Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin amyloidosis (hATTR) is a rare genetic condition with an autosomal dominant pattern that leads to progressive systemic dysfunction. In hATTR, mutations in the transthyretin (TTR) gene potentiate the deposition of TTR protein in multiple sites as amyloid fibers.¹

Transthyretin Protein

The TTR protein was known first as prealbumin. It is a 55-kDa transport protein for both thyroxine (T4) and retinol-binding protein, which forms a complex with vitamin A (holoRBP). The liver is the main source of TTR, which is then secreted into the blood.^1,2 Mature TTR protein is formed following the cleavage of an amino acid signal sequence.³ This production of TTR in the liver is the main source of hATTR clinical manifestations, including polyneuropathy and cardiomyopathy.⁴ Other sources of TTR synthesis include the choroid plexus, the retinal and ciliary pigment epithelia of the eye, and the pancreas.^1-3 The protein synthesized in these structures is believed to play a role in activities such as the transport of thyroid hormones. It has also been proposed that TTR protein may play a neuroprotective role in the central nervous system.¹

TTR circulates in a soluble form in the serum and cerebrospinal fluid of healthy individuals.² This protein typically circulates as a homotetramer, with 8 antiparallel beta-sheets.^2,3 TTR contains 2 binding sites for T4 and 4 binding sites for holoRBP,¹ and in physiological conditions, it circulates with its central channel occupied in only 1 of its 2 T4 binding sites.² 

Amyloid Formation and Deposition

Hereditary transthyretin amyloidosis is precipitated by a misfolding of TTR protein. Many of the mutations identified in the TTR gene are missense mutations that cause a decrease in the stability of the tetramer conformation of the protein, promoting its dissociation into monomers and consequent misfolding.^2,5 There are about 130 mutations currently identified, and most of them are pathogenic.⁶ Following the dissociation and misfolding events, the aggregation and deposition of insoluble TTR and nonbranching amyloid fibers, typically with a diameter of 10 nm, occur in the extracellular spaces of many tissues and organs.^2,4,5 As amyloid fibers accumulate, patients experience progressive dysfunction. However, symptoms may not start until years after the initial amyloid formation and deposition.² 

Both amyloid deposition and its effects on the surrounding organs establish the phenotype of the disease.⁴ Amyloid fibers can cause direct compression or obstruction in neighboring structures, which manifests as conditions such as carpal tunnel syndrome and vitreous opacities.⁶ In hATTR with polyneuropathy, amyloid deposits form in the endoneurial blood vessels and the surrounding endoneurium and consequently cause the degeneration of both Schwann cells and the blood-nerve barrier.⁵ The malfunctioning of nonmyelinating Schwann cells results in the loss of unmyelinated nerve fibers. With the progression of the disease, amyloid deposits in the dorsal root ganglia promote distal axon degeneration and narrowing of the lumen of the blood vessels, culminating in motor weakness, cachexia, heart failure, and death as other organs become involved.⁵

A different mechanism for amyloid formation has been described in the wild-type form of hATTR. In these cases, TTR protein is structurally dissociated and misassembles in amyloid fibers. This is a condition most often related to older ages, and it was therefore initially known as senile amyloidosis.²

Other studies have reported that nonfibrillar TTR plays a potential role in neurodegeneration. Oligomers of amyloidogenic proteins have been suggested to intervene in toxic events of neurodegenerative diseases such as Alzheimer’s or Parkinson’s, however, further research is still needed to allow a full comprehension of these events.⁴

References

1. 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-2021-32790

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. Koike H, Katsuno M. Ultrastructure in transthyretin amyloidosis: from pathophysiology to therapeutic insights. Biomedicines. 2019;7(1):11. doi:10.3390/biomedicines7010011

5. Schwartzlow C, Kazamel M. Hereditary transthyretin amyloidosis: clinical presentation and management updates. J Clin Neuromuscul Dis. 2020;21(3):144-156. doi:10.1097/CND.0000000000000270

6. Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. Published online November 14, 2020. doi:10.1007/s10072-020-04889-2

Reviewed by Kyle Habet, MD, on 7/29/2022.

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Diana Diez Gaspar, PharmD, PhD

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.