Optimal practices for the management of hereditary transthyretin amyloidosis: real-world experience from Japan, Brazil, and Portugal

Abstract

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.

Keywords: ATTR amyloidosis; Asymptomatic; Biopsy; Cardiomyopathy; Gene mutation carrier; Genetic counseling; Neuropathy; Noninvasive testing; Practical guidance; Predictive genetic testing.

Fig. 1

Follow-up program for the management of TTR gene mutation carriers. ^aThe prerequisites for offering predictive genetic testing should follow the local guidelines for genetic testing and diagnosis. ATTRv hereditary transthyretin, DMT disease-modifying treatment, TTR transthyretin

Fig. 2

Model for a referral network in the post-onset management of ATTRv amyloidosis. Collaboration between referral centers and local clinics can be achieved by knowledge dissemination, patient referral, or other forms. ATTRv hereditary transthyretin

Fig. 3

Set of practical tests and examinations for monitoring ATTRv amyloidosis progression. ^aCardiac and ophthalmologic assessments can be scheduled more frequently when any apparent symptoms are observed. ATTRv hereditary transthyretin, BNP brain natriuretic peptide, CMAP compound muscle action potential, COMPASS-31 Composite Autonomic Symptom Score 31, CTS carpal tunnel syndrome, ECG electrocardiography, eGFR estimated glomerular filtration rate, EQ-5D EuroQol 5-dimension, mBMI modified body mass index, NT-proBNP N-terminal pro-brain natriuretic peptide, NYHA New York Heart Association, QoL-DN Quality of Life-Diabetic Neuropathy, SNAP sensory nerve action potential