hATTR

Hereditary transthyretin-mediated amyloidosis, abbreviated hATTR, is a genetic disorder caused by mutations in the TTR gene that encodes transthyretin, a transport protein produced mainly by the liver. Mutant transthyretin tends to misfold and form amyloid fibrils that accumulate in various tissues. The condition is typically inherited in an autosomal dominant manner with variable penetrance, and more than 100 TTR variants have been linked to disease. Geographic clusters exist, such as the Val30Met mutation in parts of Portugal, Sweden, and Japan.

The most characteristic manifestations are a progressive sensorimotor polyneuropathy and autonomic neuropathy. Patients often report numbness, tingling, or burning pain in the feet and hands, orthostatic symptoms, erectile dysfunction, gastrointestinal disturbances, and impaired sweating. Cardiac involvement can occur, presenting as restrictive or hypertrophic cardiomyopathy, arrhythmias, or conduction abnormalities. Ocular and renal involvement may also occur, and carpal tunnel syndrome can be an early sign in some patients.

Diagnosis relies on a combination of genetic testing for TTR mutations and tissue or imaging evidence of amyloid deposition. Biopsy specimens showing Congo red–positive deposits support the diagnosis. In suspected cardiac disease, technetium-99m pyrophosphate scintigraphy can help differentiate ATTR from other forms of amyloidosis; serum and urine studies help exclude AL amyloidosis. Ancillary imaging such as echocardiography and cardiac MRI assess organ involvement.

Treatment aims to reduce mutant transthyretin or stabilize the protein. Approaches include TTR stabilizers (tafamidis, diflunisal), and gene-silencing therapies (patisiran, inotersen). Liver transplantation has historical relevance but is now infrequently used. Management is multidisciplinary, focusing on symptom control, organ-specific care, and monitoring disease progression. Prognosis varies with mutation and extent of organ involvement, but disease-modifying therapies can slow progression and improve quality of life for many patients.