New study links TTR mutation to nerve-related ATTR and better survival
Thai study compares outcomes of p.Ala117Ser mutation and wild-type ATTR
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Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) was a common clinical manifestation among people carrying a mutation in the TTR gene called p.Ala117Ser, according to a study conducted in Thailand.
Similar to findings from other studies in parts of Asia, p.Ala117Ser was the most common mutation among people with transthyretin amyloidosis (ATTR), a group of diseases that includes hATTR-PN. The data also showed that people with this mutation had significantly lower rates of organ transplant and longer event-free survival than those with wild-type ATTR, the nonhereditary form of the disease.
“These findings highlight the value of [genetic profile-guided] evaluation and the potential for precision therapies tailored to regional TTR variants,” the researchers wrote.
The study, “The phenotypic landscape of p.Ala117Ser transthyretin amyloidosis: distinct clinical profiles and outcomes versus wild-type ATTR,” was published in BMC Cardiovascular Disorders.
How ATTR affects the nerves and heart
ATTR refers to a group of progressive diseases caused by the buildup of abnormal transthyretin protein. These proteins form toxic clumps called amyloid deposits, which accumulate in tissues throughout the body and cause damage over time.
The disease typically appears in two main forms. In ATTR with polyneuropathy (ATTR-PN), amyloid deposits damage peripheral nerves — the nerves outside the brain and spinal cord — leading to symptoms such as numbness, tingling, and muscle weakness.
In transthyretin amyloid cardiomyopathy (ATTR-CM), amyloid builds up in the heart muscle. This can cause thickened heart walls, abnormal heart rhythms, and heart failure. Some people develop damage in both the nerves and the heart, known as a mixed disease profile.
ATTR can occur because of mutations in the TTR gene (hereditary ATTR) or as a result of aging (wild-type ATTR). The wild-type form usually affects older adults and mainly involves the heart.
More than 100 mutations in the TTR gene have been identified worldwide. Some mutations — such as p.Val50Met and p.Val142Ile — are commonly reported globally. In parts of Asia, however, the p.Ala117Ser variant appears to be particularly common, though its clinical features and long-term outcomes have not been well defined.
Study examines ATTR patients in Thailand
To better understand how genetic differences affect how ATTR appears in patients, researchers in Thailand conducted a single-center study of 50 people with ATTR, including both hereditary and wild-type forms of the disease.
More than half of the participants (53%) had hereditary ATTR; among them, p.Ala117Ser was the most common mutation, representing 40% of those cases. The remaining 47% of the study participants had wild-type ATTR. Seven people with TTR mutations had not yet developed symptoms at the time of the study.
Researchers compared 12 symptomatic patients with the p.Ala117Ser mutation with 21 patients who had symptomatic wild-type ATTR.
Patients with the p.Ala117Ser mutation were diagnosed at a younger age than those with wild-type ATTR (mean of 60 vs. 79 years). The mutation group also included fewer men (58.3% vs. 100%). Neuropathy was seen in all symptomatic patients with the p.Ala117Ser mutation, compared with 47.6% of patients with wild-type ATTR.
Among patients with the p.Ala117Ser mutation, half had a primarily neurologic form of the disease, hATTR-PN, while the other half had a mixed pattern involving both nerves and the heart. In contrast, the most common presentation among patients with wild-type ATTR was heart involvement (ATTR-CM), seen in 71.4% of patients, while the remaining 28.6% had a mixed profile.
Although heart involvement was seen in both groups, patients with the p.Ala117Ser variant tended to have less advanced heart disease than those with wild-type ATTR.
Researchers evaluate survival and transplant outcomes
During a median follow-up of 43 months (about 3.5 years), 17 participants (34%) died and two (4%) underwent organ transplant — one combined heart-liver transplant and one heart transplant.
Researchers then analyzed event-free survival, defined as the time from diagnosis to death or heart or heart-liver transplant. Across the whole group, the median event-free survival was 61 months (about five years).
Median event-free survival was 52 months (a little over four years) in patients with wild-type ATTR. In contrast, median event-free survival was not reached in the p.Ala117Ser group, meaning that more than half of these patients were still alive and had not undergone transplant at the last follow-up.
Additional statistical analyses showed significantly lower rates of death or transplant among patients with the p.Ala117Ser mutation compared with those with wild-type ATTR. This association remained significant even after adjusting for hospitalization due to heart failure, a strong predictor of outcomes.
Mutation linked to better event-free survival
When researchers specifically looked at patients who were already experiencing symptoms, those with the p.Ala117Ser mutation again showed significantly better event-free survival than those with wild-type ATTR.
After adjusting for the use of medications that can improve outcomes in people with heart failure, the p.Ala117Ser variant remained a significant predictor of better event-free survival.
Overall, the findings suggest that the p.Ala117Ser mutation is strongly associated with hATTR-PN, and that disease linked to this mutation may have a more favorable prognosis than wild-type ATTR.
These findings may “in part, be attributed to the earlier stage of disease at presentation in patients with ATTR associated with the p.Ala117Ser variant,” the researchers wrote.
