celrep.2013.03.024] [Citation(s) in RCA: 430] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Revised: 10/12/2012] [Accepted: 03/15/2013] [Indexed: 11/21/2022] Open
Abstract
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small-molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selective restoration of aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR activation.
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Planté-Bordeneuve V, Suhr OB, Maurer MS, White B, Grogan DR, Coelho T. The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry: design and methodology. Curr Med Res Opin 2013. [PMID: 23193943 DOI: 10.1185/03007995.2012.754349] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
UNLABELLED Abstract Background: Transthyretin (TTR) amyloidosis - the most common type of hereditary amyloidosis - also has an acquired form and is observed in geographically dispersed populations. TTR amyloidosis is marked by considerable clinical heterogeneity, and the main phenotypes are neurologic and cardiovascular. METHODS THAOS is an international, noninterventional, longitudinal, observational registry designed to evaluate overall survival in patients, better understand genotype-phenotype relationships and the natural history of TTR amyloidosis, and evaluate the effects of liver transplantation and other treatments on disease progression in TTR amyloidosis. All individuals with a confirmed TTR mutation with or without a diagnosis of TTR amyloidosis and patients with wild-type TTR amyloidosis are eligible to be enrolled in the registry. PURPOSE To describe the design and methodology of the recently established registry. Procedures for data collection are outlined and a minimum set of assessments for the standard evaluation of all subjects with TTR amyloidosis is described. Demographic information, TTR genotype, medical history, family history of the disease, and transplant history are assessed at baseline. On return visits, signs and symptoms of the disease are evaluated, general examinations are conducted, and laboratory data, measures of neurologic and cardiovascular function, and quality of life are assessed according to the standard of care for patients. Visits on at least a biannual basis are recommended. The registry will remain open for a period of at least 10 years. RESULTS The initial experience suggests that the registry is characterized by a comprehensive set of data elements which can be completed by providers from the various clinical backgrounds who administer care to individuals with TTR amyloidosis. CONCLUSION As of September 2011, 30 centers in 15 of the 19 countries participating in the THAOS registry have enrolled 975 patients. Such data provide a representative sample of the global TTR amyloidosis patient population, including asymptomatic TTR variant carriers, which can inform the natural history of the disease and offer the potential to evaluate novel therapeutic modalities in diverse patient subpopulations.
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Nelson LM, Penninga L, Sander K, Hansen PB, Villadsen GE, Rasmussen A, Gustafsson F. Long-term outcome in patients treated with combined heart and liver transplantation for familial amyloidotic cardiomyopathy. Clin Transplant 2012; 27:203-9. [DOI: 10.1111/ctr.12053] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2012] [Indexed: 11/28/2022]
Affiliation(s)
| | - Luit Penninga
- Department of Surgical Gastroenterology; Rigshospitalet; Copenhagen; Denmark
| | - Kaare Sander
- The Heart Centre; Rigshospitalet; Copenhagen; Denmark
| | | | | | - Allan Rasmussen
- Department of Surgical Gastroenterology; Rigshospitalet; Copenhagen; Denmark
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Castaño A, Helmke S, Alvarez J, Delisle S, Maurer MS. Diflunisal for ATTR cardiac amyloidosis. CONGESTIVE HEART FAILURE (GREENWICH, CONN.) 2012; 18:315-9. [PMID: 22747647 PMCID: PMC3727153 DOI: 10.1111/j.1751-7133.2012.00303.x] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Transthyretin (TTR) cardiac amyloidosis is an important, often under-recognized and potentially modifiable cause of heart failure with a preserved ejection fraction. The only proven treatment is liver or combined heart/liver transplantation, which, although effective, is not suitable for the vast majority of older adults with this condition. Diflunisal, a nonsteroidal anti-inflammatory drug, can stabilize the TTR tetramer in vitro and may prevent misfolding monomers and dimers from forming amyloid deposits in the heart. It is one of two small molecules assessed in animal safety studies and human clinical trials of TTR polyneuropathy. The authors conducted a single-arm, open-label investigation with a mean follow-up of 0.9 ± 0.3 years to determine the safety and efficacy of diflunisal administration in a cohort of 13 patients with confirmed wild-type or mutant TTR cardiac amyloidosis. Diflunisal was well tolerated from a hematologic standpoint, although a 6% decline in estimated glomerular filtration rate was noted. Therapy was discontinued in one patient who rapidly developed volume overload. There was no significant mean change in cardiac structure (left ventricular mass: -53 g/m(2) change, P=.36), function (ejection fraction: -2% change, P=.61), or biomarkers (Troponin I: +0.03 ng/mL, P=.08; BNP: +93 pg/mL change, P=.52) during the course of therapy. These data suggest that at low dosages and with careful monitoring, diflunisal can be safely administered to compensated patients with cardiac TTR amyloidosis. Further study in a randomized placebo-controlled trial is warranted.
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Affiliation(s)
- Adam Castaño
- Center for Advanced Cardiac Care, Division of Cardiology, Columbia College of Physicians and Surgeons, New York, NY, USA
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Cannon RM, Hughes MG, Jones CM, Eng M, Marvin MR. A review of the United States experience with combined heart-liver transplantation. Transpl Int 2012; 25:1223-8. [PMID: 22937819 DOI: 10.1111/j.1432-2277.2012.01551.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Since first described by Starzl, combined heart and liver transplantation (CHLT) has been a relatively rare event, although utilization has increased in the past decade. This study was undertaken to review the United States experience with this procedure; UNOS data on CHLT was reviewed. CHLT was compared with liver transplantation alone and heart transplantation alone in terms of acute rejection within 12 months, graft survival, and patient survival. Survival was calculated according to Kaplan-Meier and Cox proportional hazards. Continuous variables were compared using Student's t-test and categorical variables with chi-squared. Between 1987 and 2010, there were 97 reported cases of CHLT in the United States. Amyloidosis was the most common indication for both heart (n = 26, 26.8%) and liver (n = 27, 27.8%) transplantation in this cohort. Liver graft survival in the CHLT cohort at 1, 5, and 10 years was 83.4%, 72.8%, and 71.0%, whereas survival of the cardiac allograft was 83.5%, 73.2%, and 71.5%. This was similar to graft survival in liver alone transplantation (79.4%, 71.0%, 65.1%; P = 0.894) and heart transplantation alone (82.6%, 71.9%, 63.2%; P = 0.341). CHLT is a safe and effective procedure, with graft survival rates similar to isolated heart and isolated liver transplantation.
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Affiliation(s)
- Robert M Cannon
- Division of Transplantation, Department of Surgery, University of Louisville, Louisville, KY 40202, USA
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Suhr OB, Gustavsson S, Heldestad V, Hörnsten R, Lindqvist P, Nordh E, Wiklund U. New insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience. Degener Neurol Neuromuscul Dis 2012; 2:93-106. [PMID: 30890882 PMCID: PMC6065582 DOI: 10.2147/dnnd.s24652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Over the last decade, new medical treatment modalities have emerged based on increased insights into amyloid formation. With the increased possibilities for treatment of amyloidosis caused by transthyretin (TTR) amyloid deposits comes the need for diagnostic procedures for early diagnosis and better tools to follow disease progression. This is of particular importance in clinical trials evaluating the efficacy of new treatments. Until recently, the treatment of TTR amyloidosis (ATTR) was based solely on liver transplantation, a procedure that has halted disease progression in many patients. Liver transplantation has been especially effective in patients under the age of 50 years carrying the TTR V30M mutation, whereas the outcome of the procedure has been variable for others, particularly elderly male patients and those carrying a non-V30M mutation. This review concentrates on new insights derived from our center's experience with liver transplantation, how to implement this experience in evaluation of new treatment modalities for ATTR, and how to facilitate early diagnosis of neuropathy with easily available diagnostic tools. Attention has focused on manifestations of the disease that involve the heart and the peripheral nervous system; change in peripheral nerve function has been the primary endpoint in two controlled clinical trials, one finished and one ongoing. New insights into the amyloid formation process and the lessons learned from liver transplantation give the opportunity to design potentially effective treatment modalities for ATTR. It appears reasonable to suspect that a combination of different treatment modalities may be required to treat the disease, and that different treatment regimes will be designed according to the phenotype of the disease. For the patients and their relatives there is now a solid foundation for optimism, with prospects of several effective medical treatment possibilities within the coming decade.
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Affiliation(s)
- Ole B Suhr
- Department of Public Health and Clinical Medicine,
| | | | | | - Rolf Hörnsten
- Department of Surgical and Perioperative Sciences, Clinical Physiology, Heart Centre
| | | | - Erik Nordh
- Department of Pharmacology and Clinical Neuroscience
| | - Urban Wiklund
- Department of Radiation Sciences, Biomedical Engineering, Umeå University, Umeå, Sweden
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Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, Falk RH, Cheung KN, Patel AR, Pano A, Packman J, Grogan DR. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J 2012; 164:222-228.e1. [PMID: 22877808 DOI: 10.1016/j.ahj.2012.04.015] [Citation(s) in RCA: 202] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Accepted: 04/10/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans. METHODS Patients with ATTRwt (n = 18) and V122I ATTRm (n = 11) were longitudinally assessed every 6 months for up to 2 years by functional class assessments, biochemical markers, and echocardiography. RESULTS At baseline, no differences in clinical characteristics, biomarkers, or echocardiographic parameters were noted between patients with ATTRwt and patients with ATTRm. After 15.5 ± 8 months, there were 11 deaths and 1 cardiac transplant, with higher mortality (73% vs 22%, P = .03) and cardiovascular hospitalization (64% vs 28%, P = .02) among patients with ATTRm. The median survival from diagnosis was 25.6 months for ATTRm vs 43.0 months for ATTRwt (P = .04). Univariate predictors of mortality included disease duration, heart rate ≥ 70 beats/min, baseline stroke volume, left ventricular ejection fraction <50%, and ATTRm status. For each 6-month increment, the mean 6-minute walk distance declined by 25.8 m, N-terminal pro b-type natriuretic peptide increased by 1,816 pg/mL, and left ventricular ejection fraction fell by 3.2%, for the entire cohort. CONCLUSIONS In this prospective study, disease progression, morbidity, and mortality were observed in ATTR cardiomyopathy, particularly due to V122I, over a short duration. Given the prevalence of this mutation, further study of V122I in at-risk African American patients is warranted.
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Hereditäre kardiale Amyloidosen mit Mutationen des Transthyretin. Herz 2012; 37:456-60. [DOI: 10.1007/s00059-011-3566-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 09/27/2011] [Accepted: 11/08/2011] [Indexed: 11/26/2022]
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Guan J, Mishra S, Falk RH, Liao R. Current perspectives on cardiac amyloidosis. Am J Physiol Heart Circ Physiol 2011; 302:H544-52. [PMID: 22058156 DOI: 10.1152/ajpheart.00815.2011] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed "cardiac amyloidosis" or "amyloid cardiomyopathy." Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis.
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Affiliation(s)
- Jian Guan
- Cardiac Muscle Research Lab., 77 Ave. Louis Pasteur, NRB 431, Boston, MA 02115, USA
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Schenone A, Nobbio L, Monti Bragadin M, Ursino G, Grandis M. Inherited neuropathies. Curr Treat Options Neurol 2011; 13:160-79. [PMID: 21286948 DOI: 10.1007/s11940-011-0115-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OPINION STATEMENT Inherited peripheral neuropathies are among the most common hereditary diseases of the nervous system. Charcot-Marie-Tooth (CMT) disease, also known from previous classifications as hereditary motor and sensory neuropathy (HMSN), is certainly the most common inherited neuropathy. In the past several years, various treatments for CMT have been proposed, although specific therapies are not yet available. In clinical practice, rehabilitative strategies remain the most helpful therapeutic approach to these patients. There is still a lack of consensus on the best way to rehabilitate patients affected by CMT. Based on our personal experience and on a review of the literature, we first recommend the prescription of ankle-foot orthoses (AFO) for patients affected by CMT; the choice of which patient, which AFO, and when to apply it depends on the individual condition of each patient and on the experience of the physician/therapist. Second, adaptive equipment (eg, button hook, long-handled shoehorn, elastic shoe laces) is available to compensate for hand deformities, sensory loss, and weakness. Third, moderate to intense strength training and aerobic exercise are well tolerated by patients affected by CMT; further studies are needed to establish whether these approaches are effective in improving their motor function and strength. There is not enough evidence to recommend muscle stretching exercises or proprioceptive kinesiotherapy, although in our experience both approaches may be helpful in selected CMT patients to prevent tendon retractions, muscle tightening, and loss of strength, and to improve balance. There is growing knowledge of the underlying genetic defects and molecular pathophysiology in CMT. To date, only a few clinical trials in CMT patients have been performed. A neurotrophic factor, neurotrophin 3, was used in a small sample of CMT1A patients with promising results, but it has not been tested in a larger cohort and there is currently no reason to suggest this therapy for CMT1A neuropathy. Based on positive results in an animal model of CMT1A, three trials with ascorbic acid (AA) were completed in a large number of patients with this neuropathy, with results that were negative overall. Therefore, it is not possible to recommend the use of AA in CMT1A patients at this time, but the results of a larger Italian-UK study and an American trial with higher doses of AA are still awaited. It is important to remember that a superimposed inflammatory/disimmune process may complicate the course of the neuropathy; in this case, severe worsening (especially motor) in a matter of weeks or months is a "red flag" that should suggest immunosuppressive or immunomodulatory treatment such as steroids, intravenous immunoglobulin, or plasma exchange. In fact, steroid-sensitive cases of HMSN were described many years ago, well before the genetic diagnosis was available. Symptomatic treatment to reduce neuropathic and nociceptive pain, both of which have been reported in patients affected by CMT, should be prescribed according to recently published guidelines for the therapy of pain. No evidence suggests any specific surgical intervention or change in diet or lifestyle for patients affected by various types of CMT.
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Affiliation(s)
- Angelo Schenone
- Department of Neuroscience, Ophthalmology, and Genetics, University of Genoa, Via De Toni 5, 16132, Genova, Italy,
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Characterization of End-Stage Renal Disease After Liver Transplantation in Transthyretin Amyloidosis (ATTR V30M). Transplant Proc 2011; 43:189-93. [DOI: 10.1016/j.transproceed.2010.11.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Obayashi K, Hörnsten R, Wiklund U, Karlsson M, Okamoto S, Ando Y, Suhr OB. Blood pressure overshoot after tilt reversal in patients with familial amyloidotic polyneuropathy. Hypertens Res 2010; 34:133-8. [PMID: 20927118 DOI: 10.1038/hr.2010.181] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Wiklund U, Hörnsten R, Olofsson BO, Suhr OB. Cardiac autonomic function does not improve after liver transplantation for familial amyloidotic polyneuropathy. Auton Neurosci 2010; 156:124-30. [PMID: 20478749 DOI: 10.1016/j.autneu.2010.04.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Revised: 04/21/2010] [Accepted: 04/21/2010] [Indexed: 01/16/2023]
Affiliation(s)
- Urban Wiklund
- Department of Biomedical Engineering & Informatics, University Hospital, SE-901 85 Umeå, Sweden.
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Choi S, Reixach N, Connelly S, Johnson SM, Wilson IA, Kelly JW. A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity. J Am Chem Soc 2010; 132:1359-70. [PMID: 20043671 DOI: 10.1021/ja908562q] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Transthyretin aggregation-associated proteotoxicity appears to cause several human amyloid diseases. Rate-limiting tetramer dissociation and monomer misfolding of transthyretin (TTR) occur before its aggregation into cross-beta-sheet amyloid fibrils. Small molecule binding to and preferential stabilization of the tetrameric state of TTR over the dissociative transition state raises the kinetic barrier for dissociation, imposing kinetic stabilization on TTR and preventing aggregation. This is an effective strategy to halt neurodegeneration associated with polyneuropathy, according to recent placebo-controlled clinical trial results. In three recent papers, we systematically ranked possibilities for the three substructures composing a typical TTR kinetic stabilizer, using fibril inhibition potency and plasma TTR binding selectivity data. Herein, we have successfully employed a substructure combination strategy to use these data to develop potent and selective TTR kinetic stabilizers that rescue cells from the cytotoxic effects of TTR amyloidogenesis. Of the 92 stilbene and dihydrostilbene analogues synthesized, nearly all potently inhibit TTR fibril formation. Seventeen of these exhibit a binding stoichiometry of >1.5 of a maximum of 2 to plasma TTR, while displaying minimal binding to the thyroid hormone receptor (<20%). Six analogues were definitively categorized as kinetic stabilizers by evaluating dissociation time-courses. High-resolution TTR.(kinetic stabilizer)(2) crystal structures (1.31-1.70 A) confirmed the anticipated binding orientation of the 3,5-dibromo-4-hydroxyphenyl substructure and revealed a strong preference of the isosteric 3,5-dibromo-4-aminophenyl substructure to bind to the inner thyroxine binding pocket of TTR.
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Affiliation(s)
- Sungwook Choi
- Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, USA
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43
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Takigawa M, Hashimura K, Ishibashi-Ueda H, Yamada N, Kiso K, Nanasato M, Yoshida Y, Hirayama H. Annual electrocardiograms consistent with silent progression of cardiac involvement in sporadic familial amyloid polyneuropathy: a case report. Intern Med 2010; 49:139-44. [PMID: 20075578 DOI: 10.2169/internalmedicine.49.2703] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Understanding the clinical characteristics of transthyretin familial amyloid polyneuropathy (TTR-FAP) is critical for early diagnosis and timely referral for liver transplantation. Here, we describe a 52-year-old man who had slight paresthesia for four years and whose final diagnosis of TTR-cardiac amyloidosis caused by sporadic FAP was delayed despite annual electrocardiography. Curative liver transplantation was postponed because of progressive cardiac involvement. This experience highlights the difficulties associated with diagnosing TTR-FAP, especially when it is sporadic, and underscores the importance of slight changes in ECG that could indicate FAP.
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Affiliation(s)
- Masateru Takigawa
- Cardiovascular Center, Department of Internal Medicine, Japanese Red Cross Society, Nagoya Daini Hospital, Nagoya.
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Dattilo PB. Familial (ATTR) amyloidosis misdiagnosed as the primary (AL) variant: a case report. CASES JOURNAL 2009; 2:9295. [PMID: 20062619 PMCID: PMC2803959 DOI: 10.1186/1757-1626-2-9295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2009] [Accepted: 12/09/2009] [Indexed: 12/02/2022]
Abstract
Introduction Primary (AL) Amyloidosis is arguably the most recognizable variant of the disease with many classic signs. However, it has been argued that the Familial variant (ATTR) is actually more prevalent. It is less recognizable, however, as its spectrum of organ involvement is frequently much more limited. The two variants carry significantly different prognoses, have divergent treatment strategies, and very different implications for the family members of patients. There is now a small amount of data that would suggest Familial Amyloidosis may be misdiagnosed as the AL form 2-4% of the time as a result of laboratory error. Case presentation Herein a case of Familial Amyloidosis initially mistaken for the AL form based on a false positive laboratory result is presented. This case illustrates the high index of suspicion required for proper diagnosis of this rare disease. Conclusion Clinician awareness of the various forms of Amyloidosis and the potential for lab error is key to ensuring an accurate diagnosis. The two most common forms carry significantly different implications for treatment and for potential impact on relatives. A high index of suspicion is required particularly for the Familial form of Amyloidosis.
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Affiliation(s)
- Philip B Dattilo
- Division of Cardiology, University of Colorado, Denver, Denver, CO, USA
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Ueda M, Misumi Y, Mizuguchi M, Nakamura M, Yamashita T, Sekijima Y, Ota K, Shinriki S, Jono H, Ikeda SI, Suhr OB, Ando Y. SELDI-TOF Mass Spectrometry Evaluation of Variant Transthyretins for Diagnosis and Pathogenesis of Familial Amyloidotic Polyneuropathy. Clin Chem 2009; 55:1223-7. [DOI: 10.1373/clinchem.2008.118505] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Background: Mass spectrometric analyses are valuable for detection of transthyretin (TTR) variants, which cause familial amyloidotic polyneuropathy (FAP). However, those methods require an immunoprecipitation step with an anti-TTR antibody and are not suitable for quantitative detection. We investigated the usefulness of SELDI-TOF mass spectrometry (MS) without an immunoprecipitation step.
Methods: We used ProteinChips with chromatographic capture formats to detect TTRs. We attempted to correlate the intensity of mixed samples of amyloidogenic TTR (ATTR) V30M to wild-type (WT) TTR. We analyzed the proportion of ATTR V30M in amyloid-laden cardiac tissues from FAP patients, and also evaluated samples from FAP patients with 16 other TTR mutations.
Results: Detection of ATTR required only 3 h of SELDI-TOF MS analysis. We determined that SELDI-TOF MS was suitable for quantitative detection of ATTR V30M and demonstrated that the proportion of ATTR V30M to WT TTR was 46.6% in amyloid-laden cardiac tissue from an FAP patient who died 10 years after liver transplantation. With this method, we identified 12 of 17 TTR variants. Small mass shifts and low concentrations of variants prevented ATTR detection. By changing the analytical conditions, we achieved detection of low concentrations of ATTR Y114C in serum.
Conclusions: SELDI-TOF MS is a reliable tool for quantitative evaluation of TTR variants, in both tissue amyloid deposits and body fluids. This method is useful for the diagnosis and investigation of the pathogenesis of FAP.
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Affiliation(s)
| | - Yohei Misumi
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | | | - Masaaki Nakamura
- Clinical Medicine Section, Department of Clinical Medicine, National Institute for Minamata Disease, Kumamoto, Japan
| | - Taro Yamashita
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshiki Sekijima
- Department of Neurology and Rheumatology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | | | | | - Shu-ichi Ikeda
- Department of Neurology and Rheumatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ole B Suhr
- Department of Medicine, Umeå University Hospital, Umeå, Sweden
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Johnson SM, Connelly S, Wilson IA, Kelly JW. Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. J Med Chem 2009; 52:1115-25. [PMID: 19191553 PMCID: PMC2698027 DOI: 10.1021/jm801347s] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures--using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl)benzamides. Coconsideration of amyloid inhibition potency and ex vivo plasma TTR binding selectivity data reveal that 2,6, 2,5, 2, 3,4,5, and 3,5 substituted aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR.inhibitor crystal structures (1.31-1.35 A) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers.
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Affiliation(s)
- Steven M. Johnson
- Department of Chemistry, and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
| | - Stephen Connelly
- Department of Molecular Biology, and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
| | - Ian A. Wilson
- Department of Molecular Biology, and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
| | - Jeffery W. Kelly
- Department of Chemistry, and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
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Abstract
Liver transplantation aims to halt the progression of the disease in patients with familial amyloidotic polyneuropathy (FAP) caused by hereditary transthyretin-related (ATTR) amyloidosis. Insight in health-related quality of life of these transplanted FAP-patients can be of help to optimize health care delivery. The aim of this cross-sectional study was to assess the health-related quality of life of patients with FAP long-term after transplantation. Nine patients with a post-transplant follow-up of 4 years or more were included in the study. During the annual checks, health-related quality of life was measured with the Short Form-36 (SF-36). Data were compared with non-FAP transplanted patients with the same duration of follow-up and with the normal Dutch population. Pre-transplant, all patients had signs of mild to moderate peripheral polyneuropathy. The results showed that in patients with FAP health-related quality of life was stable in the first 4 years after transplantation. The domain of physical well-being at 4 years after transplantation was significantly lower compared to non-FAP transplanted patients and control Dutch population. The domain of emotional well-being was comparable with non-FAP controls. However, on most health areas patients with FAP scored lower than the non-FAP transplanted patients and the Dutch controls. After four years, the three patients with FAP with longest follow-up (9-12 years) deteriorated in all health domains, except in self-perceived mental health. This study, including only a small number of patients with FAP, shows a relatively low health-related quality of life after liver transplantation, which may deteriorate further with longer follow-up.
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Li YF, Hou N, Iok Sun U, Leong W. Clinical and genetic analysis of three families with familiar amyloid polyneuropathy. ACTA ACUST UNITED AC 2008; 23:230-3. [DOI: 10.1016/s1001-9294(09)60044-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Johnson SM, Connelly S, Wilson IA, Kelly JW. Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies. J Med Chem 2008; 51:6348-58. [PMID: 18811132 PMCID: PMC2587341 DOI: 10.1021/jm800435s] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X 2 or a 3,5-X 2-4-OH phenyl substructure (X = Br or CH 3). Coconsideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls or linkage through nonpolar E-olefin or -CH 2CH 2- substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR.inhibitor crystal structures (1.4-1.8 A) provide insight into why such linkers afford inhibitors with greater potency and selectivity.
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Affiliation(s)
- Steven M. Johnson
- Department of Chemistry, The Scripps Research Institute, BCC 265, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
| | - Stephen Connelly
- Department Molecular of Biology, The Scripps Research Institute, BCC 265, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
| | - Ian A. Wilson
- Department Molecular of Biology, The Scripps Research Institute, BCC 265, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
- The Skaggs Institute for Chemical Biology, The Scripps Research Institute, BCC 265, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
| | - Jeffery W. Kelly
- Department of Chemistry, The Scripps Research Institute, BCC 265, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
- The Skaggs Institute for Chemical Biology, The Scripps Research Institute, BCC 265, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
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50
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Hörnsten R, Suhr OB, Jensen SM, Wiklund U. Outcome of heart rate variability and ventricular late potentials after liver transplantation for familial amyloidotic polyneuropathy. Amyloid 2008; 15:187-95. [PMID: 18925457 DOI: 10.1080/13506120802193290] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Reduced heart rate variability (HRV) is common in familial amyloidotic polyneuropathy (FAP), as well as cardiac arrhythmias. We examined the effects of liver transplantation (LTx) on 24-h HRV and ventricular late potentials. Twenty-one liver-transplanted FAP patients underwent Holter-ECG recordings and signal average electrocardiography recordings (SAECG) before and after LTx. Mean follow-up time after LTx was 21.7 months. Three patients had marked increased HRV after LTx, but this was in all cases caused by the development of subtle atrial arrhythmia and did not reflect an improvement in the cardiac autonomic control. In total, ten patients were excluded from analysis of HRV because of arrhythmia. Spectral analysis of HRV showed no significant differences before and after LTx in the remaining 11 patients. Positive late potentials were found in 33% of patients before LTx and this proportion was unchanged after LTx. Reduced HRV and positive late potentials are common in Swedish FAP patients, and remain stable, at least within the short term after transplantation. If an increase of HRV after transplantation is observed, it should raise the suspicion that the patient has developed subtle atrial arrhythmia.
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Affiliation(s)
- Rolf Hörnsten
- Clinical Physiology, Heart Center, University Hospital, Umeå, and Department of Surgical and Perioperative Sciences, Clinical Physiology, Umeå University, Umeå, Sweden.
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