Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein ...destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan. Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.
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.
Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering ...RNA targeting transthyretin messenger RNA, to treat the disease.
Cerebrotendinous xanthomatosis (CTX) is likely to be underdiagnosed and precise epidemiological characteristics of CTX are largely unknown as knowledge on the disorder is based mainly on case ...reports. We conducted a nationwide survey on CTX to elucidate the frequency, clinical picture, and molecular biological background of Japanese CTX patients. In this first Japanese nationwide survey on CTX, 2541 questionnaires were sent to clinical departments across Japan. A total of 1032 (40.6%) responses were returned completed for further analysis. Forty patients with CTX (50.0% male) were identified between September 2012 and August 2015. The mean age of onset was 24.5 ± 13.6 years, mean age at diagnosis was 41.0 ± 11.6 years, and corresponding mean duration of illness from onset to diagnosis was 16.5 ± 13.5 years. The most common initial symptom was tendon xanthoma, followed next by spastic paraplegia, cognitive dysfunction, cataract, ataxia, and epilepsy. The most predominant mutations in the CYP27A1 gene were c.1214G> A (p.R405Q, 31.6%), c.1421G> A (p.R474Q, 26.3%), and c.435G> T (p.G145=, 15.8%). Therapeutic interventions that included chenodeoxycholic acid, HMG-CoA reductase inhibitor, and LDL apheresis reduced serum cholestanol level in all patients and improved clinical symptoms in 40.5% of patients. Although CTX is a treatable neurodegenerative disorder, our nationwide survey revealed an average 16.5-year diagnostic delay. CTX may be underdiagnosed in Japan, especially during childhood. Early diagnosis and treatment are essential to improve the prognosis of CTX.
The vein stump created after lung lobectomy has been reported to cause thrombus and subsequently cerebral infarction. However, its assessment after a long-term postoperative course remains ...unreported. The pulmonary vein stump is a structure near the left atrial appendage; therefore, such patients may be at a constant risk of thrombus formation. We herein report two cases of cerebral infarction associated with lung lobectomy. Transesophageal echocardiography revealed mobile thrombi in the pulmonary vein stump. Both patients had cancer recurrence, and hypercoagulability may have contributed to thrombus formation. This vein stump should be investigated as an embolic source, even after a long postoperative duration.
We report the case of an 80-year-old man with Frey syndrome that developed 30 years postoperatively, which is an exceptionally long period before its occurrence. Sweating and flushing occurred on ...only the side of his face where the surgery was performed, and he had no other causative abnormalities. Following treatment with botulinum toxin, the patient's symptoms resolved. Extremely early- and late-onset cases do not fit the conventional paradigm of this pathology. Various surgical methods to prevent this syndrome have been explored, but complete prevention has not yet been achieved. These findings suggest that the underlying pathophysiology of Frey's syndrome may be more complex than previously recognized.
Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a life‐threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR‐CM has stimulated increased ...awareness of the disease and patient identification. Stratification of patients with ATTR‐CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best‐practice guidance. In this report, experts with experience in treating amyloidosis and ATTR‐CM developed consensus recommendations for monitoring the course of patients with ATTR‐CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR‐CM will help to elucidate, refine and define these and other measurements.
This consensus document from an international expert panel recommends a set of clinically feasible tools for the long‐term monitoring of patients with transthyretin amyloid cardiomyopathy (ATTR‐CM), including meaningful thresholds for defining disease progression and the frequency of measurements. 6MWT, 6‐min walk test; ECG, electrocardiogram; EQ‐5D, EuroQol five dimensions; GLS, global longitudinal strain; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVEF, LV, left ventricular ejection fraction; NAC, UK National Amyloidosis Centre; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; QoL, quality of life.
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