Eye Problems Were 1st Symptoms of FAP for Family With Rare Mutation

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by Steve Bryson, PhD |

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Members of a Chinese family carrying a rare gene mutation causing familial amyloid polyneuropathy (FAP) experienced abnormal protein deposits in the eye — manifesting as “floaters” — before having any other noticeable disease symptoms, a case series reported.

Such protein deposits can lead to functional abnormalities of the retina, a layer of tissue at the back of the eye that sends signals to the brain, according to researchers, who noted that two patients in this family remained asymptomatic.

Given these findings, the researchers recommended follow-up eye examinations be done, even for FAP patients without eye-related symptoms.

“Careful follow-up of structural and functional changes in the retina is needed, even in asymptomatic patients with FAP,” the team wrote.

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Eye Abnormalities May Serve as Early Biomarkers for hATTR Amyloidosis

The case series, “Ocular Manifestations in a Chinese Pedigree of Familial Amyloidotic Polyneuropathy Carrying the Transthyretin Mutation c.401A>G (p.Tyr134Cys),” was published in the journal Genes.

Hereditary transthyretin amyloidosis (hATTR) is a group of inherited diseases mainly caused by mutations in the protein transthyretin, known as TTR. These mutations lead to the buildup of amyloid deposits made up of misfolded transthyretin, which damages nerves and other tissues.

FAP is a specific form of hATTR in which these deposits mainly accumulate in peripheral nerves found outside the brain and spinal cord, though they also may be found in other tissues, including the heart, kidneys, and eyes.

More than 100 different TTR mutations have been associated with FAP, the most common being Val30Met. With this mutation, the amino acid valine is replaced by the methionine amino acid at position 30 along the protein chain. Amino acids are protein building blocks.

A rare TTR mutation — called Tyr114Cys, which causes tyrosine to be replaced by cysteine at position 114 — has been found in patients with more eye involvement as compared with those with the Val30Met mutation.

Because of its rarity, little is known about the disease-related effects of Tyr114Cys regarding amyloid deposits in eye tissue.

In this report, researchers at Fudan University, in China, described the findings of detailed eye examinations conducted on a family in which five members were carriers of this mutation.

The disease affected two sisters, now deceased, one of whom had one affected daughter. The other sister had three affected sons (one deceased) and two affected grandsons. The daughter, the two living sons, and the two grandsons were assessed.

‘Floaters’ among primary eye-related symptoms

The affected daughter was a 44-year-old woman whose main symptom was worsening vitreous opacities — floating objects, commonly called floaters, in her field of vision. These floaters occur inside the clear gel, called vitreous, that fills the space between the lens and the retina at the back of the eyes.

An examination revealed symptoms of impaired vision, significant floaters, and yellowish spots at the back of each eye. The woman had a vitrectomy in both eyes to remove some vitreous. The doctors also removed part of the internal limiting membrane, a very thin and transparent membrane on the surface of the retina that separates it from the vitreous.

Further tests revealed the presence of markers related to amyloid deposits in different parts of the retina.

Although the woman’s vision improved after surgery, there were recurrent floaters and amyloid deposits within the retina after four years. There was no evidence of peripheral nerve or heart involvement.

One of the affected sons, a 40-year-old man who was cousin to the 44-year-old woman, complained of progressive blurred vision in his left eye for more than two years. The man’s right eye was blind for an unknown reason and had never been treated. Vitrectomy to remove significant floaters found high amounts of amyloid floaters and deposits, some tightly sticking to the retina.

One month after surgery, the patient’s vision improved slightly, but an examination found blurred retinal structures and amyloid deposits in his retina, as well as tiny bleeding spots. He was treated with retinal laser surgery. Tests also revealed elevated levels of a blood marker for heart damage, and thickening of the heart muscle, consistent with amyloid-related heart disease.

His 43-year-old brother had impaired vision only in the left eye, with significant floaters. A vitrectomy improved his vision to the normal range. A six-month follow-up found normal pressure in both eyes; unlike his brother, there was no sign of peripheral nerve or heart involvement.

Patients can be asymptomatic

Both grandsons, the 15-year-old son of the 40-year-old man, and his cousin, the 22-year-old son of the affected, but deceased brother, had normal vision and reported no symptoms. Mild vascular tortuosity — an abnormal blood vessel curvature — was seen in both individuals.

Vascular changes, even without symptoms, “may be due to the mechanical compression from gradual amyloid deposition in the optic disc,” the researchers wrote.

The thickness of the retinal nerve fiber layer (RNFL) was measured by optical coherence tomography angiography (OCTA) in the two grandsons and their 43-year-old uncle and compared with healthy controls.

All three individuals had small or absent optic cups — a white, cup-like area in the center of the optic disc, the place where the optic nerve passes through the back of the eye. The optic discs also showed a crowded appearance compared with those from healthy controls. Furthermore, the average thickness of the RNFL was higher than in controls (130.3 vs. 118.7 micrometers).

“Amyloid deposition may explain the apparently thicker RNFL and crowded optic disc,” the researchers wrote.

“The results highlight the amyloid deposition of mutant TTR in the optic disc and retina, even in the asymptomatic stage,” the team wrote, adding, “Aside from the vitreous opacities in the advanced stage, we also identified early structural and functional changes in the retina, even before clinical symptoms in cases with FAP.”