家族性淀粉样多发性神经病.doc

familial amyloid polyneuropathy1. J Peripher Nerv Syst. 2015 Dec 13. doi: 10.1111/jns.12153. Epub ahead of printRed-flag symptom clusters in transthyretin familial amyloid polyneuropathy.Conceio I(1), Gonzlez-Duarte A(2), Obici L(3), Schmidt HH(4), Simoneau D(5),Ong ML(6), Amass L(6).Author information: (1)CHLN - Hospital de Santa Maria, and Clinical and Translational PhysiologyUnit, Physiology Institute, Faculty of Medicine-IMM, Lisbon, Portugal.(2)Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, MxicoCity, Mxico. (3)Amyloidosis Research and Treatment Center, Fondazione IRCCSPoliclinico San Matteo, Pavia, Italy. (4)Klinik fr Transplantationsmedizin,Universittsklinikum Mnster, Mnster, Germany. (5)Pfizer IO, Paris, France.(6)Pfizer Inc, New York, NY, USA.BACKGROUND: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare,progressive, life-threatening, hereditary disorder caused by mutations in thetransthyretin gene and characterized by extracellular deposition oftransthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease isdifficult to recognize due to phenotypic heterogeneity.METHODS: Based on published literature and expert opinion, symptom clusterssuggesting TTR-FAP are reviewed, and practical guidance to facilitate earlierdiagnosis is provided. Results and conclusions TTR-FAP should be suspected ifprogressive peripheral sensory-motor neuropathy is observed in combination withone or more of the following: family history of a neuropathy, autonomicdysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAPis suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy,large- and small-fiber assessment by nerve conduction studies and autonomicsystem evaluations, and cardiac testing should be performed.This article is protected by copyright. All rights reserved.PMID: 26663427 PubMed - as supplied by publisher2. Transplantation. 2015 Dec 11. Epub ahead of printSurvival After Transplantation in Patients With Mutations Other Than Val30Met:Extracts From the FAP World Transplant Registry.Suhr OB(1), Larsson M, Ericzon BG, Wilczek HE; FAPWTRs investigators.Author information: (1)1 Department of Public Health and Clinical Medicine, Ume University Hospital,Ume, Sweden. 2 Division of Transplantation Surgery, Karolinska Institutet,CLINTEC, Karolinska University Hospital, Huddinge, Stockholm, Sweden.BACKGROUND: Liver transplantation (LTx) has been performed for hereditarytransthyretin amyloidosis (ATTR) since 1990. Outcomes for a relatively largeseries of LTx ATTR patients with the Val30Met (mutation are available, but fornon-Val30Met patients, only a few reports with a small number of patients exist. Here, we present outcomes for non-Val30Met ATTR patients after LTx, as reportedto the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR).METHODS: Data regarding outcome were extracted for all non-Val30Met patientsreported to the registry. Survival rates were analyzed by the Kaplan-Meier methodand log-rank test.RESULTS: The total number of patients with a non-Val30Met mutation in theregistry was 264 (174 men and 90 women), representing 57 mutations. The 10-yearsurvival varied markedly for the 9 most common mutations, ranging from 21% forSer50Arg to 85% for Val71Ala. Poor survival was noted for all mutations withleptomeningeal complications except for those with the Tyr114Cys mutation.CONCLUSIONS: Large differences in survival were observed relative to differentmutations and between mutations with similar phenotypes. Excellent survival wasnoted for mutations, such as Leu111Met, Val71Ala, and Leu58His. Patients withmutations other than Val30Met are not a homogeneous group, and the termnon-Val30Met should be used with caution or avoided. Moreover, for severalmutations, data are too limited to allow evaluation of the efficacy of LTx, andcontinuous international collaboration is important for obtaining treatmentguidance.This is an open-access article distributed under the terms of theCreative Commons Attribution-Non Commercial-No Derivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.PMID: 26656838 PubMed - as supplied by publisher3. Ann Med. 2015 Dec;47(8):625-38. doi: 10.3109/07853890.2015.1068949. Epub 2015 Nov27.Evolving landscape in the management of transthyretin amyloidosis.Hawkins PN(1), Ando Y(2), Dispenzeri A(3), Gonzalez-Duarte A(4), Adams D(5), SuhrOB(6).Author information: (1)a National Amyloidosis Centre, Royal Free Hospital, University College London , London , UK. (2)b Department of Neurology , Graduate School of Medical SciencesKumamoto University , Kumamoto , Japan. (3)c Mayo Clinic, Division of Hematology , Rochester, Minnesota, USA. (4)d Instituto Nacional de Ciencias Mdicas yNutricin Salvador Zubirn , Mexico City , Mexico. (5)e National Reference Centrefor FAP, APHP, CHU Bictre, Universit Paris-Sud, INSERM U788 , Paris , France.(6)f Department of Public Health and Clinical Medicine , Ume University , Ume ,Sweden.Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic,multigenotypic disease resulting from deposition of insoluble ATTR amyloidfibrils in various organs and tissues. Although considered rare, the prevalenceof this serious disease is likely underestimated because symptoms can benon-specific and diagnosis largely relies on amyloid detection in tissuebiopsies. Treatment is guided by which tissues/organs are involved, althoughtherapeutic options are limited for patients with late-stage disease. Indeed,enthusiasm for liver transplantation for familial ATTR amyloidosis withpolyneuropathy was dampened by poor outcomes among patients with significantneurological deficits or cardiac involvement. Hence, there remains an unmetmedical need for new therapies. The TTR stabilizers tafamidis and diflunisal slowdisease progression in some patients with ATTR amyloidosis with polyneuropathy,and the postulated synergistic effect of doxycycline and tauroursodeoxycholicacid on dissolution of amyloid is under investigation. Another therapeuticapproach is to reduce production of the amyloidogenic protein, TTR. Plasma TTRconcentration can be significantly reduced with ISIS-TTRRx, an investigationalantisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. Theevolving treatment landscape for ATTR amyloidosis brings hope for furtherimprovements in clinical outcomes for patients with this debilitating disease.PMID: 26611723 PubMed - in process4. J Am Coll Cardiol. 2015 Dec 1;66(21):2451-66. doi: 10.1016/j.jacc.2015.09.075.Diagnosis, Prognosis, and Therapy ofTransthyretin Amyloidosis.Gertz MA(1), Benson MD(2), Dyck PJ(3), Grogan M(4), Coelho T(5), Cruz M(6), Berk JL(7), Plante-Bordeneuve V(8), Schmidt HH(9), Merlini G(10).Author information: (1)Division of Hematology, Mayo Clinic, Rochester, Minnesota. Electronic address:. (2)Indiana University School of Medicine, Indianapolis,Indiana. (3)Division of Peripheral Nerve, Mayo Clinic, Rochester, Minnesota.(4)Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.(5)Hospital de Santo Antonio, Porto, Portugal. (6)Federal University of Rio deJaneiro of Brazil, University Hospital, Rio de Janeiro, Brazil. (7)AmyloidosisCenter, Boston University School of Medicine, Boston, Massachusetts.(8)University Hospital, Henri Mondor, Crteil, France. (9)UniversittsklinikumMnster, Mnster, Germany. (10)Department of Molecular Medicine, University ofPavia, Pavia, Lombardy, Italy.Transthyretin amyloidosis is a fatal disorder that is characterized primarily by progressive neuropathy and cardiomyopathy. It occurs in both a mutant form (with autosomal dominant inheritance) and a wild-type form (with predominant cardiacinvolvement). This article guides clinicians as to when the disease should besuspected, describes the appropriate diagnostic evaluation for those with knownor suspected amyloidosis, and reviews the interventions currently available foraffected patients.Copyright 2015 American College of Cardiology Foundation. Published by ElsevierInc. All rights reserved.PMID: 26610878 PubMed - in process5. Neurol Ther. 2015 Dec;4(2):61-79. doi: 10.1007/s40120-015-0031-3. Epub 2015 Aug15.A Review of Tafamidis for the Treatment of Transthyretin-Related Amyloidosis.Waddington Cruz M(1), Benson MD(2).Author information: (1)Amyloidosis Research and Treatment Center (CEPARM), University Hospital(HUCFF), Federal University of Rio de Janeiro, Rio De Janeiro, B. (2)Department of Pathology and Laboratory Medicine,Indiana University School of Medicine, Indianapolis, IN, USA.Transthyretin (TTR)-related amyloidosis (ATTR) is a devastating disease whichaffects a combination of organs including the heart and the peripheral nerves,and which has a fatal outcome if not treated within a average of 10years.Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-typenative TTR and mutant TTR; tafamidis therefore has the potential to halt theamyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding,and aggregation. The first tafamidis trial, Fx-005, evaluated the effect of18months of tafamidis treatment (20mg once daily) on disease progression, aswell as assessing its safety in TTR-FAP Val30Met patients. The secondaryobjective of this trial was to study the pharmacodynamic stabilization of mutatedTTR. Tafamidis proved effective in reducing the progress of neuropathy, and inmaintaining the nutritional status and quality of life of stage 1 (able to walkwithout support) Val3OMet TTR-FAP patients. Furthermore, TTR stabilization wasachieved in more than 90% of patients. An extension study, Fx-006, was conducted to determine the long-term safety and tolerability of tafamidis and to assess theefficacy of the drug on slowing disease progression. No significant safety ortolerability issues were noticed. Taken together, the results from both trialsindicated that the beneficial effects of tafamidis were sustained over a 30-monthperiod and that starting treatment early is desirable. Results are expected from an extended open-label study but data that have already been presented show that long-term use of tafamidis in Val30Met patients is associated with reducedprogression in polyneuropathy. Tafamidis was initially approved for commercialuse in Europe in 2011 and has since been approved for use in Japan, Mexico, andArgentina where it is used as a first-line treatment option for patients withearly-stage TTR-FAP. Patients should be carefully followed at referral centers toascertain the individual response to treatment. In cases of discontinuation,liver transplantation and enrollment in clinical trials of novel drugs aimedmostly toward suppression of TTR production are options.PMCID: PMC4685869PMID: 26662359 PubMed6. Parkinsonism Relat Disord. 2015 Dec;21(12):1465-8. doi:10.1016/j.parkreldis.2015.10.012. Epub 2015 Oct 21.A peripheral pathway to restless legs syndrome? Clues from familial amyloidpolyneuropathy.Teodoro T(1), Viana P(2), Abreu D(3), Conceio I(4), Peralta R(5), FerreiraJJ(6).Author information: (1)Department of Neurology, Hospital de Santa Maria, Lisboa, Portugal; ClinicalPharmacology Unit, Instituto de Medicina Molecular, Faculty of Medicine,University of Lisbon, Lisboa, Portugal; St Georges University London, London,United Kingdom. Electronic address: . (2)Department ofNeurology, Hospital de Santa Maria, Lisboa, Portugal. (3)Clinical PharmacologyUnit, Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon,Lisboa, Portugal. (4)Department of Neurology, Hospital de Santa Maria, Lisboa,Portugal; Translational and Clinical Physiology Unit, Instituto de MedicinaMolecular, Faculty of Medicine, University of Lisbon, Lisboa, Portugal.(5)Department of Neurology, Hospital de Santa Maria, Lisboa, Portugal; EEG/Sleep Laboratory, Hospital de Santa Maria, Lisboa, Portugal. (6)Department ofNeurology, Hospital de Santa Maria, Lisboa, Portugal; Clinical Pharmacology Unit,Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon,Lisboa, Portugal.BACKGROUND: The relationship between restless legs syndrome (RLS) and peripheral neuropathy remains unclear. In order to clarify this relationship, weinvestigated if RLS is increased in familial amyloid polyneuropathy related totransthyretin (TTR-FAP) and investigated factors associated with RLS in thispopulation.METHODS: RLS frequency was compared between TTR-FAP patients and controls.Secondly, TTR-FAP patients with and without RLS were compared regardingdemographic and clinical characteristics.RESULTS: RLS frequency was significantly increased in TTR-FAP, with 18/98 (18.4%)cases contrasting with 5/104 (4.8%) controls (p-value 0.002). This differenceremained significant after adjusting for confounders. In TTR-FAP patients, femalesex (p-value 0.037), obesity (p-value 0.036) and weight excess (p-value 0.048)were associated with RLS, contrary to other classical RLS risk factors.CONCLUSIONS: RLS frequency is increased in TTR-FAP, thus supporting anassociation between RLS and neuropathy. This may represent a peripheral pathwayin RLS pathogenesis. Furthermore, our results suggest that female sex andobesity/weight excess may be risk factors for RLS development among TTR-FAPpatients.Copyright 2015 Elsevier Ltd. All rights reserved.PMID: 26508424 PubMed - in process7. Rev Neurosci. 2015 Dec 1;26(6):691-8. doi: 10.1515/revneuro-2015-0003.Receptor for advanced glycation end-products in neurodegenerative diseases.Juranek J, Ray R, Banach M, Rai V.This review, for the first time, aims to summarize the current knowledge in theemerging field of RAGE (receptor for advanced glycation end-products) studies in neurodegeneration and neurodegenerative diseases. RAGE, a member of themultiligand cell surface immunoglobulin family, has been implicated in numerouspathological conditions - from diabetes and cardiovascular diseases to tumors andneurodegenerative disorders, such as Alzheimers disease, familial amyloidpolyneuropathy, diabetic neuropathy, Parkinsons disease, and Huntingtonsdisease. Until now, the detailed mechanisms of the contribution of RAGE toneurodegeneration remain elusive; however, mounting evidence suggests that itsdetrimental actions are triggered by its ligand interactions and contribute toincreased neuroinflammation, neuronal degeneration, and apoptosis. Decipheringthe role of RAGE in neurodegenerative disorders will be a milestone in our basic understanding of the mechanisms involved in the pathogenesis ofneurodegeneration, helping to delineate molecular links between complex RAGEsignaling pathways and neuronal dysfunction and neurodegeneration.PMID: 26226128 PubMed - in process8. Liver Transpl. 2015 Nov 24. doi: 10.1002/lt.24371. Epub ahead of printRecipient Aging Accelerates Acquired Transthyretin Amyloidosis After Domino LiverTransplantation.Misumi Y(1), Narita Y(2), Oshima T(1), Ueda M(1), Yamashita T(1), TasakiM(1,)(3), Obayashi K(3), Isono K(2), Inomata Y(2), Ando Y(1).Author information: (1)Department of Neurology, Graduate School of Medical Sciences, KumamotoUniversity, Kumamoto, Japan. (2)Department of Transplantation and PediatricSurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto,Japan. (3)Department of Morphological and Physiological Sciences, Graduate Schoolof Health Sciences, Kumamoto University, Kumamoto, Japan.INTRODUCTION: Domino liver transplantation (DLT) with liver grafts from patients with hereditary transthyretin (TTR) amyloidosis has been performed throughout theworld because of a severe liver graft shortage. Reports of acquired systemic TTR amyloidosis in domino liver recipients have been increasing; however, the precisepathogenesis and clinical course of acquired TTR amyloidosis remains unclear.RESULTS: We analyzed the relationship between the occurrence of acquiredamyloidosis and clinical features in consecutive 22 domino liver donors withhereditary TTR amyloidosis 10 males and 12 females; mean age at DLT: 37.2 years;TTR mutations: V30M (n = 19), Y114C (n = 1), L55P (n = 1), and S50I (n = 1) and 22 liver recipients (16 males and 6 females; mean age at DLT, 46.2 years). Themean times from DLT to amyloid first appearance and transplant recipient symptom onset were 8.2 years and 9.9 years, respectively. Kaplan-Meier analysis andquantification of the amyloid deposition revealed aging of recipients correlated with early de novo amyloid deposition. The sex of donors and recipients and theage, disease duration, and disease severity of donors had no significant effecton the latency of de novo amyloid deposition.CONCLUSION: Our results demonstrate that recipient aging is associated with theearly-onset de novo amyloidosis. Because acquired amyloidosis will likelyincrease, careful follow-up for early amyloidosis