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Amyloid-related Disorders Transthyretin-associated Familial Amyloid Polyneuropathy— Current and Emerging Therapies Mario Nuvolone, MD, 1 Laura Obici, MD 2 and Giampaolo Merlini, MD 3 1. Postgraduate Researcher, Amyloidosis Research and Treatment Center, Foundation IRCCS San Matteo Hospital and Department of Molecular Medicine, University of Pavia, Institute for Advanced Studies, Pavia, Italy, and Institute of Neuropathology, University Hospital of Zürich, Switzerland; 2. Attending Physician and Researcher, Amyloidosis Research and Treatment Center, Foundation Scientific Institute Policlinico, San Matteo, Pavia, Italy; 3. Professor, Amyloidosis Research and Treatment Center, Foundation IRCCS San Matteo Hospital and Department of Molecular Medicine, University of Pavia, Italy Abstract 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. Keywords Amyloidosis, familial amyloid polyneuropathy, transthyretin amyloidosis, hereditary neuropathy, peripheral neuropathy Disclosure: Mario Nuvolone, MD, received a travel grant from Pfizer. Laura Obici, MD, received consultancy honoraria from Pfizer. Giampaolo Merlini, MD, received speaker honoraria from Pfizer. Acknowledgments: This work was supported by the Ricerca Finalizzata Malattie Rare, Italian Ministry of Health, Istituto Superiore di Sanità (526D/63), Ministry of Research and University (2007AESFX2-003), and Italian Association for Cancer Research Special Program Molecular Clinical Oncology (grant 9965). Mario Nuvolone, MD, is partially supported by an investigator fellowship of Collegio Ghislieri, Pavia. We are indebted to Merrill Benson, MD, for generously sharing the table of the transthyretin mutations. Received: March 12, 2012 Accepted: March 30, 2012 Citation: US Neurology, 2012;8(1):24–32 Correspondence: Giampaolo Merlini, MD, Amyloidosis Research and Treatment Center, Foundation IRCCS San Matteo Hospital and Department of Molecular Medicine, University of Pavia, Piazzale Golgi 2, 27100 Pavia, Italy. E: gmerlini@unipv.it Amyloidoses encompass a heterogeneous group of disorders characterized by the accumulation and extracellular deposition of insoluble aggregates of misfolded fibrillar proteins termed amyloid, which can lead to tissue damage and organ dysfunction. 1 They can be exceptionally rare or rather frequent, acquired or hereditary, localized or systemic, quite indolent or life-threatening. Amyloidoses are classified based on the main protein forming the deposits and include, as of today, 28 different forms. 2,3 Transthyretin (TTR) amyloidoses (ATTR) retain much of the complexity of this family of maladies. Age-related deposition of wild-type TTR causes senile cardiac or systemic amyloidosis (SCA or SSA), 4 affecting up to 25 % of ultra-octogenarian people, 5 whereas mutations in the TTR gene can result in hereditary forms of the disease, 6 characterized either by 24 a predominant neurologic phenotype, also known as familial amyloid polyneuropathy (FAP), by a unique cardiac disease or by a mixture of the two. Several mutations are exceedingly rare and have been described only in single individuals or in single kindreds, 7 whereas others are highly prevalent in certain geographical regions or among certain ethnic groups (such as the Val122Ile mutation, which can lead to isolated heart involvement and is carried by up to 4 % of African-Americans). 8 In addition, TTR-derived amyloid deposits can be focal (in the ligaments and tendons of aged individuals) 9,10 or can be widespread in systemic forms of ATTR. Here we will review the pathophysiologic and clinical characteristics of TTR-associated familial amyloid polyneuropathy (TTR-FAP), with a focus on current and prospective treatments. © TOUCH BRIEFINGS 2012