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Slightly compromised kinetic stability of the TTRA81V mutation in hereditary transthyretin amyloid cardiomyopathy may indicate late-onset and gradual progression of the disease, according to a recent case study.

The various transthyretin (TTR) mutations in cardiac amyloidosis bear remarkably different biochemical and biophysical properties, resulting in diverse clinical manifestations. Characterizing these properties can aid in predicting disease onset and penetration rate and stabilizing treatment response. 

A case study in the journal ESC Heart Failure investigated the biochemical and biophysical properties of a rare TTRA81V mutation in hereditary transthyretin amyloid cardiomyopathy (hATTR-CM).

Clinical Characteristics

The patient was an 84-year-old male diagnosed with hATTR-CM. He presented with exertional dyspnea and lower limb edema over 3 years and developed heart failure. Brain natriuretic peptide and high-sensitivity cardiac troponin-I levels were mildly elevated. Echocardiography showed left atrial enlargement, symmetrical left ventricular hypertrophy, left ventricular ejection fraction of 56%, low voltage in the limb, and reduced global longitudinal strain with apical sparing on speckle-tracking echocardiography. 

Cardiac magnetic resonance showed subendocardial late gadolinium enhancement. Tc-99m-PYP scintigraphy confirmed grade-3 myocardial uptake with increased heart-to-contralateral ratios. Genetic testing showed a heterozygous missense TTR gene mutation, resulting in an alanine-to-valine change.

Biochemical Analysis Revealed Slightly Compromised Kinetic Stability of TTRA81V

Thermodynamic and kinetic stabilities of TTRA81V homozygous protein and TTRA81V:WT (wild-type) heterozygous protein were measured, with TTRWT and the early-onset mutation TTRL55P as controls. The kinetic stability of the TTR protein governs TTR dissociation. 

Biochemical analysis demonstrated slightly compromised kinetic stability in both the heterozygous TTRA81V:WT (dissociation half time (t1/2) = 21 h) and the homozygous TTRA81V (t1/2 = 17.5 h). Their kinetic stability lies between TTRWT (t1/2 = 42 h) and TTRL55P (t1/2 = 4.4 h), supporting the patient’s late-onset and slow disease progression.

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The Thermodynamic Stability of TTRA81V Was Comparable to That of TTRWT

The thermodynamic stability of homozygous TTRA81V (Cm = 3.2 M) was comparable with that of TTRWT (Cm = 3.4 M) but higher than that of TTRL55P (Cm = 2.3 M). The thermodynamic stability of heterozygous TTRA81V:WT (Cm = 3.8 M) was slightly higher than that of TTRWT. Thus, the thermodynamic stability of TTRA81V was not compromised by the disease mutation.

TTRA81V Responded to Small-Molecule Kinetic Stabilizers, Albeit to Different Extents

The inhibitory effect of small-molecule kinetic stabilizers (tafamidis, diflunisal, AG10) on TTR fibril formation of TTRA81V and TTRA81V:WT was studied. All stabilizers displayed an inhibitory effect on acid-induced TTRA81V and TTRA81V:WT fibrillation, but less effectively than with TTRWT. 

Tafamidis inhibited TTRA81V and TTRA81V:WT fibril formation more effectively than diflunisal but less effectively than AG10. Tafamidis showed near-complete inhibition of mechanical force-induced TTRA81V fibrillation.

Chromatographic Analysis Showed Reduced TTR Tetramer Concentration

A decrease in TTR tetramer concentration has been suggested as a hallmark for hATTR with polyneuropathy and hATTR-CM. Chromatographic analysis before tafamidis administration showed a slightly lower than normal concentration (3.0 µM), which did not significantly improve after one month (3.04 µM). Follow-up at 6 months and 1 year post-medication revealed a concentration of 4.59 and 2.52 µM, respectively.


Sha, Q., Zhang, Y., Wang, M., Sun, J., Zhang, Y., Zhang, X., Wang, N., Liu, Y., & Liu, Y. (2023). Biochemical and biophysical properties of a rare TTRA81V mutation causing mild transthyretin amyloid cardiomyopathy. ESC heart failure, 10.1002/ehf2.14543. Advance online publication. https://doi.org/10.1002/ehf2.14543