ATTR

ATTR, short for transthyretin amyloidosis, is a systemic amyloidosis caused by the deposition of misfolded transthyretin protein (TTR) as amyloid fibrils in tissues. It most commonly affects the nerves and heart. ATTR exists in hereditary forms (hATTR) due to TTR gene mutations and in wild-type form (ATTRwt), previously called senile systemic amyloidosis.

Transthyretin is produced mainly by the liver; mutations destabilize the protein, promoting misfolding and aggregation into amyloid fibrils that deposit in nerves, heart, and other organs.

Clinical manifestations vary by phenotype. hATTR often causes a progressive length-dependent polyneuropathy with sensory, motor, and autonomic symptoms; ATTRwt commonly presents later with cardiomyopathy and heart failure symptoms. Other organ involvement can include the eyes, kidneys, and gastrointestinal tract.

Diagnosis relies on tissue confirmation and genetic testing. Abdominal fat pad or organ biopsies stained with Congo red show apple-green birefringence. Noninvasive imaging with bone-seeking radiotracers (such as 99mTc-PYP) supports ATTR, while serum and urine tests help exclude AL amyloidosis. TTR gene sequencing confirms hereditary forms.

Treatment aims to reduce TTR production or stabilize the protein. Tafamidis is a TTR stabilizer approved for ATTR cardiomyopathy and polyneuropathy; diflunisal is an off-label stabilizer. Gene-silencing therapies, including patisiran (siRNA) and inotersen (antisense), have shown benefit for hATTR polyneuropathy. Supportive care and multidisciplinary management are essential.

Prognosis depends on phenotype and stage at diagnosis. ATTRwt tends to have a later onset with cardiac involvement, while hATTR phenotypes vary. Ongoing research seeks more effective treatments and earlier detection.