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      Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm

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          Abstract

          Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage. TTR gene mutations (e.g. replacement of valine with methionine at position 30 [Val30Met (p.Val50Met)]) lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, which form amyloid fibrils that deposit in peripheral nerves and various organs, giving rise to peripheral and autonomic neuropathy and several non-disease specific symptoms.

          Phenotypic and genetic variability and non–disease-specific symptoms often delay diagnosis and lead to misdiagnosis. Red-flag symptom clusters simplify diagnosis globally. However, in Japan, types of TTR variants, age of onset, penetrance, and clinical symptoms of Val30Met are more varied than in other countries. Hence, development of a Japan-specific red-flag symptom cluster is warranted. Presence of progressive peripheral sensory-motor polyneuropathy and ≥1 red-flag sign/symptom (e.g. family history, autonomic dysfunction, cardiac involvement, carpal tunnel syndrome, gastrointestinal disturbances, unexplained weight loss, and immunotherapy resistance) suggests ATTR-FAP. Outside of Japan, pharmacotherapeutic options are first-line therapy. However, because of positive outcomes (better life expectancy and higher survival rates) with living donor transplant in Japan, liver transplantation remains first-line treatment, necessitating a Japan-specific treatment algorithm.

          Herein, we present a consolidated review of the ATTR-FAP Val30Met landscape in Japan and summarize findings from a medical advisory board meeting held in Tokyo on 18th August 2016, at which a Japan-specific ATTR-FAP red-flag symptom cluster and treatment algorithm was developed. Beside liver transplantation, a TTR-stabilizing agent (e.g. tafamidis) is a treatment option. Early diagnosis and timely treatment using the Japan-specific red-flag symptom cluster and treatment algorithm might help guide clinicians regarding apt and judicious use of available treatment modalities.

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          Most cited references93

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          Amyloid fibrillogenesis: themes and variations.

          Recent progress has improved our knowledge of how proteins form amyloid fibrils. Both 'natively unfolded' and globular proteins have been shown to initiate fibrillization by adopting a partially structured conformation. Oligomeric prefibrillar intermediates have been extensively characterized with respect to their morphology and temporal evolution. Three-dimensional models obtained using biophysical and computational methods have provided information about fibril structure. All of these advances suggest common features of self-assembly pathways, with subtle variations accounting for differences among distinct amyloid fibrils.
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            The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways.

            The conformational change hypothesis postulates that tertiary structural changes under partially denaturing conditions convert one of 17 normally soluble and functional human proteins into an alternative conformation that subsequently undergoes self-assembly into an amyloid fibril, the putative causative agent in amyloid disease. This hypothesis is consistent with Anfinsen's view that the tertiary structure of a protein is determined both by its sequence and the aqueous environment; the latter does not always favor the normally folded state. Unlike sickle cell hemoglobin assembly, where owing to a surface mutation, hemoglobin polymerizes in its normally folded conformation, amyloid proteins self-assemble as a result of the formation of an alternative tertiary structure-a conformational intermediate formed under partially denaturing conditions. The pathway by which an amyloidogenic protein assembles into amyloid fibrils appears to involve quaternary structural intermediates that assemble into increasingly complex quaternary structures, including amyloid protofilaments, which ultimately assemble into amyloid fibrils. Several recent studies have discussed the multi-step assembly pathway(s) characterizing amyloid fibril formation.
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              Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas.

              The objective of this study was to elucidate the natural history of late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) in non-endemic areas. The authors retrospectively assessed the development of major clinical landmarks and abnormalities of nerve conduction and cardiac examination indices in 50 patients with an age of onset older than 50 years and no relationship to endemic foci. Once the neuropathic process was initiated, sensory and motor symptoms of both the upper and lower extremities appeared within a period of one and a half years. Digestive and orthostatic symptoms also tended to occur in the early phase of the disease, whereas urinary symptoms appeared in the middle of the disease progress. Along with pain in the extremities, these symptoms progressed over time and significantly disturbed the quality of life during the late phase of the disease, resulting in the need for wheelchair use. Although cardiomyopathy became clinically apparent only in the late phase of the disease, it was found to be the major cause of death. The mean duration of the disease onset to death was 7.3 years. Although values at the time of diagnosis were extremely variable, serial measurements of electrophysiological indices, the cardiothoracic ratio and interventricular septum thickness indicated a steady exacerbation in these outcomes among patients within a span of a couple of years. The ages of onset of each clinical landmark were extremely variable between patients. However, once an initial symptom appeared, the chronological sequence of other clinical landmarks tended to be uniform, occurring within a relatively short time span.
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                Author and article information

                Contributors
                sekijima@shinshu-u.ac.jp
                mitt@rb3.so-net.ne.jp
                koike-haruki@med.nagoya-u.ac.jp
                sonoko.m@mb.infoweb.ne.jp
                Tomonori.Ishii@pfizer.com
                +81-96-373-5686 , andoy709@kumamoto-u.ac.jp
                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                1750-1172
                17 January 2018
                17 January 2018
                2018
                : 13
                : 6
                Affiliations
                [1 ]ISNI 0000 0001 1507 4692, GRID grid.263518.b, Department of Medicine (Neurology and Rheumatology), , Shinshu University School of Medicine, ; Matsumoto, Japan
                [2 ]ISNI 0000 0001 0660 6749, GRID grid.274841.c, Department of Neurology, , Graduate School of Medical Sciences, Kumamoto University, ; 1-1-1 Honjo, Chuo-ku, Kumamoto-shi, Kumamoto, 860-8556 Japan
                [3 ]ISNI 0000 0001 0943 978X, GRID grid.27476.30, Department of Neurology, , Nagoya University Graduate School of Medicine, ; Nagoya, Japan
                [4 ]ISNI 0000 0004 0370 1101, GRID grid.136304.3, Department of Neurology, , Graduate School of Medicine, Chiba University, ; Chiba, Japan
                [5 ]ISNI 0000 0004 1761 4439, GRID grid.418567.9, Pfizer Japan Inc., ; Tokyo, Japan
                Article
                726
                10.1186/s13023-017-0726-x
                5773042
                29343286
                c6c96e36-e8be-415d-9922-93916fcc71d2
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 July 2017
                : 23 November 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100010793, Pfizer Japan;
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Infectious disease & Microbiology
                disease-modifying agent,tafamidis,liver transplantation,hereditary attr amyloidosis,familial amyloid polyneuropathy,amyloidosis neuropathy,carpal tunnel syndrome,cardiomyopathy,red-flag symptom clusters

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