TTR gene mutation may not be nerve damage cause in certain hATTR cases
Study: Careful assessment crucial to avoiding misattribution, overtreatment
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People carrying the p.V142I mutation in the TTR gene — which is mostly associated with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) — often have polyneuropathy, or damage to multiple nerves, a U.S. study shows.
But while TTR mutations can cause both polyneuropathy and cardiomyopathy, data suggested that in most p.V142I carriers experiencing polyneuropathy, nerve damage was likely due to other causes, such as having diabetes or chronic kidney disease, drinking alcohol, or taking nerve-toxic medications.
“Careful clinical assessment is essential to avoid misattribution and overtreatment,” researchers wrote. “Diagnostic rigor, including consideration of alternative causes and selective use of confirmatory testing, is critical to ensure appropriate management.”
The study, “Prevalence and attribution of polyneuropathy in p.V142I (V122I) hereditary transthyretin amyloidosis,” was published in the Journal of the Neurological Sciences.
In the US, the most common mutation causing hATTR is p.V142I
Hereditary transthyretin amyloidosis (hATTR) is caused by mutations in the TTR gene that result in the production of an abnormal form of TTR. This mutated protein tends to form clumps, known as amyloid deposits, that build up to toxic levels in the body.
In hereditary ATTR with polyneuropathy (hATTR-PN), TTR aggregates build up mainly in the nerves outside the brain and spinal cord, causing polyneuropathy. In hATTR-CM, they tend to build up in the heart, causing cardiomyopathy (heart damage) that can eventually lead to heart failure.
However, many people with hATTR-causing TTR mutations develop both polyneuropathy and cardiomyopathy.
In the U.S., the most common mutation causing hATTR is p.V142I (also known as V122I), particularly among Black people. This mutation is predominantly linked to hATTR-CM, “but the [frequency] of [polyneuropathy] in these individuals is not well-defined in the literature,” the researchers wrote, with some studies reporting rates of up to 98%.
To better understand the frequency and cause of polyneuropathy in people carrying the p.V142I mutation, a team of researchers in the U.S. reviewed medical records from 153 adults with TTR mutations who were seen at the University of Pennsylvania Amyloidosis Center.
Mutation carriers more likely to have diagnosis of diabetes
A total of 82 people (83% identifying as Black) carried the p.V142I mutation, and 34 of them (41%) had evidence of polyneuropathy. Polyneuropathy typically progressed slowly and mainly affected sensation in both feet and legs.
Most p.V142I carriers were initially examined for heart disease, while 21 sought genetic testing after a relative was found to carry the mutation.
Compared with the other participants, p.V142I carriers were significantly more likely to have a diagnosis of diabetes (28% vs. 5.7%) or chronic kidney disease (34% vs. 13%) or to be taking medications that are toxic to nerves (15% vs. 2.9%).
Notably, among p.V142I carriers with polyneuropathy, only 11 of them (32%) showed signs that polyneuropathy was possibly or probably related to amyloid deposits. In the subgroup of people with confirmed hATTR-CM, 35% had polyneuropathy possibly or probably attributable to hATTR.
“In every individual without [hATTR-CM], the [polyneuropathy] was determined to be unrelated to amyloidosis and was instead attributed to something else,” the researchers wrote. Other causes included diabetes, heavy alcohol use, chronic kidney disease, and/or nerve-toxic medications.
The rates of polyneuropathy attributed to amyloid deposits was 13.4% among all p.V142I carriers, regardless of whether they were showing symptoms, and 21% among those showing symptoms. This means that most cases of polyneuropathy had other causes.
If doctors assume that symptoms of polyneuropathy in p.V142I carriers are caused by amyloid deposits, patients may be misdiagnosed and receive treatments that are unnecessary, expensive, or unlikely to help, the researchers noted.
These findings have important clinical implications, particularly in avoiding misdiagnosis and overtreatment.
Therapies for hATTR are designed to slow or reduce the production of TTR protein. While these therapies can help patients whose symptoms are truly caused by amyloid deposits, they are unlikely to ease polyneuropathy caused by diabetes or chronic kidney disease, among others.
Careful evaluation is therefore needed to identify the true cause of polyneuropathy before treatment decisions are made.
“These findings have important clinical implications, particularly in avoiding misdiagnosis and overtreatment,” Christian Messina, MD, a neurologist in Catania, Italy, wrote in a letter to the editor of the Journal of the Neurological Sciences, titled “From prevalence to precision: Interpreting neuropathy in transthyretin amyloidosis.”
Still, “the absence of detailed information regarding disease duration and, importantly, the duration of treatment with [TTR-targeting] therapies represents a relevant limitation of the study,” Messina said. This is because patients on such therapies may show better nerve function, making hATTR-related polyneuropathy appear less common than it actually is.
Another important limitation was that none of the patients underwent nerve biopsy, a procedure to remove a small section of a nerve for examination under a microscope, the researchers noted.
While this procedure is invasive, explaining the “reluctance” to pursue it, the researchers wrote, “nerve biopsy may still be informative in selected cases with diagnostic uncertainty.”
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