1.1 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 its presence even in late life.

1.2 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.

1.3 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.

1.4 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.

1.5.1 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. The Institute and Moorfields work in collaboration and this research has attracted over £2.3 million in competitive grants in the last 2 years.