Chapter 235

## Abstract

Abstract

1. Retinitis pigmentosa is the name given to a set of heritable degenerations of the retina. Patients with retinitis pigmentosa typically experience night blindness and loss of the midperipheral visual field early in the disease. As the disease progresses, the visual field is reduced to a shrinking island of central vision (called tunnel vision) and scattered patches of far peripheral vision. In many cases, all useful vision is lost during middle age. In advanced cases and sometimes even in early cases, the fundus oculi exhibits the following features: thin retinal vessels, a pale optic nerve head, and clumps of intraretinal pigment. Related diseases that feature progressive degeneration of the retina include cone-rod degeneration, cone degeneration, and macular degeneration. In cone-rod degeneration, there is early loss of visual acuity due to a progressive panretinal degeneration that in early stages affects cone photoreceptors more severely than rod photoreceptors. In cone degeneration, cones but not rods degenerate. In macular degeneration (see Chap. 243), cones and rods degenerate in the macula but not elsewhere in the retina. Most forms of retinitis pigmentosa and related retinal degenerations affect only the eye, although in a minority of cases the retinal degeneration is one feature of a syndrome that includes other systemic abnormalities, such as retinitis pigmentosa and deafness in Usher syndrome. In young patients with the symptom of night blindness, it is important to differentiate retinitis pigmentosa from stationary night blindness. Both diagnostic categories feature defective vision in dim light as an early symptom, but in stationary night blindness, cone photoreceptors and daytime vision do not deteriorate substantially during the patient's lifetime.

2. Measuring the retina's electrical response to flashes of light is the best way to distinguish the early stages of progressive retinal degeneration such as retinitis pigmentosa from nonprogressive retinal diseases such as stationary night blindness. This noninvasive measurement, called the electroretinogram (ERG), can be used to diagnose young patients with retinitis pigmentosa and many other forms of retinal degeneration even before visual symptoms or funduscopic abnormalities are apparent.

3. The visual loss in retinitis pigmentosa and related retinal degenerations corresponds to the degeneration of photoreceptor cells of the retina. Molecular genetic and biochemical studies have revealed that the defects causing these cells to die can be placed into three categories depending on the mutant gene in each case: (a) a primary biochemical defect inherent in the photoreceptor cells (the rods, the cones, or both cell types), (b) a primary biochemical defect in neighboring retinal cells such as the retinal pigment epithelium, or (c) a peculiar sensitivity of the photoreceptors or the retinal pigment epithelium to a generalized metabolic defect. In stationary night blindness, rod photoreceptors malfunction because of defects inherent in them or perhaps in the cells they synapse with; however, the rod or cone photoreceptors do not degenerate at a rate symptomatically faster than that which accompanies normal aging.

4. Families with retinitis pigmentosa, cone-rod degeneration, cone degeneration, or stationary night blindness can demonstrate any of the known monogenic inheritance patterns: autosomal dominant, autosomal recessive, or X-linked. A syndromic form of retinitis pigmentosa, Kearns-Sayre syndrome, is transmitted with a maternal, or mitochondrial, inheritance pattern. In addition, in some families, retinitis pigmentosa is transmitted in a digenic fashion, where affected individuals are double heterozygotes for defects in both of two unlinked genes. There is nonallelic or locus heterogeneity within the categories of dominant (at least 10 loci implicated), recessive (over 22 loci), or X-linked retinitis pigmentosa (at least 3 loci). Stationary night blindness can be allelic to forms of retinitis pigmentosa.

5. Most retinitis pigmentosa genes remain unidentified. Of those which are known, some encode members of the rod phototransduction cascade (e.g., rhodopsin, the α or β subunits of rod cGMP-phosphodiesterase, and the α subunit of the rod cGMP-gated cation channel, and arrestin). Other identified genes encode proteins important to the structure of photoreceptor outer segments (RDS and ROM1) or encode proteins with unknown function (RPE65, TULP1, ABCR, RPGR, and RP2). Some genes causing syndromic forms of retinal degeneration also have been identified. Examples are the genes encoding myosin VIIa causing Usher syndrome type I, a presumed extracellular matrix protein causing Usher syndrome type II, α-tocopherol transfer protein causing retinitis pigmentosa and Friedrich-like ataxia, and phytanoyl-CoA α-hydroxylase causing Refsum disease. The identified retinitis pigmentosa genes account for an estimated 35 to 50 percent of all cases of the disease. Forms of cone-rod degeneration are caused by mutations in the gene encoding guanylate cyclase, the transcription factor crx, or the ABCR protein of unknown function. Cone degeneration can be caused by mutations in the gene encoding guanylate cyclase activator 1A. Rod monochromacy, a form of colorblindness due to absent or nonfunctional cone photoreceptors, can be caused by mutations in the cone cGMP-gated cation channel. Mutations in the following genes encoding proteins in the phototransduction cascade are responsible for some forms of autosomal dominant or recessive stationary night blindness: rhodopsin, the α subunit of rod transducin, the β subunit of rod cGMP-phosphodiesterase, rhodopsin kinase, and rod arrestin. A form of X-linked stationary night blindness is due to mutations in an L-type calcium channel.

6. Patients with abetalipoproteinemia (MIM 200100; see Chap. 115), Refsum disease (MIM 266510; see Chap. 132), or deficiency in α-tocopherol transfer protein can exhibit the signs and symptoms of retinitis pigmentosa as the first manifestations of disease. Because vision-saving treatments are available for these conditions, it is important to consider them in all newly diagnosed patients with retinitis pigmentosa. Also noteworthy in this regard is that at least some patients with a related hereditary retinal degeneration named gyrate atrophy (MIM 258870; see Chap. 83) may benefit from specifically modifying their diet. For the nonsyndromic forms of retinitis pigmentosa and for Usher syndrome, oral supplements of vitamin A have been reported to slow the rate of cone photoreceptor degeneration. No other therapy advocated to slow or stop the course of retinitis pigmentosa or related retinal degenerations has been tested in a large, double-blind clinical trial. However, a night vision scope can help to alleviate the symptom of night blindness in some patients. Also, acetazolamide has been reported to ameliorate temporarily the cystoid macular edema that reduces central vision in some cases, although this drug can have serious side effects.

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