Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Hereditary amyloidosis consists of a group of genetic diseases in which amyloid fibrils form and deposit in several organs and tissues in the body, causing them to malfunction.1 The most common type of hereditary amyloidosis is associated with mutations in the transthyretin (TTR) gene, which encodes the TTR protein.1,2
Hereditary Transthyretin Amyloidosis Phenotypes
Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominant and systemic disease.3 TTR protein, formerly known as prealbumin, is mainly synthesized in the liver and transports thyroxine (T4) and retinol-binding protein. The dissociation of TTR into monomers with the disruption of the blood-nerve barrier and subsequent misfolding and aggregation can occur after faulty genetic expression.2,3 The following deposition of formed TTR amyloid fibrils in different organs is the cause of many signs and symptoms of this disease.2
There are over 130 TTR variants that can cause hATTR, the most common pathogenic variants in the United States being the Val30Met, Thr60Ala, Leu58His, and Ser77Tyr mutations.4,5 The variability of TTR mutations confers a wide genetic and phenotypic variability to hATTR, with patients presenting with 3 major forms of the disease.3,6 Patients with hATTR most often present with polyneuropathy or cardiomyopathy, however, it is common for them to present with mixed symptoms of both phenotypes.2,7 A third type of hATTR affecting the central nervous system (CNS) has also been identified.6,7
The Val30Met mutation is the genetic variant most commonly identified in individuals around the world, particularly in Portugal, Spain, France, Sweden, Japan, and descendants of these areas.4,8 The clinical features associated with this mutation correspond to a neuropathic hATTR type, which affects the peripheral and autonomic nervous systems with early features of polyneuropathy and difficulties controlling body functions. The sensorimotor and autonomic impairment progresses for 10 to 20 years in these patients. Other individuals with specific TTR variants such as Leu78His or Ile127Val may develop carpal tunnel syndrome initially.6,7 In advanced stages of the disease, patients deal with cardiomyopathy and ocular, kidney, and CNS involvement.6,7 In late stages, cachexia develops.7
Cardiac hATTR is most often of late onset, with symptoms starting after the age of 50 years, and it may progress to congestive heart failure and eventually death.4,6,7,8 The Val122Ile variant is mainly found in the African American population and is linked to a cardiac hATTR type underlying the development of heart problems such as cardiomegaly, arrhythmias, and orthostatic hypotension.7
In leptomeningeal hATTR, the CNS is affected due to the deposition of amyloid in the pial and arachnoid membranes and in the walls of vessels in the subarachnoid space.6,7 Patients carrying an Asp38Gly mutation develop ATTR leptomeningeal amyloidosis with neurological involvement, and they may experience transient focal neurologic episodes, intracranial hemorrhage, dementia, ataxia, myelopathy, headache, hydrocephalus, and seizures.7
A diagnosis of hATTR is reached through TTR gene sequencing, biopsy to identify amyloid deposits, and scintigraphy to evaluate cardiac uptake of bone tracers if the biopsy results are negative. Meningeal biopsy is required to confirm the presence of amyloid in the meninges, however, typical magnetic resonance imaging features in addition to TTR sequencing may aid the diagnosis.3,7
Wild-Type Transthyretin Amyloidosis
A different type of amyloidosis is associated with TTR protein but not genetic variations. In wild-type ATTR, TTR protein is unstable and has a higher propensity to misfold and form amyloid fibrils. These fibrils most often deposit in the heart, leading to cardiac complications.9
This type of ATTR is most common in men over the age of 60 years. Patients experience congestive heart failure due to amyloid deposits in the heart, which cause the heart walls to become stiffer.9 It has also been shown that cardiac amyloidosis may progress in patients with hATTR who have undergone a liver transplant due to the deposition of wild-type TTR.3
Non-Transthyretin Hereditary Amyloidosis
In addition to TTR, there are many other proteins that have been identified as triggers for amyloid formation due to mutations in their respective encoding genes; these are responsible for non-TTR hereditary amyloidosis.4 Currently, there are at least 60 genetic variants linked to non-TTR hereditary amyloidosis, however, these diseases are even rarer than hATTR. Patients carrying non-TTR genetic variations may experience kidney, liver, and heart problems, as well as peripheral polyneuropathy.4
Hereditary amyloidosis that is unrelated to TTR protein includes the following variants1,4:
- Apolipoprotein A1 amyloidosis: associated with 22 variations and involves the kidneys, heart, skin, larynx, and nerves
- Gelsolin amyloidosis: linked to 4 variations and affects the nerves and eyes
- Lysozyme amyloidosis: linked to 7 variations and involves the kidneys, liver, and gastrointestinal tract
- Cystatin C amyloidosis: linked to 1 variation and leads to cerebral hemorrhage
- Fibrinogen Aα-chain amyloidosis: linked to 14 variations and involves the kidneys and nerves
1. Hereditary amyloidosis: disease at a glance. Genetic and Rare Diseases Information Center (GARD). Updated November 8, 2021. Accessed July 26, 2022.
2. 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
3. Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387-404. doi:10.1038/s41582-019-0210-4
4. Hereditary amyloidosis. Amyloidosis Foundation. Accessed July 26, 2022.
5. Transthyretin amyloidosis. MedlinePlus. Updated January 1, 2009. Accessed July 26, 2022.
6. Sekijima Y. Hereditary transthyretin amyloidosis. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2001. Updated June 17, 2021. Accessed July 26, 2022.
7. Hereditary ATTR amyloidosis. Amyloidosis Research Consortium (ARC). Accessed July 26, 2022.
8. Wild-type amyloidosis. Amyloidosis Research Consortium (ARC). Accessed July 26, 2022.
Reviewed by Debjyoti Talukdar, MD, on 7/31/2022.