Symptoms related to familial amyloid polyneuropathy (FAP) and other forms of hereditary transthyretin (ATTR) amyloidosis were found in African American and Hispanic or Latinx individuals who unknowingly carried a disease-related genetic variant revealed by genomic screening, according to a recent study.
These findings support further investigation of genomic screening to identify populations with a greater risk for familiar ATTR, and guide early disease management in these patients.
The study, “Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis,” was published in the Journal of Personalized Medicine.
Hereditary ATTR amyloidosis is caused by mutations in the TTR gene, which provides instructions for a protein called transthyretin. The mutations result in a defective protein that forms toxic deposits in tissues, mainly in the heart, nerves, kidneys, and eyes.
Patients can have a spectrum of clinical manifestations. When they experience symptoms of polyneuropathy, or nerve damage, they have a subtype of the disease called FAP. Cardiac symptoms, on the other hand, are associated more commonly with a subtype called hereditary ATTR amyloidosis with cardiomyopathy.
One mutation (variant) linked to familial ATTR amyloidosis — V142I — increases the risk of heart failure and is found in up to 4% of African American and 1% of Hispanic or Latinx individuals.
However, due to the nonspecific nature of symptoms, diagnosis is frequently delayed or missed, which can worsen health discrepancies in these populations. Thus, early identification of hereditary ATTR amyloidosis is key to effective treatment with new therapies that target and stabilize abnormal transthyretin.
Population-based genomic screening can uncover disease risk in people who are unaware of potential health problems. Studies suggest that screening may improve outcomes for certain treatable diseases for which preventive measures or effective treatments are available.
Recently, investigators based at the Icahn School of Medicine at Mount Sinai in New York launched a pilot program — as part of the ongoing BioMe Biobank biorepository — to screen for treatable conditions in the large, ethnically diverse population of New York City. As part of the program, eligible participants were screened for disease-related variants associated with ATTR amyloidosis.
The team now evaluated the medical records of those who received a TTR V142I-positive result from the screening program to look for any disease-related features. They also assessed follow-up and short-term outcomes to determine if genomic screening can help identify the risk of ATTR amyloidosis early on.
This analysis included 32 BioMe participants who were V142I-positive — without a previous amyloidosis diagnosis — of which 81% were female, with a median age of 57. Of these, 17 (53%) self-reported as African American and 15 (47%) as Hispanic or Latinx.
When participants were informed of the screening result, 18 (56%) had at least one ATTR amyloidosis-related systemic feature, the most common (47%) being peripheral neuropathy, a manifestation of FAP that refers to damage to the nerves outside of the brain and spinal cord.
Reported symptoms of peripheral neuropathy included walking and balance problems, muscle weakness, numbness, tingling, back and joint pain, and pain in extremities.
There also was a high prevalence of FAP-related complications, including 10 (31%) patients with carpal tunnel syndrome, one of the most commonly reported FAP symptoms, as well as 10 (31%) with spinal stenosis, characterized by the narrowing of the spinal canal in the lower back leading to lower spinal cord compression.
Autonomic neuropathy, which is damage to the part of the nervous system that controls internal organs, occurred in seven (22%) of participants and included cardiac autonomic malfunction in one (3%), incontinence in four (13%), sexual dysfunction in three (9%), and four (13%) had heart failure. An additional 12 (38%) individuals without systemic involvement had at least one of 17 hereditary ATTR-related symptoms.
The team found a family history of ATTR-related systemic symptoms in 15 (47%) of participants, in which carpal tunnel syndrome was most common, occurring in 13 relatives of eight (25%) patients. A family history of heart failure was reported for six (19%) participants, and in eight of their relatives. No family history of a familial ATTR diagnosis was reported.
After disclosure, 18 (56%) participants received follow-up with a cardiologist or cardiovascular geneticist, with visits taking place within eight months of screening disclosure. Of these, 16 (89%) had a follow-up that included an electrocardiogram, echocardiogram, or Tc-99m-PYP scintigraphy (a specific test to detect ATTR cardiac involvement).
Based on these tests, one African American participant received an hereditary ATTR diagnosis.
During follow-up, 19 (59%) of the V142I-positive individuals were found to have an ATTR-related systemic feature. Following evaluations by a specialist, 31 of 32 (96%) had either a systemic feature or a related symptom of the disease.
The proportion of ATTR-related features was not significantly different in those 60 or older compared to 60 or younger, or between males and females, or African American vs. Hispanic or Latinx participants.
“This study helps to inform genomics-first approaches for an under-recognized condition that largely impacts [African American] and [Hispanic or Latinx] populations in the U.S.,” the investigators wrote. “Despite having potentially related features of [hereditary ATTR], none of our study participants had prior knowledge of their genomic risk.”
“Genomic screening can help identify [hereditary ATTR] risk and guide management early on, avoiding potential delays in diagnosis and treatment,” they added. “Further questions remain regarding the appropriate implementation of genomic screening, cost-benefit of this approach, and equitable access to recommended follow-up care.”
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