TransthyretinEdit
Transthyretin is a small, soluble transport protein circulating in human blood and cerebrospinal fluid. It is produced mainly by the liver, with additional contributions from the choroid plexus and retina, and it plays a critical role in the transport of thyroxine ([thyroxine]] and retinol bound to retinol-binding protein. The name transthyretin reflects its function: it carries thyroid hormone and retinol through the circulation to tissues that need them. In many discussions of human biochemistry, transthyretin is referred to as prealbumin, a legacy name that persists in some clinical literature. Transthyretin prealbumin thyroxine retinol-binding protein
Although transthyretin serves a normal physiological purpose, changes in its structure or levels can have profound consequences. In particular, mutations in the TTR gene can destabilize the protein and promote misfolding and aggregation into amyloid fibrils that deposit in various organs. This condition is known as transthyretin amyloidosis (ATTR), a systemic disease that can manifest with nerve (polyneuropathy) and heart (cardiomyopathy) symptoms among others. ATTR can be hereditary, caused by autosomal dominant mutations in the TTR gene, or occur as a wild-type form more commonly seen in older adults. Transthyretin amyloidosis transthyretin amyloidosis autosomal dominant wild-type transthyretin amyloidosis
Biology and function
Transthyretin is a homotetrameric protein composed of four identical subunits. It binds and transports lipophilic molecules, most notably thyroxine (T4) and retinol-bound vitamin A via the retinol-binding protein (RBP) complex. Its synthesis occurs predominantly in the liver, making hepatic production a central determinant of circulating TTR levels in adults. The protein’s normal function helps regulate thyroid hormone availability and vitamin A delivery, processes essential for metabolism and vision. protein thyroxine retinol-binding protein liver vitamin A
Genetics and epidemiology
Most ATTR arises from genetic variants in the TTR gene, inherited in an autosomal dominant pattern. Over 100 mutations in TTR have been described, with regional patterns that reflect founder effects and population history. The Val30Met mutation (also reported as p.Val30Met) is among the most studied and is associated with polyneuropathy in several populations, while other mutations are linked with predominant cardiac involvement or mixed phenotypes. In contrast, wild-type ATTR (wtATTR) results from the normal TTR sequence and tends to present in older adults with cardiomyopathy and/or neuropathy. Val30Met TTR gene autosomal dominant transthyretin amyloidosis wild-type transthyretin amyloidosis
Pathology and clinical features
Transthyretin amyloidosis is characterized by the deposition of misfolded TTR-derived amyloid fibrils in tissues, most notably the peripheral nerves and the myocardium, though almost any organ can be affected. Clinical presentation often includes a progressive distal sensorimotor polyneuropathy, autonomic dysfunction, carpal tunnel syndrome, and heart failure with preserved ejection fraction or restrictive cardiomyopathy. The phenotype can vary by mutation and by whether the disease is hereditary or wild-type. Diagnostic workups typically combine patient history, genetic testing, imaging (such as bone scintigraphy), and tissue biopsy to demonstrate amyloid deposition. amyloidosis polyneuropathy cardiomyopathy carpal tunnel syndrome bone scintigraphy biopsy genetic testing
Diagnosis
Diagnosis of ATTR involves a combination of laboratory and imaging methods. Genetic testing confirms TTR mutations in hereditary cases. Noninvasive imaging with specific radiotracers can suggest amyloid deposition in the heart, while biopsy of affected tissue provides definitive evidence of amyloid and allows typing of the fibrils. Identifying the specific TTR mutation helps inform prognosis and family screening. genetic testing bone scintigraphy biopsy
Treatment and management
Therapies for ATTR can be broadly categorized as those that stabilize transthyretin to prevent dissociation, those that silence TTR production, and supportive care for organ systems affected by amyloid deposition.
TTR stabilizers: Compounds that bind to the TTR tetramer and stabilize it against dissociation help slow amyloid formation. The best-known example is a small-molecule stabilizer used in clinical practice. tafamidis
TTR production silencers: RNA-based therapies reduce hepatic production of TTR, addressing the underlying source of misfolded protein. Examples include small interfering RNA and antisense oligonucleotide approaches. patisiran inotersen Onpattro Tegsedi RNA-based therapy gene silencing
Gene therapy and disease-modifying approaches: Research is ongoing into liver-directed gene therapies and other strategies to reduce or correct TTR expression, with potential for longer-term disease modification. gene therapy CRISPR liver transplantation
Traditional and supportive care: In the past, liver transplantation was used to remove the mutant TTR source in hereditary ATTR, and non-specific therapies or symptom management remains important in many patients. liver transplantation
Drug repurposing and supportive measures: Some investigators have explored repurposed drugs with TTR-stabilizing activity, while clinicians address neuropathic pain, autonomic symptoms, and heart failure with standard therapies. diflunisal cardiomyopathy
Pricing, access, and policy are also prominent in discussions around these therapies. Orphan drug designation and market exclusivity influence development decisions, while debates about price, payer coverage, and patient access shape real-world outcomes. Proponents argue that high prices reflect the cost and risk of developing breakthrough therapies and fund future innovation; critics contend that affordability and broad access should be prioritized, especially for life-altering diseases. In some circles, critics of market-based approaches argue that rapid access should come first, but supporters counter that sustainable innovation requires incentives and a path to recoupment for high-risk ventures. In this context, the conversation around ATTR medicines intersects with broader policy questions about Orphan drug incentives, FDA regulatory pathways, and health care financing. tafamidis patisiran inotersen Tegsedi Onpattro Orphan drug FDA
Research and future directions
Ongoing research seeks to expand the range of disease-modifying therapies, expand the understanding of genotype-phenotype correlations, and improve early diagnosis. Gene-silencing and gene-editing strategies continue to mature, with efforts aimed at durable suppression of hepatic TTR production or correction of pathogenic mutations. Advances in imaging and biomarkers are improving monitoring of disease progression and response to therapy. gene therapy CRISPR patisiran inotersen tafamidis