P4 Transthyretin–induced Cardiac Amyloidosis: A Rare Mutation in an Italian Familial Case

Abstract

A 65–year–old man came to our hospital for a subacute stroke of the left parietotemporal area. An aorto–coronary bypass for stable coronary artery disease and aortobisiliac bypass for infrarenal aortic aneurysm (with post–operative courses complicated by multiple atrial fibrillation paroxisms which were pharmacologically cardioverted) was reported. No undergoing anticoagulant therapy for CHADSVASc=1 was reported. Hypothesizing a cardioembolic origin of the stroke, echocardiographic analysis was performed which showed increased ventricular thickness and mass, inhomogeneous texture, reduced systolic function and strain with apical sparing, II degree diastolic dysfunction and severe left atrial dilatation. The strong suspicion of amyloidosis, raised by the echocardiographic findings, was confirmed by bone scintigraphy. The absence of free immunoglobulin chains in blood and urine and a normal protein electrophoretic pattern, would have instead excluded the diagnosis of AL amyloidosis. Thus we performed genetic testing to characterize the type of ATTR (transthyretin). An homozygous Val142Ile mutation in exon 4 of the TTR gene was found. This mutation, typically found in patients of African ancestry, is extremely rare in the Caucasian population. In fact, only 5 cases of patients with this mutation and with phenotypic manifestations very similar to the African ancestral ones have been so far reported, thus indicating that this mutation is not restricted to African ancestry but may be an underestimated Caucasian variant. The large GnomAD database estimates that this homozygous mutation is present in only 0.72% of the general population, while the remaining part of the carriers are heterozygous. Val142Ile leads to increased formation of amyloid fibrils and to the formation of a particularly unstable TTR tetramer. This variant is associated with a worse quality of life, a higher incidence of AF and a lower survival than the wild type TTR. In light of the worse clinical outcomes associated to this variant it is therefore essential to maintain a high level of clinical suspicion in order to perform an early diagnosis from a clinical and molecular point of view in order to be able to direct the patient as soon as possible to the current available therapies that can modify the course of the pathology and avoid premature fatal events.