Hereditary ATTR amyloidosis

Hereditary ATTR amyloidosis (hATTR amyloidosis), also known as hereditary transthyretin amyloidosis or familial amyloid polyneuropathy (FAP), is a progressive, life-threatening genetic disorder caused by mutations in the TTR gene, which encodes the transthyretin protein. Transthyretin is primarily produced in the liver and normally transports thyroid hormone and retinol-binding protein in the blood. Mutations destabilize the protein, causing it to misfold and aggregate into amyloid fibrils that deposit in various tissues and organs throughout the body. The disease was historically associated with endemic regions in Portugal, Sweden, and Japan, but it is now recognized worldwide with over 130 pathogenic TTR variants identified, the most common being Val30Met (p.Val50Met). The clinical presentation of hATTR amyloidosis is highly variable, even among individuals carrying the same mutation. The disease primarily affects the peripheral nervous system, autonomic nervous system, and heart. Key symptoms include progressive sensorimotor polyneuropathy (numbness, tingling, pain, and weakness beginning in the feet and hands), autonomic dysfunction (orthostatic hypotension, gastrointestinal disturbances including diarrhea and constipation, erectile dysfunction, and urinary retention), and cardiomyopathy (heart failure, arrhythmias, and conduction abnormalities). Other affected systems may include the eyes (vitreous opacities, glaucoma), kidneys (proteinuria, renal insufficiency), and central nervous system (leptomeningeal amyloidosis in certain variants). Without treatment, the disease typically progresses over 7 to 12 years from symptom onset. The treatment landscape for hATTR amyloidosis has transformed significantly in recent years. Liver transplantation was historically the standard of care, as it removes the primary source of mutant transthyretin. TTR stabilizers such as tafamidis and diflunisal work by stabilizing the transthyretin tetramer and preventing dissociation into amyloid-forming monomers. Tafamidis is approved for both polyneuropathy and cardiomyopathy manifestations. Gene-silencing therapies, including patisiran (a small interfering RNA) and inotersen (an antisense oligonucleotide), reduce production of both mutant and wild-type transthyretin by the liver and have demonstrated significant clinical benefit. Newer agents such as vutrisiran, a next-generation siRNA, offer less frequent dosing. Supportive care addressing neuropathic pain, cardiac complications, and nutritional deficiencies remains an essential component of management.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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