Familial Transthyretin Amyloidosis

Transthyretin or TTR is a protein that is produced mainly in the liver and the choroid plexus of the brain and whose function is to transport retinol and thyroid hormones in plasma and cerebrospinal fluid, respectively. TTR is the causative agent of a special group of protein aggregation diseases that result in the accumulation of amyloid fibrils in specific organs and tissues.

Protein aggregation diseases can be acquired or inherited. Familial transthyretin amyloidosis is a clear example of hereditary amyloidosis and follows an autosomal dominant pattern of inheritance.

In familial transthyretin amyloidosis there is a progressive accumulation of amyloid peptide in the peripheral nervous system and other organs/tissues such as cardiac, renal and brain.

The pathology usually manifests between the third and fifth decade of life. Depending on the variant present in TTR, the peripheral nervous system (PNS), the central nervous system (CNS) or other organs such as the heart may be more affected. We can find 3 main phenotypes.

• Amyloid polyneuropathy: sensorimotor neuropathy of the legs, carpal tunnel syndrome, psychomotor impairment, constipation or diarrhea, impotence, cardiomyopathy, vitreous opacities, glaucoma, nephropathy.
• Cerebral and meningeal amyloidosis: dementia, ataxia, tense and rigid muscles, seizures, psychosis, hydrocephalus, hemorrhage and amyloid deposits (in leptomeningeal vessels, arachnoid pia and subpial deposits).
• Cardiac amyloidosis: cardiomyopathies such as arrhythmias, angina, heart failure.

Until a decade ago the main strategy for treating patients with transthyretin amyloidosis was orthotopic liver transplantation. Currently, drugs are available that stabilize TTR, preventing its rupture and accumulation, thus slowing down the progression of the disease. One example is Vyndaqel (active ingredient Tafamidis), a drug approved by the European Medicines Agency (EMA) for the treatment of adult patients with nerve involvement (people with symptomatic polyneuropathy).

The FDA (Food and Drug Administration) approved Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) capsules in 2019 for the treatment of cardiomyopathy caused by transthyretin-mediated amyloidosis in adults.