A new study has characterized prealbumin, also known as transthyeretin (TTR), in 5 patients with hereditary transthyretin amyloidosis (hATTR) and two asymptomatic TTR E61K gene mutation carriers. The results, published in Frontiers of Molecular Neuroscience, revealed that patients with the E61K mutation tended to have a late disease onset and that serum concentration of TTR tetramer could serve as a useful biomarker in hATTR.

“In this study, five ATTRv amyloidosis families carrying TTR E61K mutation and their clinical symptoms were reported,” the authors wrote. “The biochemical properties, plasma concentration, and drug response of E61K mutant TTR were characterized to gain mechanistic insights into this disease mutation.”

The research team evaluated 5 patients and 2 asymptomatic carriers, five men and two women, with hATTR and the TTR E61K mutation at a single center in Peking, China, between April 2015 and October 2021. The patients underwent neurological examinations, nerve conduction studies, and echocardiography, and various neurological scores were calculated. The authors also studied the ability of small molecule kinetic stabilizers such as Tafamidis, Diflunisal, and AG10 to inhibit TTR-related amyloidosis.

The results showed that the patients with the E61K mutation had a late disease onset, with a mean age of onset of 62 years. Their symptoms were primarily sensory-motor polyneuropathy and severe cardiomyopathy, as revealed by the electrophysiological studies. Cardiac involvement, including heart failure, was also common. Ocular and renal involvement were not observed in this cohort.

The authors found that the TTR kinetic stabilizers evaluated could in fact inhibit the fibril formation of E61K-TTR; however, increasing the drug concentration did not increase the inhibitory effect.

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TTR tetramer serum concentrations (as opposed to total serum TTR concentrations) were higher in healthy donors than in the 5 patients with the E61K mutation, and were also higher in the asymptomatic carriers than in symptomatic patients.

This finding led the authors to speculate that concentrations of TTR tetramer in serum might serve as a useful biomarker in patients with hATTR for monitoring disease evolution, treatment window, and the response to TTR kinetic stabilizers.

Reference

Chu X, Wang M, Tang R, et al. Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation. Front Mol Neurosci. Published online October 12, 2022. doi:10.3389/fnmol.2022.1003303