Rare manifestation of familial vitreous amyloidosis caused by Gly103Arg transthyretin

Abstract

Aim: To identify and analyze the genotype of the patients with special ocular manifestations of familial vitreous amyloidosis (FVA) in a Chinese Han family.

Methods: Pars plana vitrectomy (PPV) surgery was performed on a 52-year-old Chinese woman presented with vitreous amyloidosis and progressive visual impairment, without evidence of cardiac, renal, gastrointestinal, central nervous system or peripheral nervous system dysfunction. During the surgery, the patient presented with a gray-white dense and thick cotton wool-like change in the vitreous body, accompanied by complete retinal detachment. Additionally, hard, free and movable yellow-white deposits were observed in the posterior pole and surrounding retina, the vitreous and subretinal deposits were examined by Congo red staining and immunohistochemical pathological examination, and whole exome sequencing was performed on blood samples from the patient and her cousin.

Results: During the operation, it was discovered that there was a complete detachment of the retina and a significant amount of hard, free-floating yellow-white deposits were observed beneath the posterior pole and surrounding retina. This is an exceedingly rare ocular manifestation. Pathological examination of the vitreous and subretinal deposit specimens revealed positive Congo red staining, as well as elevated vascular endothelial growth factor (VEGF) expression in vascular endothelial cells within the sediment specimens upon immunohistochemical examination. The patient and her cousin both exhibited a heterozygous mutation in Glyl03Arg within the transthyretin (TTR) gene, resulting in a substitution of glycine (Gly) at position 103 with arginine (Arg).

Conclusion: FVA may present with various ocular manifestations, but panretinal detachment is a rare occurrence. In cases where retinal detachment persists for an extended period of time, amyloid deposits may form under the retina through retinal tears, leading to subretinal deposits that can impede retinal reattachment and negatively impact visual prognosis. Elevated levels of VEGF in the eyes of FVA patients may indicate an overexpression state, necessitating careful postoperative follow-up. The heterozygous mutation Gly103Arg may represent a unique pathogenic site in Chinese individuals.

Keywords: Gly103Arg; familial vitreous amyloidosis; transthyretin gene; vascular endothelial growth factor.

Figure 1. Pedigree of the family with TTR Gly103Arg mutation

I, II, III, IV represent first, second, third and fourth generation, respectively. Normal individuals are shown as clear circles (females) and squares (males), affected individuals are shown as filled symbols. The patients passed away are shown as slash. The arrow indicates the proband. TTR: Transthyretin.

Figure 2. Fundus examination before the operation

A: Fundus photograph of the left eye. Degenerated vitreous body attached to the posterior capsule of the lens, showed “foot-like” vitreous opacity obscured the fundus. B: B-ultrasound showed weak echo mass detected in the vitreous cavity, which may be interspersed with non-echoic cavities, and not connected to the spherical wall. A smooth, uniform, moderately rough echo light band was detected, which is V-shaped and connected the video disc.

Figure 3. Subretinal deposits in the patient

A: During the pars plana vitrectomy (PPV) procedure, hard, yellow-white deposits were observed in the posterior pole and beneath the peripheral retina that were also mobile; B: A retinal stoma was created in the posterior pole to facilitate removal of these subretinal deposits; C: The excised subretinal deposits were obtained from the affected eye.

Figure 4. Pathological analysis of vitreous and subretinal deposits of FVA patient

The Congo-red staining of both retina (A) and subretinal deposit (B) showed deposits with apple-green deposits birefringence under the polarized light microscope. HE staining (C) of subretinal (200×) showed lots of eosinophilic homogeneous substance. Immunohistochemical detection (D) of VEGF protein expression in subretinal deposit tissue (200×) showed positive VEGF expression in vascular endothelial cells. VEGF: Vascular edothelial growth factor.

Figure 5. Mutation of TTR gene detected by whole exome sequencing

The arrow indicates the mutation at the nucleotide position c.G103>C in TTR gene. A: The patient under study; B: Their female cousin are depicted. TTR: Transthyretin.

Figure 6. Fundus photography of patients with FVA after PPV

Eight years post-surgery, fundus photography of the left eye revealed a plethora of neovascularization around the optic disc, peripheral omental white line-like vessels, extensive perivascular opacification except for the macula and large subretinal hemorrhages in the inferior hemisphere. FVA: Familial vitreous amyloidosis; PPV: Pars plana vitrectomy.