New questionnaire may help flag early transition to symptomatic hATTR-PN
Seventeen of 23 items were linked to clinically detectable disease
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A newly developed questionnaire may help flag early signs of hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in people carrying mutations in the TTR gene that are known to cause the disease, a study shows.
Although the tool, called asymptomatic carrier neurologic assessment (ACNA), is not designed to definitively determine disease onset, it may help identify mutation carriers who could be at higher risk of clinically detectable disease and who may need further evaluation.
The questionnaire is already being tested in larger cohorts of people carrying disease-causing TTR variants “with a diverse array of TTR variants pooled from broader geographies to further delineate its performance for early detection of [hATTR-PN],” the researchers wrote.
ACNA aims to flag early transition to symptomatic hATTR-PN
The study, “Asymptomatic Carrier Neurologic Assessment: A Tool for Early Detection of Symptomatic Transition in Pathogenic TTR Gene Variant Carriers,” was published in the European Journal of Neurology.
hATTR-PN (sometimes abbreviated as ATTRv-PN) is a progressive disease caused by mutations in the gene TTR, which provides instructions to make a protein called transthyretin. The mutated protein forms toxic clumps that damage nerves outside the brain and spinal cord, leading to symptoms such as abnormal sensations and muscle weakness.
People who carry hATTR-PN-causing mutations may remain asymptomatic, or without symptoms, for years, and whether and when symptoms develop can vary by the specific TTR mutation. With the advent of treatments that can slow disease progression, detecting early signs of transition to symptomatic disease has become increasingly important.
“Early detection of potential transition to diagnosable ATTRv-PN disease among [asymptomatic carriers] could help reduce the time to diagnosis, thereby limiting the duration and cumulative effects of untreated disease progression,” the researchers wrote.
With this in mind, an international team of researchers developed and tested ACNA, a questionnaire that aims to help identify early signs and symptoms of hATTR-PN. The tool includes 23 questions, each assessing the presence or absence of specific signs and symptoms associated with early disease.
“The ACNA tool can be easily administered in routine clinical practice, typically taking about 20–30 min to complete at the bedside,” the scientists wrote.
Study included asymptomatic and newly symptomatic carriers
ACNA’s performance was assessed in 128 asymptomatic carriers and 89 newly symptomatic carriers who had transitioned to symptomatic disease within the previous two years. Participants had a mean age of 48.7 years, 59.9% were women, and they lived in Portugal (43.3%), Spain (26.3%), the U.K. (23%), and France (7.4%).
Most participants (76.5%) carried the p.Val50Met mutation, the most common disease-causing TTR variant associated with hATTR-PN.
The researchers used statistical tests to see how well each of the 23 ACNA questions was associated with whether participants were asymptomatic or newly symptomatic. Positive responses to 17 of the 23 questions were significantly associated with transition to clinically detectable hATTR-PN.
The strongest association was seen for a positive response to the question about neuropathic pain in the arms or legs, including burning, electric shock-like, knife-like, or stabbing sensations. This was followed by questions about difficulty sensing hot or cold temperatures in the extremities and persistent, unexplained weight loss of at least 5 kg (about 11 pounds).
In participants with the p.Val50Met mutation, positive responses to 16 questions were significantly associated with transition to clinically detectable disease. The questions about pain and hot/cold sensory impairment showed, again, the strongest associations.
A positive response to the question about feeling full sooner than expected and/or having recurrent nausea or vomiting was also significantly associated with disease transition. This was consistent with the spectrum of symptoms associated with this particular mutation, including those affecting involuntary bodily functions such as digestion, the researchers noted.
Among non-p.Val50Met carriers, positive responses to four questions were significantly associated with transition to clinically detectable disease, with the pain question again showing the strongest association.
Age, location, and TTR variant may affect interpretation
Further analyses identified age, medical center, and TTR variant as factors that could affect how the results are interpreted. These factors “are consistent with the known early onset, geographic localization to Portugal, and sensory [problems] predominance of the p.Val50Met variant, respectively, and suggest that interpretation may need to account for patient and variant-specific factors,” the researchers wrote.
Overall, the findings suggest that although ACNA “does not currently provide a composite score or diagnostic threshold,” the researchers wrote, “it identifies and describes individual symptoms or sign signals or patterns of signals that may be associated with transition from asymptomatic to symptomatic ATTRv-PN disease.”
“If such signals suggest possible clinical conversion, further evaluation with established diagnostic methods … would be required to confirm disease manifestation,” they added.
The questionnaire is currently being used in an ongoing Phase 3 clinical trial, called ACT-EARLY (NCT06563895). The study is testing whether treatment with acoramidis can prevent or delay the onset of hATTR-PN or transthyretin amyloid cardiomyopathy (ATTR-CM), a related disease marked by heart damage, in people who carry disease-causing TTR mutations but do not yet have symptoms. Acoramidis is approved, under the brand name Attruby, for adults with ATTR-CM. ACT-EARLY is recruiting up to 587 asymptomatic carriers at sites worldwide.
“With further … validation in larger cohorts, a composite signal specific to age, geography, and variants may emerge from a constellation of statistically significant associations across individual questions,” the researchers concluded.
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