Clinical and Epidemiological Characteristics of Patients with TTR Mutations and Polyneuropathy Manifestations of Hereditary Transthyretin Amyloidosis: Insights from a Genetic Testing Program
Sami Khella1, Keyur Shah2, Diego Delgado3, Catherine Marti4, Andrew Keller5, John Jefferies6, Jill Dolinksy7, Aaron Gabriel8, Arvind Narayana8, Kemi Olugemo8
1University of Pennsylvania, 2VCU Health System, 3Toronto General Hospital, 4Piedmont Heart Institute, 5Pennsylvania State University College of Medicine, 6Methodist University of Tennessee Cardiovascular Institute, 7Ambry Genetics, 8Akcea Therapeutics
Objective:
To characterize the clinical profile of patients suspected of having hereditary transthyretin amyloidosis (hATTR or ATTRv [variant]) with polyneuropathy.
Background:
hATTR is a progressive and fatal disease caused by mutations in the transthyretin gene (TTR) that result in the deposition of misfolded TTR protein in major organs and systems, leading to multisystem dysfunction. Patients often experience a mixed phenotype of both cardiomyopathy and polyneuropathy. Early diagnosis, which can be facilitated with genetic testing, is key to achieve optimal patient outcomes.
Design/Methods:
This analysis utilized data from patients enrolled in the hATTR Compass program, a confidential genetic testing program offered in the United States (including Puerto Rico) and Canada for patients suspected of having hATTR with polyneuropathy or with a family history of hATTR.
Results:
Of 718 patients with a confirmed pathogenic TTR mutation, 345 had ≥1 symptom consistent with polyneuropathy. The mean age of these symptomatic patients was 69 years, most were male (59%) and African American (70%). A minority of patients reported a family history of hATTR (18%). Cardiologists and neurologists referred 65% and 8% of symptomatic patients, respectively. Patients who reported on pre-diagnosis experience (10%) saw an average of 2.4 doctors before their genetic diagnosis visit. Patients presented with a variety of symptoms/manifestations including heart disease (53%), sensory dysfunction (44%), bilateral carpal tunnel syndrome (26%), motor dysfunction (26%), and autonomic dysfunction (24%). Of note, patients with the p.53L mutation, generally considered a predominantly neurologic phenotype mutation, presented with heart disease.
Conclusions:
Diagnosis of hATTR amyloidosis is challenging, as many patients see multiple doctors before being diagnosed and many do not have a known family history of hATTR. Patients with hATTR often present with polyneuropathy and cardiomyopathy symptoms. Recognition of hATTR symptoms and performing genetic testing facilitates diagnosis of this debilitating and fatal disease.