Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans

Abstract

Since the identification of a valine-to-isoleucine substitution at position 122 (TTR V122I; pV142I) in the transthyretin (TTR)-derived fibrils extracted from the heart of a patient with late-onset cardiac amyloidosis, it has become clear that the amyloidogenic mutation and the disease occur almost exclusively in individuals of identifiable African descent. In the United States, the amyloidogenic allele frequency is 0.0173 and is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicates that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. At autopsy, the allele was found to be associated with cardiac TTR amyloid deposition in all the carriers after age 65 years; however, the clinical penetrance varies, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. At this time there are potential forms of therapy in clinical trials. The combination of a highly accurate genetic test and the potential for specific therapy demands a greater awareness of this autosomal dominant, age-dependent cardiac disease in the cardiology community.Genet Med advance online publication 19 January 2017.

Figure 1. Possible dissociation pathways of human transthyretin tetramer

The TTR homotetramer dissociates into homodimers and then monomers, which represent the fibril precursor. The most likely dissociation pathway is shown by the red arrows. The rates of misfolding and aggregation of the monomers into oligomers, protofibrils, and then fibrils are very slow under physiologic conditions. The process is accelerated by mutations in the transthyretin gene or posttranslational changes in the peptide, including proteolysis or some forms of oxidation. (Reprinted by permission from ref. .)

Figure 2. The distribution of the TTR V122I allele in Africa

DNA obtained from 2,700 subjects in various locales in Africa was genotyped for the V122I allele by either PCR single-nucleotide polymorphism analysis or complete exome sequencing. The color coding shows the greater frequency of the allele in the countries of coastal West Africa. TTR, transthyretin. (Reprinted by permission from ref. .)

Figure 3. Multimodal imaging diagnosis of TTR V122I

(a) Standard echocardiogram shows increased wall thickness (distance between each fiduciary dot is 10 mm, the upper limit of normal). (b) Echocardiographic longitudinal systolic strain illustrates the characteristic reduced basal strain. (c) Nuclear imaging with Tc99m-PYP shows diffuse grade 3 uptake. (d) Cardiac magnetic resonance imaging shows diffuse subendocardial late gadolinium enhancement. TTR, transthyretin.