The pathologic findings in an autopsied patient with hereditary transthyretin amyloidosis (hATTR) who was treated with a transthyretin (TTR) gene silencer late in the course of disease have been described in a clinicopathologic study published in the Journal of Neurology.

In individuals with the adult-onset autosomal dominant condition hATTR, mutations in the TTR gene occur. These mutations are associated with an accumulation of TTR proteins as amyloid deposits in various organs and body systems, including the heart, kidney, eye, gastrointestinal tract, and peripheral and autonomic nervous systems, thus paving the way for several life-threatening disorders.

Several novel therapeutic agents have recently been developed in an effort to prevent the progression of hATTR, including the TTR tetramer stabilizers tafamidis and diflunisal, TTR gene silencers such as patisiran and vutrisiran, RNA interference (RNAi) agents, and inotersen antisense of TTR.

The current description is of an autopsy case of a patient with hATTR who had been treated with patisiran at a later stage of disease. This is apparently the first report of postmortem pathologic findings in a patisiran-treated patient with hATTR. Based on pathologic examination of the body, TTR synthesis in hepatocytes was significantly reduced, thus substantiating the pharmacologic effects of the agent. Despite treatment with patisiran, however, excessive amyloid depositions were detected in multiple tissues and organs, such as the heart and sympathetic ganglia.

Read more about experimental therapies for hATTR

According to these findings, although the use of RNAi-mediated gene silencers such as patisiran may be effective when initiated early in the course of hATTR, limited efficacy is observed when the agent is started in a later disease stage. Thus, to slow the pathologic progression of hATTR, patisiran treatment should be initiated as early as possible in patients with the disease.

Per medical interviews, it was revealed that the deceased patient actually had a strong family history of hATTR. The current study elucidates the pathologic features of hATTR with an E61K mutation in the TTR gene. Study results suggest that in patients with hATTR who carry an E61K mutation, use of sural nerve biopsy has much lower sensitivity for diagnosis, with pathologic examinations of blood vessels in the peripheral nerve and muscle possibly improving the diagnostic sensitivity.

Of note, in the autopsied patient, amyloid deposits were detected only on the walls of the blood vessels of the dura matter and choroidal plexus; no senile plaques or amyloid angiopathy was observed. Thus, the E61K mutation might have little relationship, if any, to increased amyloid depositions in the eyes and brain.

“Our findings lead us to strongly recommend that (i) genetic analysis should be performed in patients with polyneuropathy of unknown etiology, and (ii) that RNAi therapy should be started as early as possible in patients with genetically confirmed [hATTR],” the researchers concluded.


Beck G, Yonenobu Y, Kawai M, et al. RNA interference in late-stage hereditary transthyretin amyloidosis: a clinicopathological study. J Neurol. Published online May 8, 2023. doi:10.1007/s00415-023-11754-7