What is the general mechanism by which ATTR develops?

• A. Mutations cause increased production of transthyretin in the liver
• B. Mutations break the TTR tetramers into misfolded monomers that clump into fibrils and stiffen ventricular walls, impairing filling
• C. Transthyretin remains as stable tetramers and deposits only on the liver
• D. ATTR results from autoimmune destruction of cardiac tissue

Answer: (B)

In ATTR, the problem starts with transthyretin becoming unstable due to mutations. This destabilizes the normal tetramer, causing it to fall apart into misfolded monomers. Those monomers can aggregate into insoluble amyloid fibrils that deposit in the heart tissue, particularly in the walls of the ventricles. As these deposits accumulate, the myocardium becomes infiltrated and stiff, leading to diastolic dysfunction and a restrictive form of cardiomyopathy. The disease mechanism is driven by abnormal protein folding and extracellular deposition, not by simply making more transthyretin or by autoimmune destruction.