Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, rare, inherited, multisystemic condition caused by mutations in the transthyretin (TTR) gene. The TTR gene encodes the transthyretin protein, which is primarily produced by the liver. Mutations in the TTR gene cause dissociation during transthyretin protein folding, resulting in the production of the abnormal monomer protein, amyloid. Accumulation of amyloid occurs throughout the body’s organs and tissues, especially affecting the nervous system and heart.1,2
The global prevalence of hATTR is estimated at around 50,000 people with various manifestations depending on affected organs.2,3
In northern Portugal, the incidence of hATTR is estimated to be 1 in every 538 people. The incidence in Americans of European descent is estimated to be 1 in every 100,000 people.1
True prevalence and incidence are underestimated due to a lack of awareness of the disease and diagnostic delays. The use of cardiac scintigraphy has improved the accuracy of hATTR diagnosis, allowing earlier recognition of infiltration of cardiac tissue with amyloid protein.4
Over 130 pathogenic variants of familial hATTR have been identified. Due to the autosomal dominant pattern of inheritance, hATTR tends to cluster in certain geographic regions or ethnic groups.4
As of 2019, hATTR has been documented in 29 countries throughout the world. Originally, hATTR occurred in 3 main endemic locations in Portugal, Japan, and Sweden, with smaller clusters in Cyprus and Majorca. Incidence throughout Europe and other nonendemic areas is sporadic, but increased incidence is projected due to improved diagnostic tools such as genetic testing and increased awareness of the condition.5
In the United States, the most common variants include TTR V30M, TTR T60A, TTR L58H, TTR S77Y, and TTR I84S.6
Hereditary transthyretin-mediated amyloidosis affects men and women at equal rates; however, in men, disease onset typically occurs at earlier ages and disease penetrance is higher. Additionally, the cardiac type of hATTR occurs more frequently in men. Researchers have speculated the possibility of female sex hormones providing cardioprotective effects in women with familial ATTR.6,7
Age of hATTR onset varies according to different TTR variants. Most available data are regarding disease caused by the TTR V30M variant, which typically presents during the third or fourth decade of life in gene carriers in Portugal, Japan, and Brazil. The average age of disease onset for this variant in Japan and Portugal is 32 years.6
In Sweden, the same variant causes a later onset of the disease around the fifth or sixth decade of life, with an average age of onset of 56 years.6
Age at disease onset gets progressively younger when comparing successive generations. More aggressive variants present in teenagers and young adults. Normal-sequence cardiac variants of hATTR typically manifest after the age of 70 years.6
In 2016, 37.3% of the 142 newly diagnosed cases of hATTR in the United States affected people aged 55 to 64 years, followed by 31.7% in people aged 65 years and over, 24.6% in people aged 35 to 54 years, and 6.3% in people aged 18 to 34 years.8
Hereditary transthyretin-mediated amyloidosis does not show any preference for specific races or ethnicities, affecting people of all races.6
Globally, the most frequent late-onset variant, TTR V112I, affects cardiac tissue and originated in West Africa. This variant has spread throughout West Africa, affecting over 5% of the population, and the Americas. Cardiac hATTR affects around 3.9% of African Americans in the United States and occurs more frequently in this race than in others.6
Other TTR variants originated in individuals of European, Chinese, and Japanese ancestry. The TTR V30M variant manifests throughout Europe, Japan, and the Americas, occurring most commonly in northern Sweden, northern Portugal, and specific regions in Japan.6
- Transthyretin amyloidosis. MedlinePlus. Updated January 1, 2009. Accessed July 7, 2022.
- Hereditary ATTR amyloidosis: disease overview. Alnylam Pharmaceuticals, Inc. Accessed July 7, 2022.
- Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7):S107-S112.
- Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR epidemiology, genetics, and prognostic factors. Methodist DeBakey Cardiovasc J. 2022;18(2):17-26. doi:10.14797/mdcvj.1066
- Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979
- Roberts JR. Transthyretin-related amyloidosis: epidemiology. Medscape. Updated June 16, 2022. Accessed July 7, 2022.
- Rapezzi C, Riva L, Quarta CC, et al. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid. 2008;15(1):40-48. doi:10.1080/13506120701815373
- Guthrie S, Reddy SR, Chang E, Tieu R, Tarbox M, Pollock MR. Epidemiology of hereditary transthyretin (hATTR) amyloidosis: a real-world analysis of a US commercially insured population. Poster presented at: 2019 Peripheral Nerve Society (PNS) Annual Meeting; June 22-26, 2019; Genoa, Italy.
Reviewed by Harshi Dhingra, MD, on 7/11/2022.