Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Hereditary transthyretin-mediated amyloidosis, also called as hATTR or ATTRv amyloidosis (v for “variant”), is a rare, life-threatening disorder in which systemic amyloid gradually damage various organs, resulting in disability and death.1 The tetramers of variant transthyretin (TTR) protein are unstable and dissociate into monomers. These form aggregates that eventually deposit as amyloid fibrils in the heart, nerves, and other tissues and organs, causing a myriad of symptoms.2,3 The quality of life of individuals with hATTR amyloidosis is impaired, and life expectancy usually varies between 2.5 and 5 years following diagnosis.3
Geographical Risk Factors
hATTR amyloidosis has always been considered a rare illness. Three major clusters were first identified in Portugal, Sweden, and Japan, where the disease is endemic. Subsequently, minor foci of endemicity were found in Cyprus and Majorca. The prevalence of hATTR amyloidosis varies considerably within Europe, and occurrences are mostly sporadic. The frequency of hATTR amyloidosis is anticipated to increase, particularly in regions where it is not endemic, given the growing awareness of the disease among clinicians and the currently broad availability of genetic testing. hATTR has now been reported in at least 29 nations worldwide.4
Age and Sex Risk Factors
The age at onset of hATTR amyloidosis varies substantially.5 Disease is sometimes categorized as early-onset (in individuals younger than 50 years) or late-onset (in patients older 50 years), depending on when the signs and symptoms first appear.2
The median age at the onset of the clinical manifestations of hATTR amyloidosis in all patients in a large registry was 39 years, according to a review of the global Transthyretin Amyloidosis Outcome Survey (THAOS) patient registry. The median age at symptom onset varies by country. It has been estimated to be 68.1 years in the United States; in other nations, including Portugal and Brazil, the median ages at onset are considerably earlier, estimated to be 32.4 and 31.4 years, respectively.5 The age at onset also varies considerably according to the type of TTR variant. Most of the aggressive variants of hATTR appear in teenagers or individuals in their early 20s, whereas many other variants are seen in people older than 50 years. Wild or sporadic forms of cardiac ATTR (ATTR-CM), in which the TTR sequence is normal, usually present after the age of 60 years, and especially after 70 years.6 Males and females inherit all TTR variants encoded on chromosome 18 with equal frequency. For unknown reasons, penetration is greater in males, and their age at onset is younger.6
Family History/Inheritance Risk Factors
First-degree relatives (parents, siblings, children) may share genetic variants that predispose them to the development of diseases like hATTR amyloidosis and are therefore at higher risk for such diseases. Because the inheritance pattern of hATTR amyloidosis is autosomal-dominant (which means that an individual needs to inherit only one mutated allele for the disease to manifest), the chance that the child of an affected individual will inherit the causative gene variant is 50%.3
Genetic Risk Factors According to TTR Gene Mutations
The natural history and age at onset of hATTR amyloidosis may be affected by several variables. More than 120 pathogenic TTR variants are known, and their prevalence varies with geographical region. The V30M mutation is the most prevalent TTR mutation in Europe, with prevalence rates as high as 1 in 1000 in regions of endemicity, such as Portugal, Sweden, and Japan. Comparatively, the V122I mutation, which has a reported prevalence of approximately 4% in African Americans, is the most prevalent TTR mutation in the United States. Genotype-phenotype heterogeneity is significant, and some specific TTR mutations have traditionally been linked to distinct disease presentations. The most frequent associations are V30M with predominant polyneuropathy and V122I with predominant cardiomyopathy. Nevertheless, advances in understanding the condition and thorough clinical and imaging examinations have made it clear that all TTR variants frequently involve multiple body systems, and the vast majority of affected persons have a mixed phenotype that includes polyneuropathy and cardiomyopathy. Additionally, even within families, substantial variability is seen in the penetrance, symptoms, and course of disease across TTR variants. It is difficult to diagnose the disease in symptomatic patients because of the heterogeneity and lack of specificity of the symptoms, limited awareness of the illness, and incomplete penetrance that is characteristic of this disease.1,7
The clinical heterogeneity in hATTR can be attributed to differences in genetic mutations only to a certain extent. For still unknown reasons, the onset of disease associated with the most common mutation in the world, V30M, is either early (in Portugal and Brazil, where it is endemic, with a mean age at onset of 33 years, and occasionally in other places, including Italy) or late (in Sweden, with a mean age at onset of 60 years, and in Japan in many cases and countries where it is not endemic, like Italy).8
Late-onset restrictive cardiomyopathy without substantial peripheral neuropathy is linked to the val122-to-ile substitution (V122I) variant. The estimated frequency of this allele in African Ameicans is 3.9%, and they are more likely than whites to have this mutation.9
- 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(1):411. doi:10.1186/s13023-021-01960-9
- Sequeira VCC, Penetra MA, Duarte L, et al. Hereditary transthyretin-mediated amyloidosis with polyneuropathy: baseline anthropometric, demographic and disease characteristics of patients from a reference center. Arq Neuropsiquiatr. 2022;80(3):262-269. doi:10.1590/0004-282X-ANP-2020-0590
- What is hATTR amyloidosis?. American Heart Association. Accessed July 23, 2022.
- 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
- Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7 Suppl):S107-S112.
- Roberts JR. Transthyretin-related amyloidosis. Medscape. Updated July 19, 2022. Accessed July 23, 2022.
- Hereditary ATTR amyloidosis testing & diagnosis: generalized hATTR amyloidosis diagnostic workup. hATTAR Amyloidosis. Accessed July 23, 2022.
- Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. 2020 Nov 14. doi:10.1007/s10072-020-04889-2. Epub ahead of print.
- Amyloidosis, hereditary, transthyretin-related. OMIM Entry #105210. Accessed July 23, 2022.
Reviewed by Hasan Avcu, MD, on 7/26/2022.