Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin-related (hATTR) amyloidosis is a rare, severe, inheritable, debilitating disease that tends to affect the peripheral and autonomic nervous system, heart, gastrointestinal system, and eyes. Mutations in the transthyretin (TTR) gene, inherited in an autosomal-dominant pattern, lead to the deposition of amyloid fibrils in multiple organs, which causes somatic and autonomic neuropathy, cardiomyopathy, and other signs and symptoms.¹

Of more than 140 TTR gene mutations identified worldwide, Val30Met is the most common. Owing to the variable nature of the clinical manifestations, penetrance, and disease course, the diagnosis of hATTR is difficult and often delayed. The emergence of effective therapies has improved patients’ quality of life and functional outcomes if the diagnosis is established in a timely manner and treatment is provided early in the disease course.²

In a retrospective study of 266 patients with hATTR amyloidosis, multifaceted impairment related to the disease was found to be associated with a poor prognosis; the median overall survival (mOS) following diagnosis was reported to be 4.7 years.^1,3 In patients presenting with cardiomyopathy-predominant hATTR amyloidosis, survival was further reduced to 3.4 years, with death usually due to progressive heart failure or life-threatening cardiac arrhythmia.^1,4 

Survival after the onset of disease in patients who have hATTR amyloidosis with polyneuropathy ranges from approximately 12 years in those with early-onset Val30Met disease to approximately 7 years in those with late-onset disease caused by other variants, such as Val30Met and Ile107Val.^5,6

In a large cohort study of 3160 consecutive Portuguese patients with the Val30Met variant, the mOS was 12 years. Survival was found to be significantly decreased among patients with late-onset disease if it was left untreated. The mOS in the cohort that received a liver transplant was 21 years following the transplant (maximum follow-up of 25 years). The mOS in the cohort treated with tafamidis had not been reached because the maximum follow-up was 10 years. The study found that the mortality risk was higher among patients with a longer duration of disease before treatment. The 10-year survival rates for the most recent liver transplant group (year 2007 and later) and the tafamidis-treated group were 85% and 93%, respectively. Compared with no treatment, both liver transplant and tafamidis significantly improved survival in patients who had stage 1 Val30Met disease with an early onset (younger than 50 years). In these patients, tafamidis was associated with significant survival gains (63% reduction in mortality risk) in comparison with liver transplant. In patients with late-onset disease, tafamidis was associated with a significant 82% reduction in mortality risk. Thus, early onset of disease, shorter duration of disease, and tafamidis treatment were found to be factors that independently had favorable and significant effects on survival.⁷       

A Swedish study evaluated the effect of liver transplant on survival in 141 patients with Val30Met disease (33 untreated, 108 treated with liver transplant). The survival rate was significantly increased in the patients who underwent liver transplant (10-year survival rate of 83%) in comparison with the survival rate in the untreated patients (mOS of 12 years and 10-year survival rate of 62%).⁸

In a study of 80 consecutive Japanese patients with Val30Met disease (43 untreated, 37 treated with liver transplant), outcomes were similar; the survival of patients who underwent liver transplant was prolonged in comparison with the survival of untreated patients.⁹

References

1. Adams D, Algalarrondo V, Polydefkis M, Sarswat N, Slama MS, Nativi-Nicolau J. Expert opinion on monitoring symptomatic hereditary transthyretin-mediated amyloidosis and assessment of disease progression. Orphanet J Rare Dis. 2021;16:411. doi:10.1186/s13023-021-01960-9
2. Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678. doi:10.1136/jnnp-2021-327909
3. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131. doi:10.3109/13506129.2015.1019610
4. Sattianayagam PT, Hahn AF, Whelan CJ, et al. Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant. Eur Heart J. 2012;33(9):1120-1127. doi:10.1093/eurheartj/ehr383
5. Mariani LL, Lozeron P, Théaudin M, et al. Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France. Ann Neurol. 2015;78(6):901-916. doi:10.1002/ana.24519
6. Koike H, Tanaka F, Hashimoto R, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from non-endemic areas. J Neurol Neurosurg Psychiatry. 2012;83(2):152-158. doi:10.1136/jnnp-2011-301299
7. Coelho T, Inês M, Conceição I, Soares M, de Carvalho M, Costa J. Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy. Neurology. 2018;91(21):e1999-e2009. doi:10.1212/WNL.0000000000006543
8. Okamoto S, Wixner J, Obayashi K, et al. Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients’ survival. Liver Transpl. 2009;15(10):1229-1235. doi:10.1002/lt.21817
9. Yamashita T, Ando Y, Okamoto S, et al. Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology. 2012;78(9):637-643. doi:10.1212/WNL.0b013e318248df18

Reviewed by Harshi Dhingra, MD, on 7/29/2022.

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Erum Naqvi, PhD

Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.