Amyloid-related Disorders Transthyretin-associated Familial Amyloid Polyneuropathy— Current and Emerging Therapies

Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP), the most common form of systemic hereditary amyloidosis worldwide, is a late-adult-onset autosomal dominant disease caused by mutations in the TTR gene, with peaks in prevalence in endemic areas. The clinical picture is dominated by a progressive length-dependent polyneuropathy with onset in the feet with loss of temperature and pain sensations, accompanied by life-threatening autonomic dysfunction and infiltrative cardiomyopathy, as well as ocular disturbances. Variable expressivity, in terms of age of onset and involvement of extra-neurologic sites, can be due to different mutations, but is also observed among individuals with the same mutation in different countries. Therefore, diagnosis of TTR-FAP is often a challenge and must rely on careful clinical assessment combined with a multidisciplinary approach. Elimination of the synthesis of mutated TTR, through liver transplantation, may arrest the progressive neuropathy but not the cardiac and ocular involvement. Novel drugs have recently been developed based on a better understanding of the molecular mechanisms of the disease. Drugs that prevent the misfolding and deposition of mutated TTR have entered clinical trials, and one of these, tafamidis meglumine, has been approved in Europe and is now clinically available. Other medicines are now in the pipeline aimed at suppressing the expression of the mutated TTR gene or at promoting amyloid fibril destructuration, favoring resorption of amyloid deposits. These recent advancements provide grounded hope of an imminent significant improvement in the care of this life-threatening multi-system disease.