About this condition
Hereditary Transthyretin Amyloidosis (ATTR)
Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disorder caused by TTR mutations, which encode transthyretin — a plasma transport protein synthesized primarily in the liver and retina. Pathogenic TTR missense variants cause protein misfolding and destabilization; mutant transthyretin molecules misfold more readily and nucleate amyloid fibril formation. Progressive amyloid deposition in peripheral nerves causes progressive sensorimotor polyneuropathy; amyloid deposition in the myocardium causes restrictive cardiomyopathy. Untreated ATTR is fatal within 7–12 years of symptom onset. Over 130 pathogenic TTR variants have been identified, with strong genotype-phenotype correlations: Val30Met causes predominantly neuropathic disease; Val122Ile causes predominantly cardiomyopathic disease.
ATTR prevalence is estimated at 1 in 100,000 overall, but the Val122Ile variant alone is carried by 3–4% of African Americans — approximately 1.5 million carriers in the United States. This variant is the most common pathogenic TTR variant in the US and is associated with predominantly cardiomyopathic disease, affecting 10–15% of African American heart failure patients over 60. Val30Met is the most common amyloidogenic variant worldwide and has founder populations in Portugal, Sweden, and Japan with predominantly neuropathic disease. The genetic variant determines the predominant phenotype: neuropathic forms (like Val30Met) cause primarily peripheral nerve symptoms; cardiac forms (like Val122Ile) cause primarily myocardial infiltration and heart failure.
A confirmed TTR pathogenic variant diagnosis is transformative. Three FDA-approved disease-modifying therapies now exist: tafamidis (Vyndaqel), a kinetic stabilizer that prevents transthyretin misfolding; patisiran (Onpattro) and vutrisiran (Alnylam/Vyr), RNA interference therapeutics that reduce hepatic transthyretin production; and inotersen (Tegsedi), an antisense oligonucleotide also reducing transthyretin. These therapies halt disease progression and can induce regression if started early. Phenotype-specific therapy selection is important: tafamidis appears most effective for neuropathic disease. Genotype also informs prognosis — Val30Met neuropathy typically progresses more slowly than other variants. Family cascade screening is critical; presymptomatic carriers can begin prophylactic therapy before symptom onset.
TTR variants predict clinical phenotype — Val30Met causes predominantly peripheral neuropathy, Val122Ile causes predominantly cardiomyopathy, with dramatic implications for surveillance and treatment strategy.
- Gene locus
- TTR (18q12.1)
