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 amyloidosis (hATTR) is a rare, life-threatening, and progressive disorder. It has been traditionally classified according to the predominant clinical features as transthyretin familial amyloid polyneuropathy (TTR-FAP) or transthyretin familial amyloid cardiomyopathy (TTR-FAC), though the majority of the patients show clinical manifestations of both nerve and heart involvement.
There is also a nonhereditary, wild-type disease form, earlier termed senile cardiac amyloidosis, that predominantly affects the heart. Hereditary transthyretin amyloidosis can affect many body systems and organs, however, including the heart, nervous system, gastrointestinal tract, and kidneys.1,2 More than 130 different transthyretin (TTR) gene variants have been found so far, with the p.Val30Met mutation being the most prevalent. Although most TTR mutations result in neuropathic or mixed types, certain variants generally present with a predominant or isolated cardiomyopathy.2,3
Hereditary transthyretin amyloidosis exhibits an autosomal dominant inheritance pattern, so it can be transmitted to offspring when only 1 parent is affected. However, cases of transthyretin amyloidosis can arise from new gene mutations and affect individuals without a family history of the condition. Rarely, reports of patients with compound heterozygous and homozygous mutations have been documented. TTR gene mutations do not result in hATTR in all individuals.3,4
Hereditary transthyretin amyloidosis is a degenerative and potentially fatal illness involving multiple organs that results from the misfolding of the TTR protein. Thyroxine (T4) and retinol are transported via the TTR protein, which is largely produced and secreted by the liver. TTR gene mutations result in amino acid substitutions in the TTR protein that make its tertiary structure susceptible to misfolding into a beta-pleated sheet, producing an insoluble form of amyloid fibrils. This autosomal dominant disorder mainly affects the heart and nerves. TTR genotype, geographical location, and other genetic and environmental variables affect the heterogeneous clinical signs and symptoms of hATTR. As a result, patient groups differ in terms of the presenting manifestations, age of onset, and rate of disease progression.5
The TTR gene is situated on chromosome 18 and has 4 exons. Most of the discovered TTR variants are pathogenic. The most frequent pathogenic variant, the TTR Val30Met variant, involves a point mutation that causes methionine to replace valine at position 30 on the mature protein. This Val30Met mutation, which accounts for roughly 50% of TTR variations worldwide, causes hATTR in endemic areas and is still the most common amyloidogenic mutation globally.3 Carriers of the Val30Met variant present with the classic hATTR “Portuguese phenotype,” in which neuropathic symptoms affect the small fibers of peripheral sensorimotor nerves and autonomic nerves.3
The most frequent mutations in the United States are Val122Ile, Thr60Ala, and Val30Met, listed from most to least frequent. The most frequent mutation worldwide is Val30Met, followed by Val122Ile and Glu89Gln. Val30Met is mainly seen in Spain, Portugal, Japan, France, Sweden, and descendants of these areas. Val30Met mainly results in polyneuropathy, while Val122Ile is typically seen in African Americans who report cardiac symptoms later in life. Other mutations, like Glu89Gln, have traditionally been connected to a mixed phenotype.5
Genetic testing is important in making a diagnosis of hATTR, as it detects specific TTR mutations.1,3 Genetic tests detect approximately 90% of TTR variants.6
Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR (melting curve analysis) testing can identify suspected TTR mutations. Genetic sequencing and PCR-single-strand conformation polymorphism (PCR- SSCP) analysis can detect unknown TTR variations.7
- Hereditary ATTR amyloidosis testing & diagnosis: generalized hATTR amyloidosis diagnostic workup. Akcea Therapeutics, Inc. Accessed July 26, 2022.
- Reza N, Damrauer SM. Toward population-based genetic screening for hereditary amyloidosis. JACC CardioOncol. 2021;3(4):562-564. doi:10.1016/j.jaccao.2021.09.005
- 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
- Transthyretin amyloidosis. MedlinePlus. Updated January 1, 2009. Accessed July 26, 2022.
- Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7):S107-S112.
- Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6. doi:10.1186/s13023-017-0726-x
- Roberts JR. Transthyretin-related amyloidosis workup. Medscape. Updated July 19, 2022. Accessed July 26, 2022.
Reviewed by Kyle Habet, MD, on 7/25/2022.