Clinical characteristics of patients with hereditary transthyretin mutations primarily associated with cardiomyopathy and other rare transthyretin mutations: insights from a genetic testing programme
Bibliographic record
Abstract
Abstract Background/Introduction Hereditary transthyretin amyloidosis (hATTR; ATTRv) is a progressive, fatal disease caused by mutations in the transthyretin gene (TTR) that results in deposition of amyloid throughout the body, including in the heart. The p.V142I and p.T80A mutations typically manifest with a cardiomyopathy (CM) phenotype. Early diagnosis, which can be facilitated by genetic testing, is key to achieving optimal patient outcomes. Purpose To characterise the clinical profile and symptom burden of patients with hereditary transthyretin mutations associated primarily with a CM phenotype and rare hereditary transthyretin mutations. Methods This analysis used data from hATTR Compass, a genetic testing programme in the United States and Canada for patients suspected of having hATTR with polyneuropathy (PN) and patients with a family history of hATTR. Sequencing was performed using a TTR single-gene test, a gene panel of inherited cardiovascular disorders (CardioNext), or a gene panel of inherited neuromuscular disorders (NeuropathySelect). Akcea is aware of isolated data quality issues. Importantly, these do not affect the conclusions of this analysis. Results Cardiology specialists referred 466 patients with p.V142I, 15 with p.T80A, and 28 with rare TTR mutations to this programme. Of patients who reported sex, 57%, 53%, and 52% with p.V142I, p.T80A, and rare mutations, respectively, were male. Of patients who reported ethnicity, most with p.V142I were African American (94%), whereas the majority of patients with p.T80A and rare TTR mutations were Caucasian (100% and 69%, respectively). 24%, 60%, and 50%, of patients with p.V142I, p.T80A, and rare TTR mutations, respectively, had a family history of hATTR. The majority of patients with p.V142I (74%), p.T80A (53%), and rare TTR (54%) mutations were 65 years of age or older. Although most patients with p.V142I, p.T80A, and rare TTR mutations experienced symptoms/manifestations of heart disease (94% vs 100% vs 85%), many also presented with bilateral carpal tunnel syndrome (23% vs 44% vs 30%) and with sensory (27% vs 44% vs 65%), motor (15% vs 11% vs 25%), and autonomic (19% vs 11% vs 30%) dysfunction. Conclusion Most patients with the p.V142I mutation were African American, whereas many with p.T80A and other rare TTR mutations were Caucasian. Family history of hATTR was more common among patients with p.T80A and other rare TTR mutations than among patients with p.V142I. Regardless of the underlying mutation variant, many hATTR patients can present with various symptoms/manifestations aside from CM, such as PN and bilateral carpal tunnel syndrome. Recognising the neurological symptoms that can occur alongside CM and performing subsequent genetic testing facilitates diagnosis of hATTR. Early diagnosis is critical in hATTR because it is progressive and fatal, and early initiation of disease-modifying therapy is essential to optimising patient outcomes. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Akcea Therapeutics, an affiliate of Ionis Pharmaceuticals, Inc.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".