Heart, nerve damage progress together in ATTRv, study finds
Distinctions may not apply, say researchers, urging 'mutation-agnostic' view
Hereditary transthyretin amyloidosis (ATTRv), a group of diseases that includes familial amyloid polyneuropathy (FAP), might not be as easily categorized into distinct neurological and heart-related disease subtypes as once thought, according to a study.
FAP has long been considered the neurological form of ATTRv, while ATTR amyloidosis with cardiomyopathy (ATTR-CM) affects the heart. The distinction is made based on which disease-causing genetic mutation is present and the first symptoms that appear. But researchers have now found that across people with all types of ATTRv-causing mutations — including ones closely linked to FAP — heart involvement is evident early and progresses as neurological dysfunction does.
“Our findings support a growing body of evidence that ATTRv is a progressive, multisystem disorder characterized by tightly linked neurological and cardiac [heart-related] deterioration, independent of [genetic mutation] or initial symptom profile,” the researchers wrote.
The scientists called for a “mutation-agnostic approach” to evaluating people with ATTRv, where all people undergo neurologic and cardiac assessments in every case. Such an approach “has the potential to enhance diagnostic accuracy, enable earlier therapeutic intervention, and ultimately improve outcomes,” the team wrote.
The study, “Parallel Neurological and Cardiac Progression in Hereditary Transthyretin Amyloidosis: An Integrated Clinical and Imaging Study,” was published in Diagnostics.
Challenging rigid categories
In ATTRv, mutations in the TTR gene lead to the production of an abnormal version of the transthyretin (TTR) protein that toxically accumulates in tissues.
The disease has classically been divided into distinct groups based on the underlying genetic mutation. Some mutations are linked to FAP, where the peripheral nerves that run through the body are mainly affected, and others with ATTR-CM, in which TTR buildup mostly affects the heart.
However, more recent research challenges these rigid categorizations, recognizing that many patients may see multiple body systems affected. For example, people with Val30Met, the most common FAP-causing mutation, often develop heart problems, and people with the Val122Ile mutation, which is linked to ATTR-CM, can have neurological issues.
Research has historically focused on evaluating individual organ systems separately, limiting scientists’ ability to understand the interrelated progression of neurological and cardiac disease in ATTRv.
“Understanding these parallel trajectories may be essential for refining diagnosis, guiding treatment, and anticipating complications,” the researchers wrote.
The team of researchers in Italy examined the relationship between neurological disease stage and heart biomarkers in 58 people (41% women) with genetically confirmed ATTRv who were evaluated at an Italian hospital.
Patients’ mean age was 60, and they carried several TTR mutations, some associated with FAP, ATTR-CM, or a mixed disease profile. Thirty-one participants were on ATTRv therapies. All underwent comprehensive neurological and cardiological assessments.
Participants were sorted into three groups based on their degree of neurological disability: no neurological symptoms, evidence of nervous system involvement but the ability to walk with or without support, and neurological involvement requiring walking aids or wheelchair dependence.
Heart tests demonstrated a clear association between heart involvement and neurological disease progression. As the neurological disease stage increased, so did blood levels of NT-proBNP, a biomarker of heart damage.
Heart imaging showed that structural and functional heart abnormalities were evident at early neurological disease stages, and worsened in parallel with the neurological disease.
“These results challenge the conventional … classification of ATTRv into ‘cardiac’ and ‘neurologic’ subtypes, which remains prevalent in clinical guidelines and trial design,” the researchers wrote, adding that rigid assumptions based on genetic mutations “can obscure the true disease burden.”
The findings could have important implications for clinical practice. Because people with FAP may have early heart involvement that does not yet cause symptoms, it won’t be caught unless clinicians do advanced heart imaging. Likewise, nervous system issues may go underdiagnosed in people initially evaluated for ATTR-CM.
“All patients with suspected or confirmed ATTRv, regardless of mutation or presenting symptoms, should undergo both neurologic and cardiac evaluations at [diagnosis] and during follow-up,” the researchers wrote.
They noted that larger studies following patients over time are still needed to establish whether neurological and cardiac dysfunction continue to progress in parallel over time.
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