Posterior Segment Retina
Insight and Advancement in Hereditary Retinal Degenerations Eric J Sigler1
and John J Huang2
1. Chief Resident, Department of Ophthalmology and Visual Science, Yale University School of Medicine; 2. Associate Professor, Department of Ophthalmology and Visual Sciences, Director of Ocular Immunology and Uveitis and Director of Clinical Trials and Translational Research, Yale University
Abstract
Hereditary retinal degenerations comprise a diverse group of inherited genetic defects in one or more retinal or retinal pigment epithelial cellular proteins. Traditionally, anatomic classification based on clinical and histopathological phenotype has been used to organise these disorders. In the modern era of advanced molecular biological techniques and genetic screening the current classification system may soon become obsolete, due to the fact that significant overlap between different retinal degenerations has been observed, resulting from variation in gene expression, common genetic pathways and variable inheritance patterns. In this article, we review the various clinical disease entities, emphasise a genetic classification system and give special attention to recent advances in molecular biology and gene therapy.
Keywords Retinitis pigmentosa, Leber congenital amaurosis, pattern dystrophy, Stargardt’s disease, Best vitelliform dystrophy, X-linked retinoschisis
Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: This research is supported by grants from Research to Prevent Blindness Challenge Grant, Allergan Horizon Grant and Connecticut Lions Eye Research Foundation. Received: 19 October 2010 Accepted: 20 February 2011 Citation: European Ophthalmic Review, 2011;5(1):74–7 Correspondence: John J Huang, Assistant Professor, Department of Ophthalmology and Visual Sciences, Director of Uveitis Service, Faculty of Vitreo-Retina Service and Director of Clinical Trials and Translational Research, Yale University, 40 Temple Street, Suite 3D, New Haven, CT 06510, US. E:
john.huang@
yale.edu
Retinitis pigmentosa (RP) is a group of disorders whose main clinical features include diffuse photoreceptor dysfunction, diminished electroretinogram (ERG) and progressive visual field loss. The disorders affect approximately one in 5,000 people worldwide.1
Clinical features
often include peripheral retinal pigment epithelial atrophy, ‘bone spicule’ pigment clumping, waxy optic disk pallor and arteriolar attenuation. Patients often experience nyctalopia as an early symptom followed by progressive visual field loss and eventual central vision loss. Pigmented vitreous cells, posterior subcapsular cataract and cystoid macular oedema have also been associated with RP.
Interestingly, RP has been associated with all forms of mendelian inheritance patterns. It appears that autosomal dominant is the most common identifiable inheritance pattern, present in approximately 15–25% of cases. Autosomal recessive inheritance is also common, as is the absence of any family history. X-linked and mitochondrial variants have also been described. There are over 100 genes that have been identified and implicated in the disease.1,2
These defects are
organised by chromosome in the RetNet subdivision of the Online Mendelian Inheritance in Man database (OMIM™). Many mutations, including the first gene discovered to cause RP, are defects in rhodopsin (RHO), the pan-rod photopigment. Many novel genetic defects in products involved in the visual pigment transduction pathway continue to be described. Among these are RHO, RDS/peripherin, pre-messenger RNA (mRNA) processing factor 31 (PRPF31), RP31, Prominin 1 (PROM1), RP GTPase regulator (RPGR) and RP25. In addition, there is a wide range of disease severity and phenotypic expressivity linked to specific mutations. This is especially evident in analysis of the
74
RDS/peripherin gene2
located on chromosome 6p, whose product
localises to a protein present in the peripheral outer rod segment. Various mutations may occur with a wide range of phenotypes, ranging from pattern dystrophies to Stargardt’s disease, to RP, even within the same family.
There has been no proven effective treatment for RP. Observations that patients taking vitamin A may have a slower decline in ERG and photoreceptor function led to a randomised controlled trial investigating vitamin A and E supplementation.3,4
The results demonstrated a role
for vitamin A supplementation in retarding ERG amplitude loss but no obvious significant effect on vision and visual field loss. A subsequent analysis of patients deemed to have more accurate visual field measurement demonstrated slower rates of visual field loss in those using vitamin A.5,6
Larger trials with longer follow-up are needed to completely assess the efficacy of this treatment. However, many retinal specialists recommend 15,000IU of vitamin A palmitate in patients with RP, excluding women who may be pregnant or are planning to become pregnant.
The future of RP treatment will rest upon pharmacogenetic and molecular biological techniques for replacing defective genes, restoring the function of defective proteins and preventing abnormal photoreceptor function; with the use of implantable electrical devices in advanced cases. Gene therapy has undergone many recent advances, particularly involving delivery of functional genes through viral vectors, especially the adeno-associated viral vector (AAVV),7,8
which has been shown to efficiently transmit DNA to both © TOUCH BRIEFINGS 2011
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