Eye Disease Common in FAP Patients with Ser77Tyr Mutation, May Serve as Biomarker, Research Suggests

People with a type of FAP caused by a Ser77Tyr mutation are more likely to develop conjunctival lymphangiectasia, an uncommon clinical condition characterized by swelling of the conjunctiva — the clear tissue covering the white part of the eye and the inside of the eyelids, a recent study found.

The presence of this eye condition was associated with more severe neurological symptoms and cardiac disease, indicating that it could serve as a potential biomarker for disease progression in FAP, also known as hereditary transthyretin amyloidosis, the researchers said.

Titled “Conjunctival lymphangiectasia as a biomarker of severe systemic disease in Ser77Tyr hereditary transthyretin amyloidosis,” the study was published in the British Journal of Ophthalmology.

The group of diseases known as amyloidosis — which includes FAP — is caused by a build-up of an abnormal protein called amyloid in organs and tissues throughout the body. When the proteins aggregate, or clump together, they form insoluble amyloid fibrils that are resistant to degradation.

Hereditary transthyretin amyloidosis (ATTRv) develops in people who have inherited genetic mutations in the TTR gene. More than 150 mutations in this gene have been reported. “In France, the V30M (62%) [substitution of the amino acid methionine for valine at position 30] TTR amyloidogenic variant is the most common,” the researchers said.

The second most common mutation in French ATTRv patients is a substitution of tyrosine for serine at position 77, known as Ser77Tyr. This variant also has been reported in the U.S., Spain, Israel, and the U.K.

People with Ser77Tyr FAP (ATTRS77Y) have unique clinical features. Specifically, they usually develop ATTRv later on in life, past the age of 50, have a frequent history of carpal tunnel syndrome, have more rapid and severe progressive neuropathy, or nerve damage, and often develop cardiac abnormalities.

Additionally, as the group of French researchers reported in 2018, ATTRS77Y patients may present with conjunctival lymphangiectasia. This eye disease is caused by amyloid deposits in the conjunctiva.

Now, the researchers evaluated the relationship between the ocular (eye-related) manifestations of ATTRS77Y and its relationship with other disease features.

Patients with genetically confirmed ATTRS77Y amyloidosis were recruited for the study and underwent complete neurological examination. This included staging with the Neuropathy Impairment Score (NIS) and the Polyneuropathy Disability (PND) score, complete cardiac evaluation, and complete ocular evaluation.

The study group consisted of 24 ATTRS77Y patients, with an average age of 58.4 years.

None of the participants presented with amyloid deposits in the anterior chamber, or the front part of the eye between the cornea and the iris filled with liquid. The patients also did not have secondary glaucoma — increased eye pressure — or vitreous amyloidosis, which is amyloid deposits in the gel-filled space between the lens and the retina of the eyeball.

However, retinal angiopathy – disease of the blood vessels that supply the retina – was observed in four patients. In one of those four, that condition was complicated with retinal ischaemia, or a lack of oxygen to the retina.

The most common ocular manifestation detected was conjunctival lymphangiectasia, which was found in 13 patients (54%).

Additionally, statistical analysis indicated that the presence of conjunctival lymphangiectasia was associated with more severe neurological disease. In fact, the average NIS score for patients with conjunctival lymphangiectasia was 43.3, while it was only 18.9 for those without the complication.

Similarly, the PND score was an average of 2.6 for the individuals with conjunctival lymphangiectasia, compared with 1.4 for those without the disease.

The patients with conjunctival lymphangiectasia also were more likely to have amyloid cardiomyopathy, or disease of the heart muscles.

“Despite a poor neurological and cardiac prognosis, this variant [ATTRS77Y] is associated with good visual outcomes. CL [conjunctival lymphangiectasia] occurs frequently in these patients in whom it could be considered as a biomarker of severe systemic disease,” the researchers concluded.