Practice of Hereditary ATTR Amyloidosis in Non-endemic Areas of Japan

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Abstract

Objective

Hereditary ATTR (ATTRv) amyloidosis was once an incurable disease; however, in recent years, disease-modifying therapies, such as tafamidis and patisiran, have become available. We herein report the medical care situation in an ATTRv amyloidosis non-endemic area of Japan.

Methods

We confirmed the information in the medical records of our department and analyzed the data retrospectively.

Patients

Patients with ATTRv amyloidosis who were treated in our department between 2010 and 2021 were included.

Results

A total of 15 ATTRv amyloidosis cases (8 men and 7 women) were treated in our department during the study period; 9 patients had a family history, and the transthyretin V30M (p.V50M) gene mutation was present in 66% of cases. The average age of the onset was 57 years old, with 73% of the initial symptoms being dysesthesia and 13% being autonomic dysfunction. Ten patients were treated with tafamidis and nine with patisiran. Although it took a long time to start treatment among our experienced cases, there were some cases in which treatment could be introduced relatively early.

Conclusion

ATTRv amyloidosis is treatable and should be included in the differential diagnosis of neuropathy so that it can be diagnosed early and introduced into treatment. In the near future, the presymptomatic diagnosis of ATTRv amyloidosis and genetic counseling will become more important.

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Most cited references 12

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Safety and efficacy of RNAi therapy for transthyretin amyloidosis.

Teresa Coelho, David George Adams, Ana Fialho Silva … (2013)

Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).

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Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas.

Fumiaki Tanaka, Toru Kawanami, Masahiro Iijima … (2012)

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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Familial amyloid polyneuropathy.

Violaine Planté-Bordeneuve, Gérard Said (2011)

Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Intern Med

Journal ID (iso-abbrev): Intern Med

Title: Internal Medicine

Publisher: The Japanese Society of Internal Medicine

ISSN (Print): 0918-2918

ISSN (Electronic): 1349-7235

Publication date (Electronic): 19 October 2022

Publication date (Print): 1 June 2023

Volume: 62

Issue: 11

Pages: 1599-1602

Affiliations

[1 ]Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Japan

[2 ]Department of Neurology, Obihiro Kosei Hospital, Japan

[3 ]Department of Neurology, Japanese Red Cross Asahikawa Hospital, Japan

[4 ]Division of Clinical Genetics, Hokkaido university Hospital, Japan

Author notes

Correspondence to Dr.　Masaaki Matsushima, mmasaaki@ 123456huhp.hokudai.ac.jp

Article

DOI: 10.2169/internalmedicine.0091-22

PMC ID: 10293005

PubMed ID: 36261369

SO-VID: 57091596-b525-422f-9812-c479824b1be3

License:

The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

Practice of Hereditary ATTR Amyloidosis in Non-endemic Areas of Japan

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Abstract

Objective

Methods

Patients

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Citation Behaviour and Practice

Most cited references 12

Safety and efficacy of RNAi therapy for transthyretin amyloidosis.

Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas.

Familial amyloid polyneuropathy.

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