Genetic testing can help uncover FAP in people with neuropathy
FAP-causing mutations seen in study participants who didn't show typical symptoms
Early genetic screening for people with unexplained nerve damage, or neuropathy, may help uncover undiagnosed cases of familial amyloid polyneuropathy (FAP), allowing faster access to treatment.
In a study from France, 1% of 400 adults with neuropathy of unknown origin were found to have a FAP-causing mutation, even though they didn’t show typical red flag symptoms like a family history of the disease or carpal tunnel syndrome, which affects nerves in the wrist.
“Our data emphasize the need for early detection because patients frequently lack red-flag symptoms,” the study’s researchers wrote. “Ultimately, early screening allows for prompt management and minimizes long-term complications in individuals with unexplained neuropathy.” The study, “Etiologic Diagnosis of Neuropathies Based on First- Line Screening of TTR Gene Mutations,” was published in the Journal of the Peripheral Nervous System.
FAP is a form of hereditary transthyretin amyloidosis (ATTRv), a group of conditions marked by the accumulation of toxic clumps of abnormal transthyretin protein in tissues due to mutations in the TRR gene. In FAP, this accumulation occurs mainly in the peripheral nerves, those outside the brain and spinal cord. The resulting neuropathy can cause peripheral symptoms that include numbness, tingling, burning pain, weakness, and problems with balance.
Many patients may also have symptoms that affect the autonomic nervous system — which regulates involuntary bodily functions — such as digestive problems, dizziness when standing, and bladder or sexual dysfunction.
When toxic transthyretin clumps build up mostly in the heart, the disease is called ATTRv with cardiomyopathy, that is, heart damage.
Diagnosing FAP as early as possible is critical, because the treatments that are available are most effective at slowing disease progression and preventing permanent nerve and organ damage earlier in the disease.
Screening for FAP
Yet diagnosing FAP remains challenging in everyday clinical practice, particularly where the disease is less common or when the usual red flag features are absent. These include a family history of FAP, carpal tunnel syndrome, early autonomic dysfunction, gastrointestinal problems, unexplained weight loss, or heart and/or kidney problems that typically trigger genetic testing.
Given advances in therapy and greater access to affordable genetic testing, researchers in France sought to evaluate the feasibility and utility of screening adults with unexplained neuropathy for FAP-causing TTR mutations. While testing the entire population “is difficult and costly,” broadening genetic testing to all people with neuropathy with no clear cause “could be feasible,” wrote the researchers, who conducted the PRE-TRANS study (NCT03190577), where 400 adults with neuropathy of unknown cause were screened for TTR mutations at 12 centers in western France between 2017 and 2022. People with a known cause of neuropathy or previous TTR testing weren’t included.
The participants ranged in age from 28 to 91 (mean age, 66.5) and had lived with neuropathy for a mean of 5.1 years. The most common coexisting health issue was high blood pressure, followed by history of cancer, excessive alcohol consumption, and prior exposure to nerve-toxic treatments, but none fully explained their neuropathy.
Nearly half (49%) had signs of large-fiber neuropathy, which can cause balance issues, muscle weakness, joint stiffness, and reduced reflexes. About a quarter (24.5%) had small-fiber neuropathy, which typically leads to burning pain, tingling, or unusual skin sensations. Others showed mixed patterns or only muscle weakness. Some reported autonomic symptoms, but these weren’t specific enough to clearly point to FAP. Nine participants (2.3%) had cardiomyopathy marked by a thickened heart muscle.
Nerve function analyses showed that, in most participants, neuropathy affected the nerve fibers, or axons (88.3%), and both sensory and motor functions (71.1%).
Identifying disease-causing mutations
Genetic screening identified four people (1%) with previously reported disease-causing TTR mutations. Two carried Val30Met, the most common FAP-causing mutation, while one carried Glu61Lys and one had Ile107Val. Due to the small number of people testing positive, the researchers weren’t able to conduct statistical analyses to detect differences between people with and without such mutations.
Still, mutation-positive patients appeared to be older (mean age, 75) and had neuropathy for a slightly shorter time (mean, 2.5 years). None came from regions where the disease is more common, such as Portugal, Sweden, or Japan, or showed heart or kidney problems, which are often seen in later stages.
Only one of these patients had a red flag (carpal tunnel syndrome), indicating that most wouldn’t have been correctly diagnosed through traditional screening criteria, which is to test patients who have a red flag.
Although the detection rate was lower than in earlier French studies, the researchers said this reflects the study’s broader, less selective patient population.
“In patients with unknown neuropathy, early screening for a TTR mutation in the absence of red flags is a rational approach,” the researchers wrote. “This strategy will aid prompt management and minimize the risk of neurological or [heart-related] deterioration.”
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