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Familial amyloid polyneuropathy (FAP) associated with mutations in the transthyretin (TTR) gene is the commonest form of hereditary amyloidosis. The incidence of vitreous opacities in FAP varies from 5.4% to 35%,1,2 but vitreous opacities as part of systemic amyloidosis are virtually pathognomonic of FAP. Hereditary non-neuropathic systemic amyloidosis is associated with mutations in the genes for lysosyme, apolipoprotein A-I, or fibrinogen A α-chain. There are some 80 known mutations in TTR gene of which the methionine 30 variant is the most common.3 The rare alanine 71 (Ala 71) variant with vitreous opacities has been described in one family from France and another from Spain.4,5 We report a case of FAP Ala 71 without a family history of the disease who presented with a monocular inferior visual field defect and a corresponding vitreous opacity. Amyloid deposition was subsequently diagnosed on vitreous and sural nerve biopsy.
A 46 year old woman presented with an inferior visual defect in her left eye. Ocular and systemic evaluation was normal including brain computed tomography scan. Eighteen months later, the patient developed bilateral floaters and visual loss in the left eye reducing her vision to 20/15 right and 20/30 left. Deposits of white “fluffy” material were noted on the posterior capsule of the left eye (fig 1A) as well as bilateral “branching” vitreous opacities, peripheral retinal haemorrhages and perivascular sheathing (fig 1B). The left eye had a partial posterior vitreous detachment (PVD), a large vitreous floater and old inferior vitreous haemorrhage (VH).
Vitreous opacification progressed and visual acuity was reduced to hand movement 1 year later. A full blood count, coagulation screen, and biochemical profile were normal. Creatinine clearance demonstrated a mild reduction in renal function and plasma cell dyscrasia was ruled out. Pars plana vitrectomy successfully cleared the vitreous debris, restoring vision to 20/20 in the left eye. Eighteen months later the patient developed a right foot drop, progressive lower limb numbness, and numbness in both hands. A sural nerve biopsy established the diagnosis of amyloidosis and immunohistochemistry confirmed that TTR was the major protein constituent of the deposits. Cardiac involvement was demonstrated on echocardiography and renal involvement was confirmed by serum amyloid P (SAP) scintigraphy. Sequencing of her TTR gene confirmed that she was heterozygous for the amyloidogenic Ala 71 variant.
The patient’s right visual acuity deteriorated to 20/120 because of increasing white vitreous opacities and nodular opacities on the anterior vitreous face. Right vitrectomy resulted in a return of visual acuity to 20/20. An undiluted right vitreous biopsy confirmed large amounts of amyloid of the TTR type (fig 2). The patient currently awaits orthoptic liver transplantation (OLT).
Vitreous opacification was initially attributed to old VH secondary to idiopathic retinal vasculitis. Vitreous biopsy subsequently confirmed amyloid in the fellow eye. VH may occur secondary to vascular adventitial amyloid deposition or vitreous separation leading to a retinal tear, although vitreous opacities may be misinterpreted as Kantarjian and de Jong first reported vitreous amyloid in FAP.6 Amyloid of the vitreous body has been described as “glass wool, sheet-like veils or string of pearls white opacities,” which differs from localised ocular amyloid in the orbit, lacrimal gland, conjunctiva, eyelids, sclera, and more specific forms in the cornea. Previous studies have reported abnormal conjunctival vessels, pupillary abnormalities, keratoconjunctivitis sicca, glaucoma, and vitreous opacities.
Almost all of the circulating TTR is produced in the liver and OLT can halt the progression of this disease and lead to clinical improvement.7 SAP scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo,7 but this technique is not sensitive enough to monitor vitreous amyloid. Surprisingly, progressive vitreous amyloid deposition has been reported following OLT, suggesting the TTR that forms vitreous amyloid may be produced locally.8 Previous reports have established that TTR has a widespread distribution in the eye but TTR mRNA has exclusively been located in the retinal pigment epithelium (RPE).9 Given that plasma TTR does not cross Bruch’s membrane, it appears that ocular TTR is synthesised at least in part in the RPE, but the exact factors determining amyloid deposition are not understood.
Bilateral “branching” vitreous deposits of unknown aetiology should always raise the possibility of systemic amyloidosis. A relevant family history should be sought, but even in its absence, mutations of the TTR gene should be looked for.