Phenotypic Sex Differences in Transthyretin Amyloidosis V122I Mutation Patients

Victoria Kalinoski-Dubose and colleagues from Ohio State University’s Wexner Medical Center in Columbus, OH, presented data on phenotypic sex differences in patients with transthyretin amyloidosis with V122I mutations during a poster session at the 2020 American Heart Association virtual meeting focused on the evaluation of cardiac amyloidosis and hypertrophic cardiomyopathy.

Recognized as an autosomal dominant disease, hereditary transthyretin amyloidosis (ATTR) results in organ dysfunction when misfolded, destabilized, transthyretin protein accretes in body tissues. Transthyretin valine 122 isoleucine (V122I), which predominantly affects African Americans, is the most common mutation in the United States. In men, V122I is most commonly associated with cardiomyopathy phenotype.

A mixed V122I phenotype that includes both cardiomyopathy and polyneuropathy has been described in studies. Researchers have not thoroughly evaluated sex differences in the clinical presentation of V122I types.

Kalinoski-Dubose and colleagues studied data from 38 ATTR patients who were treated at Ohio State University and who were identified with genetic testing as possessing the V122I mutation (69.4% male; 31.6% female). Researchers looked at multiple data points (including interventricular septal thickness, posterior wall thickness, and ejection fraction) and used a variety of diagnostic and testing modalities (including cardiac biopsy, nuclear pyrophosphate scan, echocardiography, and electromyography) to determine the extent of cardiac and nerve involvement in these patients. They also divided the cohorts by sex, excluding 2 asymptomatic patients.

Women and men differed in clinical phenotype. In women with V122I ATTR, the clinical phenotypes were polyneuropathy (75%) and cardiomyopathy (25%) with symptom onset occurring most often when patients were aged 40 to ≥50 years. In men with V122I ATTR, the most common clinical phenotypes were cardiomyopathy (52%) and mixed cardiomyopathy/polyneuropathy (48%) with symptom onset when patients were aged 70 to ≥80 years. Electromyography data showed generalized neuropathy with reduced or absent sural nerve sensory response in patients with V122I ATTR.

More men (84%) than women (36%) experienced carpal tunnel syndrome, frequently caused by thickening of the transverse ligament. Men had significant cardiac differences compared with women in terms of interventricular septal thickness (19.9 vs 12.5 mm; P <.001) and posterior wall thickness (17.3 vs 12.1 mm; P <.001). They also had worse measures of ejection fraction (40% vs 55%; P = .008).

The authors concluded that based on data from this cohort, female ATTR V122I patients are more likely to present with polyneuropathy phenotype at a younger age, and males are more likely to present with predominantly cardiovascular or mixed phenotype.


Kalinoski-Dubose V, LoRusso S, Efebera Y, et al. Phenotypically sex differences in transthyretin amyloidosis V122I mutation patients. Presented at: American Heart Association Scientific Sessions 2020; November 13-20, 2020. Abstract P2053-2020.

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