Simple eye tests may help doctors diagnose, monitor Fabry disease

Measurements of subtle eye changes in people with Fabry disease may offer a noninvasive way to support the early diagnosis and long-term monitoring of eye involvement in the rare genetic disorder, a study showed.

Researchers found that pupils in people with Fabry recovered more slowly after exposure to light, a change that may reflect early dysfunction of the autonomic nervous system, which controls involuntary body functions. They also found thinning of the outermost layer of the cornea, the eye’s clear outer surface that covers the front of the eye.

Higher blood levels of lyso-Gb3, a disease biomarker, were associated with a thinner corneal epithelium, suggesting that this ocular measure may reflect underlying disease activity and could help monitor disease burden over time.

The findings suggest that measuring how the eyes respond to light and mapping subtle changes in the cornea “may serve as complementary, non-invasive biomarkers for early diagnosis and monitoring of Fabry-related [eye] involvement,” the researchers wrote.

The study, “Evaluation of corneal morphology, pupillometry, and ocular surface parameters in Fabry disease patients: correlation with plasma Lyso-Gb3 levels,” was published in International Ophthalmology.

Recommended Reading

May 22, 2024 Columns by Jerry Walter

With Fabry disease, I didn’t expect this many eye health problems

Overlapping symptoms may delay diagnosis

Fabry disease is caused by mutations in the GLA gene that result in dysfunctional or absent alpha-galactosidase A (alpha-Gal A), an enzyme responsible for breaking down certain fatty molecules. The resulting toxic buildup of these fatty molecules in the body’s cells can damage multiple organs, including the nervous system, kidneys, heart, and eyes, driving a wide range of Fabry symptoms.

Because the disease can affect many organs and symptoms often overlap with those of other conditions, Fabry diagnosis is frequently delayed, with potentially serious consequences for organ function and long-term outcomes. As newer therapies have expanded treatment options for Fabry, there is growing interest in identifying new tools to detect and monitor disease-related changes earlier.

The autonomic nervous system is often affected in Fabry. Beyond regulating heart rate, blood pressure, and digestion, this system controls tear production and pupil response to light. Autonomic dysfunction may therefore alter pupil responses and affect tear production, potentially leading to dry eyes and changes in corneal structure.

Because these changes can be assessed with simple, noninvasive eye tests, the researchers conducted a study to determine whether measurements of pupil responses to light, corneal structure, and dry-eye features could help detect Fabry-related eye involvement and whether these features were associated with blood levels of Lyso-Gb3.

The study involved 25 people with Fabry, with a mean age of 38, and 25 age-matched healthy volunteers. Blood lyso-Gb3 measurements were available for 14 people with Fabry.

Seventy-six percent of the Fabry patients had corneal verticillata, a whorl-like corneal pattern commonly seen in the disease. No patients showed swelling of the optic nerve, which carries visual information from the eye to the brain, and two had early lens changes that did not require surgery.

Researchers first examined pupil size under different lighting conditions using pupillometry, a method that measures how pupils respond to changes in light. While people with Fabry tended to have larger pupils than healthy volunteers in dim, intermediate, and bright light, none of these differences was statistically significant.

However, a dynamic assessment of pupil responses revealed a significant difference. People with Fabry showed a lower maximal redilation velocity, meaning their pupils returned more slowly toward their original size after constricting in response to light. The researchers said this may be a sign of early Fabry-related autonomic dysfunction.

The team examined the cornea using optical coherence tomography, an imaging technique that produces detailed cross-sectional images of the eye. While the overall thickness of the cornea did not differ significantly between groups, researchers found that the corneal epithelium (the thin outermost layer of the cornea) was thinner in the peripheral (outer) region of the eye in people with Fabry.

Higher blood lyso-Gb3 levels were consistently associated with a thinner corneal epithelium across all measured regions of the eye surface, suggesting that structural changes in the cornea may become more pronounced as disease burden increases. By contrast, Lyso-Gb3 levels were not associated with pupil size, pupil redilation velocity, or the thickness of the cornea as a whole.

Dry-eye measures did not significantly differ between groups and did not correlate with Lyso-Gb3.

“The results suggest that non-invasive approaches such as dynamic pupillometry and quantitative corneal imaging may serve as complementary, eye-based biomarkers for early diagnosis and longitudinal monitoring,” the researchers wrote.

The team cautioned that the findings are preliminary and need to be confirmed in larger studies.

“If validated, integrating these non-invasive assessments into routine [eye involvement] follow-up of Fabry patients could complement existing biomarkers,” particularly in people with late-onset Fabry, for whom lyso-Gb3 levels may be less informative, the researchers said.