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.
Highlights
Transthyretin-type familial amyloid polyneuropathy (ATTR-Familial amyloid polyneuropathy (FAP)), or hereditary transthyretin amyloidosis (ATTRm amyloidosis), is an autosomal-dominant, adultonset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage [1, 2]
There are over 130 different TTR gene mutations identified worldwide, of which >40 mutations are linked with ATTR-FAP in Japan (Table 1)
Double-blind trial, where early-stage ATTR-FAP patients received tafamidis meglumine 20 mg once daily or placebo for 18 months, no differences were observed between the tafamidis and placebo groups for the Neuropathy Impairment Score– Lower Limbs (NIS-LL) responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in Norfolk Quality of Life Diabetic Neuropathy total score (TQOL; 2.0 vs 7.2; p = 0.116) in the intent-to-treat population (n = 125), a significantly greater proportion (60.0% vs 38.1%; p < 0.041) of patients receiving tafamidis were NIS-LL responders and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045) in the efficacy-evaluable population (n = 87)
Summary
Transthyretin-type familial amyloid polyneuropathy (ATTR-FAP), or hereditary transthyretin amyloidosis (ATTRm amyloidosis), is an autosomal-dominant, adultonset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage [1, 2]. A number of patients with ATTR-FAP still remain undiagnosed and untreated because of diverse clinical presentations and various non-specific symptoms of the disease; especially in Japan, presence of diverse types of patients (e.g. early-onset Val30Met in endemic areas, late-onset Val30Met in non-endemic areas, non-Val30Met variants whose cardinal symptoms are cardiomyopathy, carpal tunnel syndrome, or cerebral amyloid angiopathy) often makes accurate diagnosis difficult [15, 16, 24, 43,44,45]. In view of the enormous possibility of misdiagnosis or delayed diagnosis, Conceição and colleagues reported red-flag symptom clusters suggestive of ATTR-FAP and treatment algorithms [46] These clusters and algorithms are not necessarily applicable to Japan because situations specific to this country (e.g. presence of diverse types of patients) are not fully reflected. We provide a consolidated review of the worldwide landscape of ATTR-FAP and our treatment experience in Japanese ATTR-FAP patients to propose revised red-flag symptom clusters and treatment algorithm
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