Sir,

We present a case of familial ocular amyloidosis currently without systemic involvement. Ocular features included vitreous opacities and secondary glaucoma. The patient had a transthyretin mutation (TTR-glycine 54) previously reported in his family only.

Case report

A 38-year-old man presented to Eye Casualty with a 7-week history of floaters in both eyes. The patient’s father and paternal uncle both died from systemic complications of amyloidosis. His paternal grandmother was blind 20 years prior to her death. The family history is plotted in Figure 1.

Figure 1
figure 1

Gene sketch of the family.

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The visual acuities were 6/5 and 6/9 in the right and left eye respectively. The anterior segment was normal with open angles on gonioscopy. The intra-ocular pressures were raised (40 mmHg in the right and 42 mmHg in the left eye). Dilated fundoscopy revealed thin, wispy vitreous opacities more prominent in the left eye, and bilateral posterior vitreous detachments, Figure 2. The optic discs were cupped, C/D ratio of 0.6 in the right eye and 0.7 in the left eye. Threshold visual fields showed early glaucomatous changes. The intraocular pressure was controlled with a topical beta-blocker and latanoprost.

Figure 2
figure 2

Thin wispy cotton wool-like opacities in the vitreous, left eye.

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A mutation was found in the Transthyretin gene (TTR-glycine 54), which is capable of producing amyloidosis.

Ten months after presentation the visual acuity had dropped to 6/24 in the right eye and counting fingers at 0.5 m in the left eye. The fundal view also deteriorated due to increased density of vitreous opacities. The intraocular pressures remained under control with topical medication. The patient was offered a vitrectomy but has so far declined further treatment.

Comment

Amyloidosis is a disorder characterised by deposition of amyloid protein in one or more tissues of the body. Ocular involvement is often familial, and may occur with or without systemic abnormalities.

Currently, the disease is sub-classified according to clinical features, ancestry or geographic origin, into four types of Familial Amyloidotic Polyneuropathy (FAP). Type I FAP is associated with polyneuropathy starting in the lower limbs and severe autonomic dysfunction. Type II FAP is associated with polyneuropathy in the lower limbs and mild autonomic dysfunction (Swiss–German families). Type III FAP polyneuropathy is associated with renal failure and cranial neuropathy. Type IV FAP is associated with lattice corneal dystrophy II (Finnish, Irish, American and Japanese families).1 Types I and II are associated with transthyretin variants; type III is related to apolipoprotein A1 and type IV is related to variants of gelsolin.

Eye involvement occurs most commonly with Type I FAP. The main ocular manifestations are: abnormal conjunctival vessels, keratoconjunctivitis sicca due to lacrimal gland infiltration or autonomic neuropathy and pupillary abnormalities including anisocoria and sluggish reactions to light or accommodation. Less common features include vitreous opacities and secondary glaucoma.1

Transthyretin is a tetrameric plasma protein (prealbumin), synthesised in the liver, it polymerises into a β-pleated structure of amyloid fibril. TTR is also synthesised by the retinal pigment epithelium2 and in the choroid plexus of brain. Different mutations in the TTR gene lead to the various hereditary forms of amyloidosis. More than 40 mutations of the TTR gene have been identified but they are not all pathogenic. The most frequent mutation is TTR-met303 (methionine replacing valine at position 30 in transthyretin). Our patient, and other affected members of his family, have a rare mutation,4 TTR-glycine 54.

Isolated vitreous amyloidosis is rare,5 it is usually associated with CNS manifestations.6 The appearance of the vitreous has been likened to cotton wool or lace-like veils. The density of these opacities determines the visual acuity and symptoms. Vitreous opacities in contact with the posterior lens surface may form footplates or ‘pseudopodia lentis’. Vitreous amyloid is immunologically related to TTR in patients of different FAP kindreds.7 Results of vitrectomy have in general been satisfactory, but recurrences occur (Doft et al).8

In FAP type I, phenotypic differences in age of onset, location and severity of lesions occur despite biochemical similarities in different kindreds. Vitreous involvement occurs earlier and is more severe in Portuguese families compared to Swedish or Japanese families with the same TTR-met30 mutation. As one might predict, vitreous involvement is more severe in homozygotes than heterozygotes with TTR mutations (Sandgren et al).9

Glaucoma in FAP may be due to amyloid infiltrating the trabecular meshwork thus reducing the outflow, or due to raised episcleral venous pressure (Nelson, 1998).10 Amyloid has been found on histopathological examination of the conjunctiva and trabecular meshwork. Filtration surgery is often necessary because the glaucoma tends to be resistant to topical therapy.8

We have presented a case of type I Familial Amyloidotic Polyneuropathy. The underlying transthyretin mutation (TTR-glycine 54) has not been reported in any other family. The case illustrates the importance of taking a careful family history.