Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary transthyretin (hATTR) amyloidosis is a rare, multisystemic, progressive disease in which abnormal amyloid protein accumulates and forms deposits that damage the body’s tissues and organs over time.1

The 3 main types of hATTR amyloidosis are cardiac, neuropathic, and leptomeningeal. Cardiac hATTR amyloidosis may result in chronic progressive heart failure, which is life-threatening. Neuropathic hATTR amyloidosis affects the peripheral and autonomic nervous systems, and leptomeningeal hATTR amyloidosis affects the central nervous system.1

The pattern of inheritance in hATTR amyloidosis is autosomal dominant. Therefore, the disease can be transmitted to offspring when only one parent carries the mutant gene, with each child having a 50% chance of inheriting hATTR amyloidosis.1 Because of the autosomal-dominant inheritance pattern, hATTR amyloidosis is endemic in certain geographical regions or ethnic groups and has been found to be especially prevalent throughout Portugal, Sweden, and Japan.2  

Mutations in the transthyretin (TTR) gene cause various hATTR amyloidosis phenotypes. The TTR gene encodes transthyretin protein (TTR), which transports vitamin A (retinol) and thyroxine throughout the body. To form a functional transporter protein, 4 TTR proteins must be bound to each other in a 4-protein unit (tetramer). TTR synthesis occurs primarily in the liver but also in the retina and choroid plexus.1,3 

Mutations in the TTR gene result in misfolding of the protein complex and the dissociation of unstable tetramers to form amyloid monomer fibrils. These accumulate throughout different organs and organ systems, including the heart, nervous system, gastrointestinal tract, and kidneys, causing long-term tissue damage and organ failure.2,4

Genetic Variants

More than 130 TTR gene variants have been identified.5 The most common is the TTR V30M variant. Carriers of this variant present with the classic hATTR amyloidosis “Portuguese phenotype,” in which neuropathic symptoms affect the small fibers of peripheral sensorimotor nerves and autonomic nerves. Most TTR variants cause symptoms of neuropathy.2 The TTR V30M variant has been identified globally.6

The TTR V122I variant originated in West Africa. Typically, it is associated with hATTR amyloidosis that has a later onset, usually in individuals older than 60 years, and generally affects the heart rather than the nervous system.6

The TTR L58H variant originated in Germany. In individuals who carry this variant, the carpal ligament (flexor retinaculum) is frequently affected  along with the peripheral nerves of the upper extremity.6

The TTR T60A variant originated in northwestern Ireland. Disease affects the cardiac and nervous systems and has a later onset.6

Effect of Amyloid Protein on Cells

Following dissociation of the TTR tetramer, studies have shown that nonfibrillar oligomeric intermediates form during the process of amyloid fibril aggregation. As evidenced by nerve biopsies from individuals with ATTR, these amorphous, electron dense materials accumulate in the subperineurial space and around microvasculature near the endoneurium.7 

Researchers speculate that these nonfibrillar oligomeric materials are cytotoxic, causing tissue damage. Nonfibrillar TTR materials also disrupt endothelial cell membranes and blood-nerve barriers, allowing leakage of circulating TTR into extracellular regions prior to amyloid fibril formation and deposition.7

Additionally, abnormal deposits of amyloid protein adversely affect cellular, tissue, and organ function. Amyloid fibril formation incorporates components naturally found in basement membranes such as collagen IV, fibronectin, and lamin. Nerve biopsies from individuals with ATTR, reveal that amyloid fibrils frequently accumulate at or around the basement membranes surrounding Schwann cells and endoneurial microvessels.7   

The extent of tissue and organ damage depends on the size of the amyloid fibrils. Large amyloid fibrils mechanically affect invaded tissues as well as neighboring tissues, causing distortion and atrophy of Schwann cells especially in small diameter peripheral nerve fibers. In cardiac tissue, large amyloid fibrils cause atrophy and deterioration of the myocardium, resulting in disruption of signal conduction.7

Amyloid proteins hasten cellular death through apoptotic or necrotic pathways. Amyloid fibrils cause membrane damage that decreases cellular viability after 6 hours, provoking the release of lactate dehydrogenase that results in necrosis-like cell death. In contrast, amyloid oligomers induce apoptosis-like cell death.8 Amyloid proteins cause cellular death, resulting in organ dysfunction that progresses to organ failure without treatment. 


Available treatments for hATTR amyloidosis include RNA gene-silencing therapies, antisense oligonucleotide therapies, and TTR tetramer-stabilizing therapies, in addition to liver transplant or combined liver/cardiac or liver/kidney transplant. Under investigation are immunotherapies in which monoclonal antibodies are used to prevent the formation of amyloid fibrils and in turn the deposition of amyloid proteins.2,9 


  1. Transthyretin amyloidosis: causes. MedlinePlus. Accessed July 8, 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. hATTR amyloidosis: disease overview. Hereditary ATTR Amyloidosis. Accessed July 8, 2022.
  4. What is hereditary ATTR amyloidosis (hATTR)? hATTR Amyloidosis. Accessed July 8, 2022.
  5. Reza N, Damrauer SM. Toward population-based genetic screening for hereditary amyloidosis. J Am Coll Cardiol CardioOnc. 2021;3(4):562-564. doi:10.1016/j.jaccao.2021.09.005
  6. Roberts JR. Transthyretin-related amyloidosis: epidemiology. Medscape. Updated June 16, 2022. Accessed July 8, 2022. 
  7. Koike H, Katsuno M. Transthyretin amyloidosis: Update on the clinical spectrum, pathogenesis, and disease-modifying therapies. Neurol Ther. 2020;9(2):317-333. doi:10.1007/s40120-020-00210-7
  8. Gharibyan AL, Zamotin V, Yanamandra K, et al. Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways. J Mol Biol. 2007;365(5):1337-1349. doi:10.1016/j.jmb.2006.10.101
  9. hATTR amyloidosis: treatment overview. hATTR Amyloidosis. Accessed July 8, 2022.

Reviewed by Kyle Habet, MD, on 7/23/2022.