Prevalence and Outcomes of p.Val142Ile TTR Amyloidosis Cardiomyopathy: A Systematic Review

Abstract

Background: The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers. Methods: We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects. Results: The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy. Conclusion: The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.

Transthyretin cardiac amyloidosis

“… 5 Val122Ile TTR variant is associated with late-onset (median age of 69 years) severe cardiac involvement with highly symptomatic HF, commonly, with New York Heart Association (NYHA) class > II, lower 6-min walk times, and higher NT-proBNP levels and increased rates of incident HF compared to other TTR variants. 27 Patients carrying this TTR mutation have increased mortality rates and the shortest median survival from diagnosis among all ATTRv subgroups. 27 In this population, early diagnosis of ATTRv-CA is challenged by the higher frequency of hypertension and increased LV wall thickness.…”

Clinical Clues and Diagnostic Workup of Cardiac Amyloidosis

“… 13 , 14 In the United States, there is a higher prevalence of the p.Val142Ile mutation among people of African and Afro-Caribbean ancestry but with variable penetrance. 15 This mutation is of particular interest given its prevalence and predominantly cardiac phenotype. 16 , 17 Overall, ATTRv has a rather heterogeneous presentation depending on the underlying variant and can emerge with a polyneuropathy phenotype, cardiomyopathy phenotype, or mixed.…”

Is Hereditary Transthyretin Amyloidosis the Third Leading Cause of Monogenic Chronic Kidney Disease, Only Behind ADPKD and Alport Disease?

“…Positive results permitted to diagnose autosomal dominant polycystic kidney disease (ADPKD) (PKD1 [34.1%] and PKD2 [10.0%] genes), Alport syndrome (COL4A5 [10.9%], CO-L4A4 [6.4%], and COL4A3 [5.9%] genes), and transthyretin amyloidosis (ATTR) (TTR gene [4.1%]). Regarding the latter, all patients presented a variant c.424G>A (p.Val142Ile) in the TTR gene (formerly known as Val122Ile; [rs76992529]) which is reported in the European population with a frequency of 0.004432% while in the African descent population with a frequency of 1.5-3.5% [2,3], with a not already completely defined penetrance. Interestingly, a recent study conducted whole exome sequencing, searching for monogenic causes of CKD among a cohort of 114 adults with familial CKD but did not identify any TTR mutation, although 35.6% of the patients reported having non-European ancestry [4].…”

“…Specifically, the c.424G>A (p.Val142Ile) variant is currently recognized as the most common cause of hereditary amyloid heart disease worldwide [2,3,11]. Although the Val142Ile mutation was also described in association with a biopsy-proven renal TTR amyloid deposition [12], almost all patients with the Val142Ile mutation showed an isolated late-onset cardiomyopathy, a phenotype widely described in scientific literature [2,13,14], suggesting a potential secondary renal injury related to a cardiorenal syndrome.…”