Hereditary amyloidosis is a disease caused by mutations in the transthyretin gene that leads to systemic deposition of amyloid protein. Although patients have multisystem involvement of amyloidosis, cardiomyopathy and peripheral neuropathy with autonomic neuropathy are typically the most prominent disease manifestations and the primary drivers of disability and mortality. New small interfering RNA, or antisense oligonucleotide therapies approved by the United States food and drug administration, reduce the production of transthyretin protein and slow the progression of hereditary amyloid polyneuropathy and, in some cases, improve measures of neuropathy severity and associated disability. Although hereditary transthyretin amyloidosis is a rare disease, it is an exciting model for developing new treatments for genetic disease in neurology and in medicine broadly.
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• Hereditary amyloid polyneuropathy primarily refers to patients with mutations in the transthyretin gene although mutations in other genes may present with amyloidosis and neuropathy.
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• The symptoms of transthyretin-associated familial amyloid polyneuropathy are those of a sensorimotor polyneuropathy, with progressive sensory loss and weakness, often with prominent autonomic neuropathy. Neuropathy is often accompanied by amyloid cardiomyopathy.
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• hATTR polyneuropathy is diagnosed and confirmed with genetic testing for TTR gene mutations. Amyloidosis may be detected on tissue biopsy in workup of idiopathic neuropathy or cardiomyopathy, which may lead to suspicion of a genetic diagnosis.
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• Amyloid stabilizing agents, including diflunisal and tafamidis, may slow the progression of TTR-FAP, and liver transplantation has traditionally been used to reduce production of mutant transthyretin protein.
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• New small interfering RNA and antisense oligonucleotide therapies that reduce TTR gene expression are effective, new treatments to slow the progression of hATTR polyneuropathy.
Historical note and terminology
Rudolf Virchow first described amyloid deposits in 1858, noting their starch-like appearance and reaction to iodine and sulfuric acid. Congo red staining of amyloid was first described in 1922, and the typical apple-green birefringence was noted in 1927 in patients with Alzheimer disease (44).
Transthyretin protein is named in reference to its 2 primary transport functions: binding thyroxine and retinol-binding protein (41). The TTR gene was sequenced in 1974 by Kanda and colleagues; at that time the transthyretin protein was referred to as plasma thyroxine-binding prealbumin (29). In 1991, Benson described 10 TTR gene mutations associated with familial amyloid polyneuropathy (13). The number of TTR gene mutations associated with disease has grown. At the time of the writing of this review, 52 mutations associated with familial amyloid polyneuropathy were reported on the Online Mendelian Inheritance in Man website.