Key Information
Hereditary transthyretin (ATTRv) amyloidosis is a rare and autosomal dominant disorder associated with mutations in the transthyretin gene. Patients present with diverse symptoms related to sensory, motor, and autonomic neuropathy, as well as gastrointestinal, ocular, cardiac, renal and orthopedic symptoms, resulting from the deposition of transthyretin amyloid fibrils in multiple organs. The progressive nature of ATTRv amyloidosis necessitates pre- and post-onset monitoring of the disease. This review article is primarily based on a collation of discussions from a medical advisory board meeting in August 2021. In this article, we summarize the best practices in amyloidosis centers in three major endemic countries for ATTRv amyloidosis (Japan, Brazil, and Portugal), where most patients carry the Val30Met mutation in the transthyretin gene and the patients’ genetic background was proven to be the same. The discussions highlighted the similarities and differences in the management of asymptomatic gene mutation carriers among the three countries in terms of the use of noninvasive tests and tissue biopsies and timing of starting the investigations. In addition, this article discusses a set of practical tests and examinations for monitoring disease progression applicable to neurologists working in diverse medical settings and generalizable in non-endemic countries and areas. This set of assessments consists of periodic (every 6 to 12 months) evaluations of patients’ nutritional status and autonomic, renal, cardiac, ophthalmologic, and neurological functions. Physical examinations and patient-reported outcome assessments should be also scheduled every 6 to 12 months. Programs for monitoring gene mutation carriers and robust referral networks can aid in appropriate patient management in pre- to post-onset stages. For pre- and post-symptom onset testing for ATTRv amyloidosis, various noninvasive techniques are available; however, their applicability differs depending on the medical setting in each country and region, and the optimal option should be selected in view of the clinical settings, medical environment, and available healthcare resources in each region.
Background
Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disorder associated with mutations in the transthyretin (TTR) gene [1external link, opens in a new tab]. Pathogenic mutations in the TTR gene cause destabilization of transthyretin tetramers, resulting in the aggregation of insoluble amyloid fibrils and their deposition in multiple organs [1external link, opens in a new tab]. Patients with ATTRv amyloidosis exhibit a variety of symptoms associated with sensory, motor, and autonomic neuropathy [1external link, opens in a new tab, 2external link, opens in a new tab]. Gastrointestinal manifestations, ocular involvement, cardiac disorders, renal impairment, central nervous system manifestations, and carpal tunnel syndrome (CTS) are also common clinical symptoms [1external link, opens in a new tab,2external link, opens in a new tab,3external link, opens in a new tab,4external link, opens in a new tab,5external link, opens in a new tab,6external link, opens in a new tab].
Because ATTRv amyloidosis progresses slowly or moderately and several therapeutic options are available now, it is essential for attending physicians to capture the early signs and symptoms of disease onset [1external link, opens in a new tab, 7external link, opens in a new tab,8external link, opens in a new tab,9external link, opens in a new tab,10external link, opens in a new tab]. Family members of patients with ATTRv amyloidosis often have pathogenic mutations in the TTR gene and are at risk of developing the disease; thus, they are primary targets for monitoring early signs and symptoms [7external link, opens in a new tab, 11external link, opens in a new tab, 12external link, opens in a new tab]. Indeed, in the Transthyretin Amyloidosis Outcomes Survey (THAOS) Registry, more than one-third of asymptomatic TTR gene mutation carriers developed ATTRv amyloidosis within a median of approximately 2 years of enrolment [13external link, opens in a new tab]. Once a patient has been diagnosed with ATTRv amyloidosis, it is important to initiate treatment and continuously monitor disease progression and treatment response [13external link, opens in a new tab].
Amyloidosis experts worldwide have issued several recommendations for the management of asymptomatic TTR gene mutation carriers [7external link, opens in a new tab, 11external link, opens in a new tab, 12external link, opens in a new tab], as well as those for continuous monitoring of disease progression after disease onset [14external link, opens in a new tab, 15external link, opens in a new tab]. Additionally, in 2022, the International Society of Amyloidosis (ISA) issued guidelines for the treatment and monitoring of ATTRv amyloidosis, which include a minimum set of assessments to monitor disease progression [16external link, opens in a new tab]. Practical and convenient guidance for pre– and post–symptom onset testing for ATTRv amyloidosis that could benefit both amyloidosis specialists and general neurologists working in diverse medical settings would be useful.
This review article is based on the authors’ clinical experience and a collation of discussions from a medical advisory board meeting in August 2021. The meeting was joined by authors from Japan, Brazil, and Portugal and included physician neurologists from amyloidosis referral centers who routinely treat patients with ATTRv amyloidosis in collaboration with clinicians from other specialties. This review article was composed as an initiative to propose a practical approach for family testing and pre– and post–symptom onset testing for ATTRv amyloidosis. In this article, after summarizing the general overview of ATTRv amyloidosis, we discuss the follow-up strategy for TTR gene mutation carriers and diversity of methods used to capture the signs of disease onset. We also present the critical roles of referral centers and referral networks as well as a set of practical patient follow-up methods that can be implemented in various neurology practice settings. In addition, future perspectives in the management of ATTRv amyloidosis are highlighted.
Currently, the availability of equipment and tests to perform patient assessments differs across countries, regions, and medical institutions, and the medical procedures applied in routine practice are primarily based on each physician’s clinical experience. Published evidence from Japan, Brazil, and Portugal, the three endemic countries that share the same patient genetic background [17external link, opens in a new tab], is sufficient to discuss the optimal strategy for testing and monitoring of ATTRv amyloidosis; however, evidence derived from non-endemic countries remains lacking, which necessitates practical approaches generalizable to regions outside the endemic countries.
ATTRv amyloidosis: general overview and epidemiology
The global number of patients with ATTRv amyloidosis was estimated to be 10,186 (range: 5526–38468) [18external link, opens in a new tab]. However, the evidence supporting this estimate is heterogeneous and carries a risk of bias, and the broad range of the estimated prevalence indicates the need for increased awareness regarding this rare disease among neurologists [18external link, opens in a new tab].
More than 140 different mutations in the TTR gene have been reported [19external link, opens in a new tab], and the primary symptoms of ATTRv amyloidosis may vary depending on the genetic mutations involved [1external link, opens in a new tab]. The most common mutation associated with the onset of ATTRv amyloidosis is Val30Met (p.Val50Met) [1external link, opens in a new tab, 20external link, opens in a new tab]. Patients with ATTRv amyloidosis carrying this mutation can be categorized into two groups: patients with early-onset disease (age < 50 years), who are more common in the endemic areas, and those with late-onset disease (age ≥ 50 years), who are also observed in non-endemic areas [21external link, opens in a new tab]. The late-onset disease can sometimes manifest as sporadic cases [22external link, opens in a new tab, 23external link, opens in a new tab]. According to the THAOS Registry, approximately 35%–40% of patients with ATTRv amyloidosis carrying the Val30Met mutation were classified as having late-onset disease [2external link, opens in a new tab, 24external link, opens in a new tab]. The severity of the initial symptoms has been reported to differ between late-onset and early-onset diseases [21external link, opens in a new tab, 24external link, opens in a new tab]. The penetrance of the Val30Met mutation is generally high in early-onset disease and low in late-onset disease [1external link, opens in a new tab], may be greater in cases of maternal inheritance and in men [25external link, opens in a new tab, 26external link, opens in a new tab], but varies greatly among families or individuals [26external link, opens in a new tab, 27external link, opens in a new tab]. Data for other mutations remain insufficient to establish the exact penetrance [28external link, opens in a new tab].
Several countries, such as Portugal, Brazil, Japan, and Sweden, have been historically considered endemic foci of the disease [10external link, opens in a new tab, 20external link, opens in a new tab]. In addition, cases have been reported in other countries, and non-Val30Met mutations have been often observed [2external link, opens in a new tab]. The characteristics of patients with ATTRv amyloidosis differ substantially among regions [29external link, opens in a new tab,30external link, opens in a new tab,31external link, opens in a new tab,32external link, opens in a new tab,33external link, opens in a new tab,34external link, opens in a new tab,35external link, opens in a new tab,36external link, opens in a new tab,37external link, opens in a new tab,38external link, opens in a new tab,39external link, opens in a new tab,40external link, opens in a new tab] (Table 1external link, opens in a new tab). However, these results should be interpreted with caution because the sample size varies widely among reports. Moreover, some publications are not based on nationwide surveillance, and thus, the number of patients assessed in each publication may be substantially lower than the total number of patients in each country or region.