Genetic Insights May Enhance the Differential Diagnosis and Understanding of Patients with Transthyretin Mutations

Recognizing critical differences in genotype and phenotype among patients with transthyretin amyloidosis or other inherited cardiovascular diseases is imperative for optimal outcomes.

Hereditary transthyretin amyloidosis (hATTR or ATTRv [variant]) is a progressive, fatal disease caused by mutations in the transthyretin (TTR) gene. Amyloid deposits are caused by mutations that destabilize protein folding; the ensuing result is cardiomyopathy, which may be attributed to cardiovascular disease historically, but is actually caused by multiple related dysfunctions.

The diagnostic toolkit for patients with ATTR with cardiomyopathy has recently been expanded and refined with genetic testing.

To enhance the differential diagnosis and understanding of the prevalence and characteristics of patients living with TTR mutations, clinicians need to understand how molecular diagnostic programs can be used to differentiate between these patients and patients with other inherited cardiovascular conditions associated with mutations.

Keller and colleagues utilized ATTRv Compass program data to investigate the association. This program provides confidential genetic testing to patients in the United States (including Puerto Rico) and Canada who may possibly have ATTRv with polyneuropathy or have a family history of ATTRv.

A panel of 92 genes associated with inherited cardiovascular conditions was used in the analysis incorporating DNA next-generation sequencing.

Patients who were under the care of cardiologists (N = 978) were referred for testing using this specific panel, whereas 52 patients were positive for other non-TTR cardiovascular pathogenic mutations, and 74 patients were positive for TTR mutations. Notably, the most common type of TTR mutation was p.V142I, yet approximately two-thirds (66.2%) of these patients with a TTR mutation did not have a family history of ATTRv.

In the non-TTR mutations cohort, 16 patients with mutations in the MYBPC3 loci that was associated with cardiomyopathy were included. The investigators found that these patients with TTR mutations were on average older (age 67 years) compared with those patients with non-TTR mutations (age 53 years).

Heart disease was found in similar proportions: 89% in the TTR mutations cohort compared with 90% in the other cardiovascular diseases cohort. A comparison of the presence of symptoms was conducted between patient cohorts, specifically comparing the non-TTR mutations with the TTR mutation groups. Respectively, 21% of the patients with non-TTR mutations compared with 14% of patients with TTR mutations had autonomic symptoms. In these populations, gastrointestinal dysfunction occurred in 17% compared with 8% of patients, respectively, and motor symptoms occurred in 19% compared with 12%, respectively. However, in patients with TTR mutations, bilateral carpal tunnel syndrome (26% vs 0%, respectively) and symptoms of sensory dysfunction (28% vs 15%, respectively) were more prevalent than in patients with non-TTR mutations.

Because individuals volunteered to participate in the study rather than being automatically enrolled, the investigators recognized that there were limitations in data collection. Patients with TTR mutation had more diagnostic testing (eg, pyrophosphate imaging, biopsy) than those with non-TTR mutations, at a rate of 34% compared with 15%.

Keller and colleagues reported that ATTRv is frequently undiagnosed, despite diagnostic advances such as pyrophosphate imaging. Because ATTR can progress rapidly and be fatal, it is imperative that an accurate diagnosis be made early to initiate appropriate therapy; genetic testing is key for obtaining an accurate diagnosis. Heart failure nurses play a critical role in recognizing the multiple symptoms that should raise clinical suspicion and aid in the early diagnosis of ATTR.

Source: Keller A, Akinboboye O, Delgado D, et al. Genotypic and phenotypic differences and similarities among patients with transthyretin amyloidosis or other inherited cardiovascular diseases: insights from a genetic testing program. J Am Coll Cardiol. 2021;77(suppl_1):888.

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