Vitreous amyloidosis in alanine 71 transthyretin mutation
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《英国眼科学杂志》
1 Moorfields Eye Hospital, Vitreoretinal Service, London, UK
2 Mayday University Hospital, Ophthalmology Department, London, UK
3 Institute of Ophthalmology, Pathology Department, London, UK
4 Mayday University Hospital, Neurology Department, London, UK
5 National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, London, UK
Correspondence to:
Dr H Zambarakji
Angiogenesis, Massachusetts Eye and Ear Infirmary, 325 Cambridge Street, Boston, MA 02114, USA; hzambaraji@aol.com or HZ@meei.harvard.edu
Accepted for publication 20 October 2004
Keywords: amyloidosis; transthyretin; mutation; alanine
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 -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.
Case report
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).
Figure 1 Dense nodular white deposits on the posterior capsule of the left eye were presumed to be of amyloid origin (A), and fundus periphery demonstrates intraretinal haemorrhages and perivascular white deposits (B).
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).
Figure 2 Apple-green birefringence with Congo red stain viewed with polarised microscopy of a vitreous biopsy confirming the presence of amyloid deposits.
Comment
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.
References
Ando E, Ando Y, Okamura R, et al. Ocular manifestations of familial amyloidotic polyneuropathy type I: long term follow up. Br J Ophthalmol 1997;81:295–8.
Koga T, Ando E, Hirata A, et al. Vitreous opacities and outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy. Am J Ophthalmol 2003;135:188–93.
Connors LH, Richardson AM, Theberge R, et al. Tabulation of transthyretin (TTR) variants as of 1/1/2000. Amyloid 2000;7:54–69.
Benson MD, Turpin JC, Lucotte G, et al. A transthyretin variant (alanine 71) associated with familial amyloidotic polyneuropathy in a French family. J Med Genet 1993;30:120–2.
Almeida MR, Lopez-Andreu F, Munar-Ques M, et al. Transthyretin ALA 71: a new transthyretin variant in a Spanish family with familial amyloidotic polyneuropathy. Hum Mutat 1993;2:420–1.
Kantarjian AD, de Jong RN. Familial primary amyloidosis with nervous system involvement. Neurology 1953;3:399–409.
Rydh A, Suhr O, Hietala SO, et al. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation. Eur J Nucl Med 1998;25:709–13.
Munar-Ques M, Salva-Ladaria L, Mulet-Perera P, et al. Vitreous amyloidosis after liver transplantation in patients with familial amyloid polyneuropathy: ocular synthesis of mutant transthyretin. Amyloid 2000;7:266–9.
Cavallaro T, Martone RL, Dwork AJ, et al. The retinal pigment epithelium is the unique site of transthyretin synthesis in the rat eye. Invest Ophthalmol Vis Sci 1990;31:497–501.(H J Zambarakji1, D G Char)
2 Mayday University Hospital, Ophthalmology Department, London, UK
3 Institute of Ophthalmology, Pathology Department, London, UK
4 Mayday University Hospital, Neurology Department, London, UK
5 National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, London, UK
Correspondence to:
Dr H Zambarakji
Angiogenesis, Massachusetts Eye and Ear Infirmary, 325 Cambridge Street, Boston, MA 02114, USA; hzambaraji@aol.com or HZ@meei.harvard.edu
Accepted for publication 20 October 2004
Keywords: amyloidosis; transthyretin; mutation; alanine
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 -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.
Case report
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).
Figure 1 Dense nodular white deposits on the posterior capsule of the left eye were presumed to be of amyloid origin (A), and fundus periphery demonstrates intraretinal haemorrhages and perivascular white deposits (B).
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).
Figure 2 Apple-green birefringence with Congo red stain viewed with polarised microscopy of a vitreous biopsy confirming the presence of amyloid deposits.
Comment
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.
References
Ando E, Ando Y, Okamura R, et al. Ocular manifestations of familial amyloidotic polyneuropathy type I: long term follow up. Br J Ophthalmol 1997;81:295–8.
Koga T, Ando E, Hirata A, et al. Vitreous opacities and outcome of vitreous surgery in patients with familial amyloidotic polyneuropathy. Am J Ophthalmol 2003;135:188–93.
Connors LH, Richardson AM, Theberge R, et al. Tabulation of transthyretin (TTR) variants as of 1/1/2000. Amyloid 2000;7:54–69.
Benson MD, Turpin JC, Lucotte G, et al. A transthyretin variant (alanine 71) associated with familial amyloidotic polyneuropathy in a French family. J Med Genet 1993;30:120–2.
Almeida MR, Lopez-Andreu F, Munar-Ques M, et al. Transthyretin ALA 71: a new transthyretin variant in a Spanish family with familial amyloidotic polyneuropathy. Hum Mutat 1993;2:420–1.
Kantarjian AD, de Jong RN. Familial primary amyloidosis with nervous system involvement. Neurology 1953;3:399–409.
Rydh A, Suhr O, Hietala SO, et al. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation. Eur J Nucl Med 1998;25:709–13.
Munar-Ques M, Salva-Ladaria L, Mulet-Perera P, et al. Vitreous amyloidosis after liver transplantation in patients with familial amyloid polyneuropathy: ocular synthesis of mutant transthyretin. Amyloid 2000;7:266–9.
Cavallaro T, Martone RL, Dwork AJ, et al. The retinal pigment epithelium is the unique site of transthyretin synthesis in the rat eye. Invest Ophthalmol Vis Sci 1990;31:497–501.(H J Zambarakji1, D G Char)