Nerve damage often goes unrecognized in adults with hATTR-CM
More than half of patients have polyneuropathy, study finds
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More than half of adults with hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM), a condition marked by heart damage, also have multi-nerve damage, according to a new study from the University of Toronto.
The findings suggest that many people treated for the heart-related form of the disease may have unrecognized polyneuropathy, or nerve damage, that could qualify them for additional life-changing therapies.
Because certain disease-modifying therapies (DMTs) are currently approved only for hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), identifying this “mixed phenotype” is critical. Without a formal neurological diagnosis, many hATTR-CM patients are ineligible for treatments that target the underlying production of toxic proteins.
“Patients with hATTR-CM should be systematically referred to a specialized neurologist for routine assessment, especially patients who report neurologic symptoms,” researchers wrote.
The study, “Detecting Polyneuropathy in Patients with Hereditary Transthyretin Amyloid Cardiomyopathy,” was published in the journal CJC Open.
Understanding the mixed profile of hATTR
hATTR is a rare genetic disorder in which the transthyretin protein misfolds and forms toxic clumps, called amyloid deposits, in organs due to mutations in the TTR gene.
When deposits form mainly in the heart, the disease is referred to as hATTR-CM, and patients develop symptoms such as abnormal heart rate, fatigue, and shortness of breath. When the toxic clumps primarily accumulate in the nerves, the disease is called hATTR-PN or familial amyloidosis polyneuropathy, and symptoms include muscle weakness, burning pain, and numbness.
Some hATTR-CM patients may eventually develop polyneuropathy, while, conversely, those with hATTR-PN may develop cardiomyopathy. In these cases, people are said to have a mixed phenotype, or profile, with both heart and neurologic manifestations.
Some DMTs that target transthyretin production are approved only for hATTR-PN, meaning that those with hATTR-CM are not eligible unless they also have signs of polyneuropathy.
Therefore, a team led by researchers at the University of Toronto, in Canada, investigated the prevalence of polyneuropathy in adults with hATTR-CM to “highlight the need for regular screening for [polyneuropathy] to provide the optimal treatment for patients.”
The study included 60 hATTR-CM patients (51.7% men) who were followed at a single Canadian center. Participants, most of whom were of Afro-Caribbean descent, underwent a physical exam and nerve conduction studies (NCSs) to detect nerve damage in the upper and lower extremities.
Following neurologic testing, half of the participants, 60% of whom were women, showed signs of polyneuropathy, as indicated by both the physical exam and NCSs, and reported neurological symptoms.
The remaining 30 patients reported no neurological symptoms. Most of them, 12 women and 12 men (40% of all participants), showed no signs of polyneuropathy on either test. However, the other six patients (10% of all participants), five of whom were women, showed NCS abnormalities despite normal physical examinations.
Across all three groups, the predominant New York Heart Association class was functional class 2, meaning mild cardiac symptoms that caused minimal problems during daily activities.
The mean PYP ratio, a diagnostic marker for hATTR-CM, was the same for those with and without clear polyneuropathy signs (1.88), but lower (1.45) for the six patients with NCS abnormalities alone. Values above 1.5 indicate amyloid deposition in the heart.
Identifying hidden nerve damage
Physical examination of the hATTR-CM patients with clear polyneuropathy revealed abnormalities in ankle and knee reflexes and in pinprick sensation. Other findings were normal in most of them, including in language, motor ability, muscle strength, and coordination.
The team noted that NCS findings varied across the hATTR-CM patients with polyneuropathy. Some had evidence of nerve fiber damage and carpal tunnel syndrome (36.7%), a common condition marked by numbness, tingling, and pain in the hand and forearm. Smaller groups had nerve fiber damage alone (30%) or neither condition (6.7%).
When researchers compared the different mutations in the TTR gene among individuals with and without polyneuropathy, the differences were statistically significant.
More hATTR-CM patients with polyneuropathy carried the TTR mutation called Val50Met or Val30Met, the most common hATTR-PN-causing mutation, than those without polyneuropathy (20% vs. 4.2%). The Val142Ile mutation was more prominent in the hATTR-CM group without polyneuropathy (70.8% vs. 30%), but was, nonetheless, the most common mutation in patients with polyneuropathy.
“Patients with hATTR-CM may often have underlying [polyneuropathy] that goes unrecognized,” the researchers concluded. “Our research supports the systematic referral of all patients presenting with hATTR-CM (especially those with a Val142Ile or Val50Met mutation) to a neurologist who specializes in TTR, for regular screening.”
