Institute of Ophthalmology

UCL INSTITUTE OF OPHTHALMOLOGY

Home

About Us

Courses

Research

Eye Disease

Jobs

Seminars

Eye Science

Feedback

Library

Links

Request for Information

Inherited Retinal Degeneration

Background
Inherited retinal degeneration affects about 1:2000 of the UK population. The disorders may be inherited in any one of the recognised patterns, and fall within a spectrum ranging from retinitis pigmentosa(RP) to macular dystrophies. In RP the initial symptom is loss of night vision and subsequently loss of side vision. In late-stage disease vision is restricted to a narrow central cone but detailed vision remains good. There is also an intermediate group that causes progressive loss of side and central vision equally. In macular disease central vision is lost but side vision remains good. Several hundred disorders exist within this family of diseases that vary in their age of onset, speed of progression and final vision. In severe disease there may be loss of all useful vision in early life, whilst others may be unaware of the presence of disease even in late life.

There is currently no effective treatment by which the course of the disorder can be modified. However, research has already contributed considerably to counselling. Four specialist clinics are held each week supported by genetic nurses and counsellors. During the last year over 682 new families have been seen and over 1,200 individuals have attended for review. In addition we have seen over 1,000 first-degree relatives of affected patients. Although the bulk of new cases come from the Thames regions (45% North, 25% South), 30% are from outside this area. A genetic register exists with over 4,000 pedigrees and 30,000 separate entries, which is the largest register of its kind. We believe that we have ascertained 100% of X-linked families, and 70% of dominant families in England and Wales.

Current Research
The research involves documentation of families with retinal dystrophies, and genomic research in which the gene loci and genes are sought. During the last 2 years we have contributed to the identification of 5 new genes as causes of retinal degeneration: NRL, CRX causing retinitis pigmentosa, RetGC1, GCAP1 causing cone/rod dystrophy, and EFEMP1 causing Doyne honeycomb dystrophy and Malattia Leventinese. The phenotype associated with each has been defined using specialised imaging techniques, psychophysics and electrophysiology. For this purpose recording of on- and off-responses of the electroretinogram have been used, confocal scanning laser ophthalmoscopy recording of autofluorescence of the retinal pigment epithelium, and confocal ocular coherence tomography for visualising the photoreceptor inner and outer segments. The study of very early disease is permitted by knowledge of the mutation so that the phenotype can be studied before there is significant cell death. In parallel the metabolic abnormality at a cellular level has been characterised by expressing the mutant gene in cell systems by site directed mutagenesis. This work has given good insight into the pathogenesis of disease. This programme of work contributed to the 5* rating in the last review by Higher Education Funding Council assessments.

The work has had an impact on clinical management. Knowledge of the gene or gene locus allows full identification of the distribution of gene within a family, which is crucial to genetic counselling. The characterisation of the phenotype permits a more accurate prognosis to be made. Through the register a precise diagnosis can be made in a family new to us in a few minutes if it can be recognised as part of a pedigree known to us. In addition the gene or gene locus may be identified. Potentially, this can generate maximum benefit to management of current research.

Three forms of biological treatment are being developed in the Institute of Ophthalmology, namely the use of growth factors to delay cell death, gene transfection and cell transplantation. All have been shown to modify naturally occurring retinal degeneration. If these become applicable the availability of the genetic register, and a large body of well-characterised patients will be crucial to the identification of those suitable for treatment. We have established longitudinal recording of visual function in some patients to establish the speed of visual loss. This information will be important in the design of therapeutic trials.

Funding
The work is undertaken between clinicians and applied scientists at Moorfields Eye Hospital and the Institute of Ophthalmology, UCL. Collectively we have attracted over £2.3 million in competitive grants in the last 2 years for this work. Our work in age-related macular disease currently has £306,000 in grant support

Age-Related Macular Disease
Age-related macular disease (AMD) accounts for over 50% of blind registration in the UK, and treatment is of benefit to less than 5% of those affected. We have three clinics each week devoted largely to the investigation and care of patients with this disorder, and we see about 20 new cases each week. New forms of treatment are being sought. We took part in an International multicentre trail of alpha-interferon treatment that proved negative. We are currently involved in a multicentre trial of ionising radiation, and single centre trial of photocoagulation as prophylaxis for patients at high risk of loosing vision in their second eye. A randomised controlled trial of prophylaxis is also underway.

We have identified evidence that polypoidal choroidopathy, which was thought to be confined black patients, is common in the Caucasian population. A cross-sectional study is currently underway to determine its prevalence in our population with AMD. The importance of this work is underlined by the observation that treatment of this variant appears to be effective.

A study of our patients has shown that there is undoubtedly a genetic component to AMD, and evidence from others implies that it is a complex disorder. Blood is being collected from our patients, and their siblings for molecular genetic studies. They are being segregated according to their phenotype using photography, fluorescein angiography and autofluorescence imaging. Spouses of patients free of AMD provide a comparison group.

In parallel, histological studies are being undertaken to document the variation of age-changes at the macula. The findings are compatible with the concept that several genes are involved in conferring risk of visual loss.

Lectures given by Prof Bird

1999	William Havener Memorial Lecture, U. of Ohio.
1999	Rustom Ranji Lecture, LV Prasad Eye Institute, Hyderabad.
2000	Curtin Visiting Professor, Bascom Palmer Institute, University of Miami.
2000	Mahlon Barlow Memorial Lecture, Wilmer Eye Institute, Johns Hopkins University.

Selected Publications

Okubo A, Rosa RH, Bunce KV, Alexander RA, Fan JT, Bird AC, Luthert PJ. The relationships between age changes in retinal pigment epithelium and Bruch's membrane. Invest Ophthalmol Vis Sci 1999;40:443-9.

Hingorani M, Nischall KK, Vivian A, Baker AJ, Bird AC, Aclimandos WA.. Ocular abnormalities in Alagille syndrome. Ophthalmology 1999;106:330-7.

Lois N, Halfyard AS, Bunce C, Bird AC, Fitzke FW. Reproducibility of fundus autofluorescent measurements obtained using a confocal scanning laser ophthalmoscope. Br J Ophthalmol 1999; 83:267-9.

Owens SL, Guymer RH, Gross-Jendroska M, Bird AC. Fluorescein angiographic changes following prophylactic macular photocoagulation for high risk age-related maculopathy. Am J Ophthalmol 1999;127:681-7.

Chong NHV, Alexander RA, Barnett KC, Bird AC, Luthert PJ. An immunohistochemical study of an autosomal dominant rod / cone dysplasia. Exp Eye Res 1999;68:51-7.

Chong NHV, Alexander RA, Waters L, Barnett KC, Bird AC, Luthert PJ. Repeated injections of a CNTF analogue lead to long-term photoreceptor survival in hereditary retinal degeneration. Invest Ophthalmol Vis Sci 1999;40:1298-305.

Webster AR, Maher ER, Bird AC, Gregor ZG, Scott JD, Moore AT. A clinical and molecular genetic analysis of solitary ocular angioma. Ophthalmology 1999;106:623-9.

Von Ruckmann A, Fitzke FW, Bird AC. Distribution of pigment epithelium autofluorescence in retinal disease state recorded in vivo and its change over time. Graefe's Arch Clin Exp Ophthalmol 1999;237:1-9.

Downes SM, Fitzke FW, Holder GE, Payne AM, Bessant DAR, Bhattacharya SS, Bird AC. Clinical Features of Codon 172 RDS Macular Dystrophy. Arch Ophthalmol 1999,117:1373-83

Hardcastle AJ, Thiselton DL, Van Maldergem L, Saha BK, Jay M, Plant C, Taylor R, Bird AC, Bhattacharya S. Mutations in the RP2 gene cause disease in 10% of families with familial x-linked retinitis pigmentosa assessed in this study. Am J Hum Genet 1999;64:1210-5.

Bessant DAR, Payne AM, Mitton KP, Wang Q-L, Swain PK, Plant C, Bird AC, Zack DZ, Swaroop A, Bhattacharya SS. A Mutation in the bZIP transcription factor NRL is associated with autosomal dominant retinitis pigmentosa in a family linked to a novel locus on 14p. Nat Genet 1999;21:355-6.

Kermani S, Gregory-Evans K, Tarttelin EE, Bellingham J, Plant C, Bird AC, Fox M, Bhattacharya SS, Gregory-Evans CY. Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy. Hum Genet 1999;104:77-82.

Pauleikhoff D, Spital G, Radermacher M, Brumm GA, Lommatzsch A, Bird AC. A fluorescein and ICG angiographic study of the choriocapillaris in Age-related Macular Disease. Arch Ophthalmol 1999;117:1353-7.

Stone EM, Lotery AJ, Munier FL, Heon E, Piguet B, Guymer RH, Vandenburgh K, Cousin P, Nishimura D, Swiderski RE, Silvestri G, Mackey DA, Hageman GS, Bird AC, Sheffield VC, Schorderet DF. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet 1999;22:199-202.

Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC. Intrafamilial variation of phenotype in Stargardt macular dystrophy - Fundus flavimaculatus. Invest Ophthalmol Vis Sci 1999;40:2668-75.

Payne AM, Downes SM, Bessant DA, Plant C, Moore AT, Bird AC, Bhattacharya SS. Genetic analysis of the guanylate cyclase activator 1B(GUCA1B) gene in patients with autosomal dominant retinal dystrophies. J Med Genet 1999;36:691-3.

Flaxel CJ, Jay M, Thisleton DL, Nayadu M, Hardcastle AJ, Wright A, Bird AC. The difference between RP2 and RP3 in X-linked retinitis pigmentosa. Br J Ophthalmol 1999;83:1144-8.

Treatment of age-related macular degeneration with photodynamic therapy group. Verteporfin therapy on subfoveal neovascularization in age-related macular degeneration. One year results of two randomized clinical trials - TAP report#1. Arch Ophthalmol 1999;117:1329-44.

Zito I, Thisleton DL, Gorin MB, Stout JT, Plant C, Bird AC, Bhattacharya SS, Hardcastle AJ. Identification of six novel RPGR (retinitis pigmentosa GTPase regulator) mutations in a subset of X-linked retinitis pigmentosa families segregating with RP3 locus. Hum Genet. 1999;105:57-62.

Bowne SJ, Daiger SP, Hims MM, Sohocki MM, Malone KA, McKie AB, Heckenlively JR, Birch DG, Inglehearn CF, Bhattacharya SS, Bird A, Sullivan LS. Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa. Hum Mol Genet 1999;8:2121-8.

Sarraf D, Gin T, Yu F, Brannon A, Owens SL, Bird AC. Long-term drusen study. Retina 1999;19:513-9

Webster AR, Maher ER, Bird AC, Moore AT. Risk of multi-system disease in isolated ocular angioma. J Med Genet 2000;37:62-3.

Chong NHV, Alexander RA, Gin T, Bird AC, Luthert PJ. TIMP-3, collagen and elastin immunohistochemistry and histopathology in the ciliary body and Bruch membrane of Sorsby fundus dystrophy. Invest Ophthalmol Vis Sci 2000; 41: 898-902.

Ahuja RM, Stanga PE, Vingerling JR, Bird AC. Laser photocoagulation treatment of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol - in press.

Bessant D, Payne A, Bird A et al. Refinement of the autosomal recessive retinitis pigmentosa locus on chromosome 1q31-q32.1 (RP12) and mutation analysis of RGS16 (RGS-r) J Med Genet - in press.

Gregory-Evans K, Kelsell RE, Gregory-Evans CY, Downes SM, Fitzke FW, Holder GE, Simunovic M, Mollon JD, Taylor R, Hunt DM, Bird AC, Moore AT. RETGC-1 mutation autosomal dominant cone-rod retinal dystrophy (CORD6). Ophthalmol 2000;107:55-61

Lois N, Halfyard AS, Bird AC, Fitzke FW. Quantitative evaluation of fundus autofluorescence imaged "in vivo" in eyes with retinal disease. Br J Ophthalmol 84: 741-745.

Ahuja RM, Stanga PE, Vingerling JR, Reck AC, Bird AC. Polypoidal choroidal vasculopathy in exudative and haemorrhagic pigment epithelial detachments. Br J Ophthalmol 2000;84:479-484.

Sarraf D, Sehmi KS, Kitchen ND, Payne AM, Bird AC. Familial intraocular hemangioma. Arch Ophthalmol 118: 969-973.

Downes SM, Payne AM, Kelsell RE, Fitzke FW, Holder GE, Hunt DM, Moore AT, Bird AC. Autosomal dominant cone-rod dystrophy with mutations in the retinal guanylate cyclase GUCY2D gene encoding RetGC-1. Arch Ophthalmol - in press

Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC. Stargardt macular dystrophy - fundus flavimaculatus: phenotypic subtypes. Arch Ophthalmol - in press

Papaioannou M, Ocaka L, Bessant D, Lois N, Bird A, Payne A, Bhattacharya S. An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci 2000;41:16-9.

Zito I, Gorin M, Plant C, Bird AC, Bhattacharya SS, Hardcastle AJ. Novel mutations of the RPGR gene in RP3 families. Hum Mut 2000;15:386.

Downes SM, Holder GE, Fitzke FW, Payne AM,Bhattacharya SS, Bird AC. Phenotype of autosomal dominant cone dystrophy caused by a mutation in the GUCA 1A gene. Arch Ophthalmol - in press.

This page last modified 4 April, 2006 by David Daniel

Institute of Ophthalmology- 11-43 Bath St - London - EC1V 9EL -