Insights from a Genetic Testing Program into Characteristics of Patients with P.V142I Mutations Associated with Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis (hATTR or ATTRv [variant]), the rapidly progressing and fatal disease, is caused by fibril deposits of misfolded mutant transthyretin (TTR) proteins in a range of major organs and vital systems, frequently leading to multisystem dysfunction.

Clinical signs include carpal tunnel syndrome and polyneuropathy. Genetic testing can facilitate early diagnosis critical to improving patient outcomes through early treatment with the latest therapies.

Keyur Shah, MD, of the VCU Health Pauley Heart Center and Chief of the Section of Heart Failure, described the hATTR Compass program, a confidential genetic testing program available in the United States (including Puerto Rico) and Canada, for patients suspected of having hATTR with polyneuropathy or with a family history of hATTR. In this study, patients were examined for p.V142I/V122I TTR mutations. Real-world data were collected, and sequencing was performed either using an 81-gene panel associated with neuromuscular disorders or a 92-gene panel associated with inherited cardiovascular disorders.

In total, 584 of the 718 patients identified with TTR mutations were found to have the p.V142I/V122I mutation. Over half (56%) of the patients were male. The vast majority (92%) of patients with p.V142I were African American, and <30% with the mutation had a known family history of hATTR. Most (76%) of the patients were referred by cardiologists, while 9% were referred by internal medicine physicians. This is not surprising, because most patients present with cardiac manifestations. Prediagnosis information was provided by 45 patients, and the average number of doctors seen in this context to date was 2.2 among these patients. While most patients presented with symptoms of heart disease, neuropathy was also common in the study cohort. Among the patients with p.V142I/V122I who reported symptoms, the vast majority (91%) had symptoms of heart disease and more than half (57%) had polyneuropathy symptoms.

The following polyneuropathy manifestations were found: autonomic dysfunction (20%), gastrointestinal symptoms (10%), motor dysfunction (14%), and sensory dysfunction (30%). Symptoms or manifestations, such as bilateral carpal tunnel syndrome and renal disease, were found in 25% and 24% of patients, respectively. Due to limitations of data collection and participation in the program, the investigators suggested that symptoms may be underreported overall.

The authors concluded that patients with p.V142I/V122I commonly presented with heart disease (91%), polyneuropathy (57%), and bilateral carpal tunnel syndrome (25%), according to this analysis. To initiate disease-modifying treatment earlier in the course of the disease and thereby change the course of the disease and optimize outcomes by making meaningful interventions, it is essential for clinicians to recognize “red flag” symptoms to diagnose hATTR amyloidosis symptoms earlier. Patients may then be referred for genetic testing to facilitate diagnosis of the devastating disease.

Source: Shah K, Bumma N, Delgado D, et al. Characteristics of patients with P.V142I mutations associated with hereditary transthyretin amyloidosis: insights from a genetic testing program. Presented at: American College of Cardiology 70th Annual Scientific Session, May 15-17, 2021.

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