Carpal tunnel syndrome often precedes ATTRv diagnosis in US
Problems with nerves in wrist could signal presence of disease-causing mutations
In the U.S., one-third of people with hereditary transthyretin amyloidosis (hATTR) — a group of disorders that includes familial amyloid polyneuropathy (FAP) — are diagnosed with carpal tunnel syndrome years before a hATTR diagnosis, a study indicated.
This finding suggests that a history of carpal tunnel, a condition that affects nerves in the wrist, may be an important signal in prompting a diagnostic workup for hATTR among U.S. patients, the researchers noted.
The study, “Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis,” was published in Neurology.
Study into common disease-causing mutations among 56 patients in US
Familial amyloid polyneuropathy refers to forms of hATTR, or ATTRv, where the disease affects the nerves outside the brain and spinal cord. These conditions are mostly caused by mutations in the TTR gene that provides instructions for making the transthyretin protein.
As a result, transthyretin forms abnormal clumps in tissues that are toxic and damaging, leading to disease symptoms.
Over 100 different hATTR-causing TTR mutations have been identified. For a few of the most common, typical patterns of disease progression are well-established.
For instance, the most frequently found global mutation, called Val30Met, is usually associated with neurological symptoms that start manifesting around age 30. This mutation is particularly common in some areas of Portugal, where FAP is endemic.
Less is known about common hATTR-causing mutations in the U.S., where the disease is not endemic. A team of scientists with Johns Hopkins University looked at data covering 56 people diagnosed with hATTR between January 2008 and January 2020 at their center.
Among these people, 31 had a mutation called Val122Ile, 13 carried a mutation known as Leu58His, and 12 had the Val30Met mutation.
In line with prior findings, nearly all patients with the Val122Ile mutation (97%) were Black, while one (3%) was Hispanic/Latino. In contrast, all patients with the Leu58His mutation were white. Among those carrying the Val30Met mutation, two-thirds (67%) were white, while 17% were Asian and 17% were Hispanic/Latino.
Val122Ile “is the most common [disease-causing] variant in the United States affecting 3-4% of Black individuals,” the researchers wrote.
They added that the Leu58His mutation is common in Maryland among families of German descent, but its clinical features “have not been systematically described to our knowledge.”
Most of the patients (69%) carrying the Leu58His mutation were aware of a family history of hATTR. More than 80% of those with any of the two other mutations were not aware of the condition in their family.
Age at symptom onset varied according to mutation. Patients with the Val122Ile mutation sought medical attention for what turned out to be hATTR symptoms at a mean age of 72.5 years, whereas patients with any of the two other mutations tended to show symptoms in their mid-60s.
Unlike the more common early-onset pattern of disease associated with the Val30Met mutation in endemic regions, all U.S. patients carrying that variant had late-onset disease, with symptoms not manifesting until after age 50.
“These patterns underscore the variability in ATTRv and highlight the importance for clinical suspicion to make a diagnosis,” the researchers wrote.
Nearly all patients with the Val122Ile mutation initially sought medical attention due to heart-related problems. However, “60% reported that their [nerve damage-related] symptoms began concurrently with or even proceeded” those affecting the heart, the team wrote.
This means that many of these people began experiencing signs of nerve damage before cardiac issues, but did not seek medical attention until the appearance of heart problems.
Carpal tunnel, Romberg sign can be ‘clinical clues’ in finding disease
Researchers specifically highlighted that nearly one-third of patients carrying the Val122Ile mutation had been diagnosed with carpal tunnel syndrome seven or more years before their hATTR diagnosis.
“These rates are higher than what has been reported in other variants,” they wrote, adding that “an opportunity for early diagnosis of penetrant [Val122Ile] ATTRv is to educate target populations about [carpal tunnel syndrome] and its link to ATTRv.”
While found less frequently than in Val122Ile carriers (97%), carpal tunnel syndrome also was reported among more than half of patients with the Val30Met (58%) or Leu58His mutations (77%).
Compared with people carrying the Val122Ile mutation, those carrying any of the other mutations more commonly sought medical attention initially due to neurological problems.
Nerve damage-related problems also tended to progress faster and be more severe in these two groups of patients, with the greatest severity of neurological symptoms generally reported in those with the Val30Met mutation, results indicated.
Patients in all three groups usually were positive for the Romberg sign, a phenomenon where a person loses their balance when standing with eyes closed. This sign often was clearly present even in patients who didn’t have other substantial nerve issues.
“This clinical examination sign along with a history of carpal tunnel syndrome, which was a common finding across variants, can serve as clinical clues to diagnosis,” the researchers wrote.
“Taken together, this report highlights the challenge of diagnosing ATTRv in the US,” they concluded, adding that “there is a broad heterogeneity of presentation within and between variants that delays diagnosis of a rare disorder in non-endemic areas.”