Study links hATTR-PN mutations to symptoms beyond nerve damage
Findings highlight need for earlier symptom recognition, better treatment access
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Although mutations that cause hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) most frequently lead to nerve damage, they can also cause heart damage and other symptoms, a study highlights.
The findings “emphasize the need for earlier symptom recognition and patient identification via efforts to raise awareness of the constellation of clinical manifestations of” this genetic disease, researchers wrote. The team also called for better access to treatments for hATTR-PN and related diseases.
The study, “Contemporary Description of Clinical Characteristics and Outcomes in Patients with Hereditary ATTR Amyloidosis: Results from the Multicountry OverTTuRe Study,” was published in Cardiology and Therapy. The work was funded by AstraZeneca, which markets the approved hATTR-PN treatment Wainua (eplontersen).
Sizable portion of patients had a mixed profile
Hereditary transthyretin amyloidosis, abbreviated hATTR or ATTRv, is a genetic disorder caused by mutations in the TTR gene, which encodes the protein transthyretin. The mutated protein forms toxic clumps that damage tissue, driving disease symptoms.
In most cases, hATTR affects mainly the nerves outside the brain and spinal cord; this is known as hATTR-PN. The toxic protein clumps can also accumulate in and damage the heart, leading to a condition called hereditary transthyretin amyloid cardiomyopathy (hATTR-CM). It’s also increasingly recognized that some people with TTR mutations experience both nerve and heart damage, which is referred to as having a mixed profile.
Seeking to better understand the spectrum of ways that hATTR can manifest, AstraZeneca is sponsoring an observational study called OverTTuRe (NCT06355934). The goal is to collect long-term data from hATTR patients in countries worldwide using established data sources like electronic health records and insurance claims information.
Here, a team of researchers at study sites and AstraZeneca reported the clinical manifestations, outcomes, and healthcare resource utilization from 1,502 people with hATTR across the U.S., the U.K., Japan, Denmark, and Sweden who enrolled in OverTTuRe. Date of diagnosis ranged from January 2014 to December 2023.
Across all countries, the majority of patients (51.3% to 63.7%) specifically had hATTR-PN. However, in every country, a sizable portion of patients — from 36.3% to 48.8% — had a mixed profile, with both nerve and heart damage.
“While [hATTR-PN] was the predominant [clinical profile] observed across all countries, the mixed [profile] accounted for a considerable and growing proportion of patients in the US and Sweden,” the researchers wrote.
Patients with mixed profile frequently had documented heart problems
HATTR-CM was comparatively rare, with only five to 90 cases reported in each country. As such, the researchers focused most of their analyses on hATTR-PN and hATTR-mixed.
They found that people with hATTR-PN were generally younger (median age range 48.5 to 69 vs. 75 to 78 years, were more likely female (36.6% to 64.1% vs. 19.3% to 56.4%), and had fewer or less severe coexisting health conditions compared with those with hATTR-mixed.
Symptoms related to nerve damage, including abnormal sensations and gastrointestinal problems, were frequently reported prior to diagnosis of hATTR-PN, and these were also common as an initial sign of hATTR-mixed. People with hATTR-mixed frequently had documented heart problems, such as heart failure or abnormal heart rhythms, prior to being formally diagnosed.
Median time to diagnosis after any initial nerve-related manifestation ranged from zero to nearly three years in the hATTR-PN group and from about eight months to nearly 2.5 years in the mixed group. The longest diagnostic processes were reported in the U.S., regardless of the disease form.
For people with initial heart-related symptoms, the median time to a hATTR-mixed diagnosis ranged from nearly six months to about 1.5 years.
Regardless of specific disease manifestations, the five years preceding diagnosis often involved heavy use of healthcare resources, with frequent doctor’s visits and hospitalizations.
These results indicate a critical need for recognition of initial symptoms in [people known to carry TTR mutations], heightened clinical suspicion to enable earlier diagnosis, and timely access to targeted therapies.
This reflects how long and complex diagnostic journeys can put a burden on the healthcare system as a whole, in addition to being arduous for patients themselves.
“The [varied] clinical manifestations of [hATTR], which often mimic other conditions, may result in patients having multiple healthcare interactions before receiving an accurate diagnosis,” the researchers wrote.
Data also showed that “most patients in all countries except Sweden did not receive any [hATTR-specific] treatments,” the researchers wrote. This was largely due to the fact that such treatments were approved late in the study period.
In addition, “international variability exists in the implementation of national access pathways, thus impacting the time from treatment approval to initiation in patients,” the team wrote. “This inequality emphasizes the need to expand the availability of disease-specific treatment since they meaningfully impact patient quality of life, autonomy, and physical function.”
Across countries, five-year mortality rates were generally higher among people with hATTR-mixed (21% to 73%) than those with hATTR-PN (14.6% to 36.2%).
“This analysis from the OverTTuRe study highlights [a variability in clinical profiles] associated with diverse clinical manifestations in patients with ATTRv amyloidosis, which translates into broad differences in outcomes,” the researchers wrote. “These results indicate a critical need for recognition of initial symptoms in [people known to carry TTR mutations], heightened clinical suspicion to enable earlier diagnosis, and timely access to targeted therapies.”
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