Generalized Inherited Retinal Dystrophies

12.1  Introduction

Inherited retinal dystrophies are a major cause of visual deficit worldwide. This chapter focuses on generalized forms that diffusely affect the outer retinal function, primarily the photoreceptors and the adjacent structures. Diagnostic entities in this broad category range from the relatively common retinitis pigmentosa, occurring in up to 1 in 2,500 persons, to the far more obscure forms of stationary night blindness. The more severe variants of these heterogeneous disorders will commonly present in the pediatric age range. Ophthalmologists facing this group of young patients have the challenging task of clinically sifting through these diagnostic entities with a relatively limited history and exam. The judicious combination of ophthalmic examination, physiologic testing, and family history can be extremely helpful in approximating the diagnosis and disease prognosis. One should be mindful of the limitations of determining visual prognosis from clinical findings alone, given the substantial variability of phenotype even within the same family.

Widespread incorporation of molecular diagnostic technology into this field will likely added another crucial layer of precision to the diagnostic workup in the near future. Advances toward understanding the molecular basis of retinal disease will bring about new

S.C. Khani (*)

Retina Care Institute and Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114, USA

e-mail: skhani@buffalo.edu, shahrokh.khani@schepens. harvard.edu

A. Fasiuddin

University at Buffalo, Ross Eye Institute, 1176 Main Street, Buffalo, NY 14209, USA

treatments for these disorders, including retinitis pigmentosa. Metabolic, dietary, or genetic interventions for these historically untreatable conditions will likely become a reality in the upcoming years.

Major strides have already been made in the past two decades toward molecular genetic characterization of many of the retinal degenerative disorders. The development of polymerase chain reaction technology has been a key advance that has enabled investigators in the late 1980’s to examine individual patients for mutations in genes expressed in known retina-specific genes [1]. Ready access to this technology, together with access to large families with known genealogy, has led to the development of linkage maps and the identification of novel genes carrying disease-causing mutations [2, 3]. Finally, the more recent availability of the linkage map, the sequence of the human genome (www.ncbi.nlm.nih.gov/projects/genome/guide/ human), and single nucleotide polymorphism maps [4] have placed the identification of previously unknown genes within reach. What we have discovered so far is the remarkable heterogeneity of these diseases at the molecular level, with RP being caused by at least 100 separate mutations in multiple genes [5]. This knowledge and availability of testing with animal models for disease, either, naturally occurring or generated by targeted gene disruption, have enabled the development of innovative therapies. The notion that therapies for these disorders are not available is rapidly being outdated with advances in the fields of genetics, preventive therapies, artificial vision, and other nanotechnological developments [6, 7].

This chapter is intended to provide an overview of practical useful information with greatest relevance to the practice of modern pediatric retina and ophthalmology; hence, the later onset retinal degenerative disorders are beyond the scope of this chapter.

12.2  Historical Context

The origins of inherited retinopathies in human populations are possibly very early in evolution, since many of the same inherited retinopathies have their counterparts in animals such as mice and even the fruit fly drosophila. For example, the same retinal degeneration slow (RDS) gene that causes retinal degeneration in the mouse [8] has also been found to underlie the human diseases of retinitis pigmentosa, pattern dystrophy, choroidal atrophy, and retinitis punctata albescens [9, 10].

Retinitis pigmentosa is thought to have been first recognized and coined by Donders [11] in the mid-­ nineteenth century, within a few years of the development of the Helmholtz ophthalmoscope. It has since become known as the most common form of the pigmented inherited retinopathies, with a relentless course and no effective therapy. In 1869, Leber [12] recognized and named a congenital retinopathy with severe visual impairment in children before 1 year of age. He described a “retinitis pigmentosa with congenital amaurosis,” including nystagmus, poor pupillary reflexes, and autosomal recessive inheritance, which is today known as the classic form of Leber congenital amaurosis (LCA). Usher syndrome was described at approximately the same time by German ophthalmologist Von Graefe in 1858 and later by British ophthalmologist Charles Usher in 1914. This is the most common syndromic form of retinitis pigmentosa, consisting of retinal degeneration and associated deafness.

The development of electrodiagnostic studies in the mid 1900s led to more precise diagnostic and prognostic classification of the pigmentary retinopathies. Dr. Karpe [13] was the first to utilize electroretinography to measure the darkand light-adapted electrical activity of the retina using a corneal surface electrode. In 1962, electrooculogram became available for the first time to measure the resting potential of the pigment epithelium [14]. These electroretinographic measurements were further improved and standardized by Gouras using the Ganzfeld stimulation method [15]. Additional modifications such as standardization of various centers [16] and computer averaging have improved the consistency of the diagnosis and ERG measurements among various clinicians. Technology for retinal function assessment has thus become a cornerstone in disease classification in the current clinical practice.

12.3  Patient Evaluation

and Diagnostic Criteria

Evaluation of pediatric patients for retinal degenerative disorders can pose a significant challenge even for the specialist, given the variable cooperation and communication skills of children at various stages of development. Accuracy of exam findings can range from a rough estimate based on glimpses of the fundus in a very young and uncooperative patient to a more precise diagnosis in an older child who can tolerate electroretinography and fluorescein angiography. Parents must also be informed that a primary purpose of diagnostic workup includes determination of visual prognosis. The relative risks and benefits of diagnostic testing, with potential complications of sedation and the stress of repeated exams, should be considered in deciding whether to proceed with aggressive workup. Regardless of the level of information collected in the initial visit, the diagnosis can generally be sharpened over the course of several visits and a period of years.

Historical determination of the quality and duration of the visual compromise in the pediatric patient is an important part of any evaluation. Children with congenital disorders of the photoreceptors and retina are noted to manifest difficulties with nyctalopia as early as infancy. Parents may report visual inattention or difficulty with evening feedings in the dark. In the later, more communicative stages, children may complain of not seeing stars in the sky. Difficulty in finding and retrieving dropped objects in dim light is noted in patients who suffer from visual field loss in addition to night blindness. In their school years, children may have increasing difficulty with visual tasks and athletic activities, especially due to peripheral field loss. Historic evaluation can therefore be helpful in distinguishing congenital stationary disease from the progressive degenerative disorders in which dysfunction is combined with concomitant loss of visual field. Generally, in the stationary congenital forms of night blindness, visual field will be unaffected, whereas patients with progressive degenerative conditions suffer from some visual compromise and eventual loss of peripheral vision. In addition to symptoms of poor night vision and visual field loss, the patients can complain of mild reduction in central and color vision as well as photopsias.

Family history can further help narrow the diagnosis and determine the general mode of inheritance. Involvement of a sibling with the disease in the absence