Noninvasive eye test can help with early hATTR diagnosis

Shorter corneal nerve fibers seen in patients with minor symptoms

by Katherine Poinsatte, PhD | September 30, 2024

People with hereditary transthyretin amyloidosis (hATTR), a group of diseases that includes familial amyloid polyneuropathy (FAP), have significantly shorter nerve fibers in their corneas, the eye’s outermost layer, relative to healthy people, a study showed.

Shorter corneal nerve fibers could be detected using a noninvasive technique known as corneal confocal microscopy (CCM) in recently diagnosed hATTR patients with low levels of disability.

These and similar findings from a few other studies suggest that “CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms,” the researchers wrote.

The study, “Value of multi-modality small fiber assessments in a genotypically diverse cohort of transthyretin-related amyloidosis in the early stages of disease,” was published in Medicina Clínica.

hATTR comprises a group of conditions caused by mutations in the TTR gene, leading to the formation of toxic clumps of transthyretin (TTR) protein that accumulate in tissues, affecting their health and function.

In FAP, these disease-causing TTR aggregates are mainly found in peripheral nerves, and FAP symptoms are primarily neurological. When the toxic clumps mainly accumulate in heart tissue, the condition is called hATTR cardiomyopathy and is characterized by cardiac-related symptoms. When there are both neurological and heart-related symptoms, it is classified as mixed.

TTR clumps also can build in the eyes, and previous studies have pointed to eye abnormalities, including in the cornea, as early FAP biomarkers. The cornea is innervated by a dense network of sensory nerves that have a similar structure to peripheral nerves.

Corneal confocal microscopy is a rapid, noninvasive imaging technique that uses a high-resolution microscope to capture images of the cornea and the nerve fibers within it. It allows for measures of fiber length and density.

A team of researchers in Canada used CCM to see if corneal nerve fibers differed between 20 hATTR patients from 17 families and 20 age- and sex-matched healthy adults as a control group.

Patients’ mean age was 50.3 years and 70% were male. Most had mainly neurological symptoms, consistent with FAP. Of the remaining patients, six primarily had heart-related symptoms consistent with hATTR cardiomyopathy.

Val30Met (V30M) the most common FAP-causing mutation, was present in six patients (30%), while different mutations mostly were detected in one patient each.

All but two patients were considered to be at FAP stage 1, with initial symptoms causing mild and abnormal sensations, numbness, or weakness, typically in the feet. The two remaining patients were classified as stage 2, which is marked by moderate symptoms affecting the hands, arms, and torso, as well as the feet and legs, with aids like a crutch or cane required for walking.

Most patients exhibited low levels of disability, with 75% being classified as stage I on the Polyneuropathy Disability Score system, a stage marked by abnormal sensations but no difficulty walking.

A total of eight patients had polyneuropathy, or damage to several nerves, and 10 had carpal tunnel syndrome, a condition that affects nerves in the wrist and is usually an early hATTR symptom.

“There was no difference in age of onset, positive family history, duration of disease or measures of disability between groups of V30M and non-V30M variants,” the researchers wrote.

While other measures of small nerve fiber function were abnormal in up to half of all patients, all 19 patients who agreed to undergo corneal confocal microscopy showed abnormal corneal nerve fibers.

Specifically, hATTR patients had significantly shorter corneal nerve fibers than controls. There were no significant differences in corneal nerve fiber length based on the underlying disease-causing genetic mutation.

In addition, fiber length did not significantly associate with disease duration, disability measures, or other small fiber tests.

“In a diverse [group] of patients with ATTRv, with common (V30M) and less common variants, we found that [corneal nerve fiber length] was abnormal in all patients, including those with either a predominantly neuropathy or a predominantly cardiomyopathy [clinical profile],” the researchers wrote.

“An important aspect of our study was the demonstration of the usefulness of CCM tests in all patients, regardless of [mutation] type, and the lack of differences between V30M and non-V30M patients,” they added.

The team emphasized the benefits of the early, and highly sensitive, detection of nerve fiber loss with corneal confocal microscopy.

“The utility of CCM measurements in the investigation of suspected [early-stage] neuropathy, when other tests are normal, cannot be underestimated, as it may help select patients for both interventional studies and for potentially disease modifying approved therapies,” the researchers concluded.