The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS

Disclosures

Compr Ophthalmol Update. 2005;6(1):39-62. 

In This Article

Abstract and Introduction

In recent years, advances in molecular genetics have impacted the understanding and the classification of hereditary retinal and optic nerve disease perhaps more than any other group of eye diseases. This new molecular knowledge now offers the opportunity to learn more about the pathophysiology of these diseases, to begin to devise rational treatment strategies, and to characterize molecularly affected patients in a systematic fashion, laying the ground for forthcoming multicenter studies and trials of molecularly verified cases of rare diseases. This update will review the recent advances in progressive retinal degenerations, congenital stationary retinal disease, optic neuropathies, and syndromes that include a retinopathy or an optic neuropathy in their phenotypic spectrum.

In a recent update, my colleagues and I reviewed the basic concepts of medical and molecular genetics and the recent advances in the genetics of glaucoma, cataracts, and corneal dystrophies.[1] In this update, I will focus on the recent advances in the genetics of hereditary retinal diseases and optic neuropathies. The first sections will review progressive degenerative retinal diseases, which are classified on the basis of clinical and functional criteria in diseases with greater rod disease components (rod-cone dystrophies) and those with greater (cone-rod dystrophies) or exclusive (cone dystrophies) cone disease components. Subsequently, vitreoretinal dystrophies (i.e., progressive retinal diseases that have a clear-cut clinical and pathogenetic vitreal component) will be discussed, followed by the large group of nonprogressive retinal diseases and the hereditary optic neuropathies. Lastly, the ocular syndromes that include retinal degenerative features or optic neuropathies will be illustrated. While these conditions share retinal or optic nerve features often indistinguishable from nonsyndromic ocular diseases, they are clinically broader and genetically distinct entities, laden with fundamental systemic implications of which the comprehensive ophthalmologist must be aware and are therefore presented separately.

With rare exceptions, some of which will be discussed when applicable, it must be noted that all diseases illustrated in this update are intended as monogenic, disorders such that mutation(s) in a single gene are necessary and sufficient to cause the disease. This is, of course, very different from other much more prevalent disorders, such as age-related macular degeneration, in which multiple genetic factors concur, along with environmental factors, dietary factors, and lifestyle habits, to the pathogenesis of the disease, its age of onset, and its severity. However, it is important to remain aware that also monogenic disorders, like the ones that will be reviewed here, remain susceptible to another common and conceptually straightforward phenomenon that geneticists define as epistasis (i.e., a form of gene-gene interaction such that gene(s) not directly involved in causing the disease in question have an effect (stasis) upon (epi) the phenotypic expression of the disease trait directly caused by another gene). Epistatic effects are likely to explain, for example, why within a given family, in which a disease is caused by the same exact mutation(s) in one gene, there can be individuals affected with different degrees of disease severity and/or with substantial differences in the ages of onset. These far more complex levels of genetic interaction upon disease expression are just beginning to be understood both in monogenic and nonmonogenic disorders, and will therefore not be addressed further in this setting. Additional details on genetic terminology and concepts have been reviewed elsewhere.[1]

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