Problems Swallowing, Carpal Tunnel Could Be A97S Mutation Biomarkers

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by Patricia Inacio PhD |

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Early signs of swallowing difficulties and carpal tunnel syndrome may serve as biomarkers for familial amyloid polyneuropathy (FAP) patients carrying the Ala97Ser (A97S) mutation, a study suggests.

According to researchers, these factors may help identify A97S patients who might benefit from early treatment.

The study, “Unique Phenotypes With Corresponding Pathology in Late-Onset Hereditary Transthyretin Amyloidosis of A97S vs. V30M” was published in Frontiers in Aging Neuroscience.

FAP is a rare progressive disease caused by genetic mutations in the TTR gene, which contains instructions to produce a protein called transthyretin. These mutations lead to a faulty transthyretin protein being produced that forms toxic amyloid deposits in different tissues and organs, particularly in the heart, nerves, and kidneys.

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The disease can manifest differently among patients with different mutations. This includes the time of symptom onset.

In patients carrying the Val30Met mutation (V30M) — the most common TTR gene mutation associated with FAP in Japan and around the world — the disease has both an early- and late-onset manifestation. However, patients with the A97S mutation — the most common in Taiwan — don’t develop disease manifestations usually until after the age of 50 (late-onset disease).

Identifying the factors underlying early disease onset and faster progression among patients with different gene mutations would allow for treatment at early stages of the disease, when they are more likely to have an effect.

A team led by researchers in Japan and Taiwan compared the clinical manifestations and lab tests between two patient groups, a Taiwanese group of 105 patients (74.3% men) carrying the A97S mutation and a Japanese late-onset group of 50 people (86 % men) carrying the V30M mutation.

Patients in the A97S group had two unique features — swallowing difficulties (dysphagia) and carpal tunnel syndrome — both early symptoms. Carpal tunnel syndrome develops due to pressure on the median nerve — a major nerve in the arm — causing tingling, numbness and pain in the hand and fingers.

Dysphagia was significantly more prevalent in the A97S compared with the V30M group (53.4% vs. 2.0%). Patients carrying the A97S mutation also experienced choking (43.6%) and hoarseness (31.7%).

“The presence of dysphagia at an early stage would suggest a faster progression in the A97S cohort,” the researchers wrote.

At an early disease stage and before being formally diagnosed, 22 of 56 patients with the A97S mutation had dysphagia, choking, or hoarseness.

Carpal tunnel syndrome was seen in 43.3% of those carrying the A97S mutation, appearing almost three years earlier than other symptoms of nerve damage. Despite surgical interventions, symptoms were only mildly and temporarily alleviated.

An autopsy of an A97S patient revealed the presence of amyloid deposits in the tongue, larynx, and esophagus, as well as in certain nerve fibers. Also, amyloid deposits were particularly prominent in the median nerve.

Researchers then compared the shape of amyloid fibrils between three groups of patients: 20 carrying the A97S mutation; six carrying the V30M mutation with early-onset disease; and 32 with the V30M mutation with late-onset disease.

Results showed that amyloid fibrils were generally shorter and thinner in the A97S and late-onset V30M group, while they tended to be longer in the early-onset V30M group.

More patients carrying the A97S mutation had neuropathic symptoms (except carpal tunnel syndrome) affecting the arms than late-onset V30M patients (25.7% vs. 10.0%), examinations showed. Other clinical manifestations were similar between both groups.

Three patients carrying the V30M mutation had eye symptoms at disease onset. All three had eye surgery and amyloid deposits were detected in one patient.

The natural disease course differed between groups. Patients in the A97S group were younger by four to five years at disease onset, as well as when entering more advanced stages of the disease compared with those in the V30M group.

Also, being a male was linked to an earlier disease onset in A97S patients. Early dysphagia in the A97S group was also associated with faster disease progression. No such link was seen in the V30M group.

These results confirm that different TTR gene mutations are associated with distinct disease manifestations and indicate that early dysphagia and carpal tunnel syndrome may serve as biomarkers for patients carrying the A97S mutation.

“Such observations may serve as a foundation to explore and analyze unique [disease manifestations] among various [genetic backgrounds],” the researchers wrote.