Retinitis Pigmentosa

Retinitis Pigmentosa 263

Retinitis Pigmentosa E L Berson, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA ã 2009 Elsevier Ltd. All rights reserved.

Retinitis pigmentosa has a prevalence of about 1 in 4000 worldwide. About 50 000–100 000 people are affected in the United States. Affected patients typically report night blindness in adolescence, loss of mid-peripheral vision in young adulthood, and loss of far peripheral and then central vision in middle life. Clinical findings on ophthalmoscopy include intraretinal pigment around the mid-peripheral retina for which the condition is named, attenuated retinal vessels, and waxy pallor of the optic disks. Histologic examinations of autopsy eyes have shown that loss of vision is due to degeneration of both rod and cone photoreceptor cells across the retina. This group of diseases can be inherited by an autosomal dominant, autosomal recessive, X-linked, digenic, or mitochondrial mode of transmission; uniparental isodisomy has also been rarely reported. Assuming most isolate cases (i.e., cases with no relatives known to be affected) are inherited by an autosomal recessive mode, it is estimated that some 30–40% of cases are inherited as an autosomal dominant trait, 50–60% as an autosomal recessive trait, and 10–15% as an X-linked trait. Some 15% of all cases have associated partial hearing loss (Usher syndrome, type II) and another 2–6% have associated profound congenital deafness and vestibular ataxia (Usher syndrome, type I). About 1% of patients with retinitis pigmentosa have adult-onset hearing loss with or without ataxia (Usher syndrome, type III). Retinitis pigmentosa can be detected in early life by electroretinographic testing. Electroretinograms (ERGs) are recorded in response to flashes of light with a contact lens electrode placed on the topically anesthetized cornea; responses are electronically amplified and displayed on an oscilloscope. Patients with early retinitis pigmentosa typically have reduced rod and cone ERG responses which are delayed in their peak implicit times (i.e., time interval between stimulus flash onset and the peak of the corresponding response). Abnormal ERGs have been detected in asymptomatic children years to a decade before diagnostic changes are seen on routine ocular examination. ERG amplitudes become smaller as the disease progresses (Figure 1). Most patients with remaining vision have detectable responses when ERGs are recorded with computer averaging and narrow bandpass

filtering. Patients aged 6 and older with normal ERGs in families with retinitis pigmentosa have not been observed to develop this condition at a later time. More than 100 gene loci that cause retinitis pigmentosa have been identified or mapped; an updated list of genes causing this condition is maintained on the RetNet website. Genes so far identified as causes of nonsyndromic retinitis pigmentosa as well as Usher syndrome are given in Table 1. Molecular genetic analyses have revealed defects in genes encoding proteins involved in the phototransduction cascade (see Figure 2), the retinoid cycle, maintenance of photoreceptor cell structure, cell–cell interactions, RNA intron-splicing factors, intracellular transport of proteins, regulation of carbon dioxide/bicarbonate balance, phagocystosis, and in yet-to-be-defined functions in the photoreceptors or retinal pigment epithelium. About 50–60% of cases of retinitis pigmentosa have known molecular genetic abnormalities. Variability of clinical expression has been observed both within and between families among patients with the same gene defect, leading to the hypothesis that some factor or factors other than the gene defect itself contributes to the pathogenesis of disease. Light exposure, nutritional factors, and/or modifying genes have been proposed as possible risk factors that might contribute to severity of disease at a given age. More than 100 mutations have been found in the rhodopsin gene alone and severity of disease has been correlated with the region of the opsin molecule affected by a given mutation; for example, patients with a mutation near the C-terminus (e.g., rhodopsin, Pro347Leu) have more severe disease at a given age than patients with a mutation near the N-terminus (e.g., rhodopsin, Pro23His). Mutations in the peripherin/ RDS gene have been associated with retinitis pigmentosa, retinitis punctata albescens, and retinal degenerations primarily involving the macula, showing that abnormalities in the same gene can be associated with different phenotypes. A severe form of retinitis pigmentosa is called Leber congenital amaurosis. Mutations in at least ten genes have been implicated as causes of this recessively inherited condition; these genes are GUCY2D, CRB1, IMPDH1, RPE65, AIPL1, RPGRIP1, RDH12, CRX, TULP1, and LRAT. Affected children are typically born with little, if any, vision, nystagmus, and hyperopia. Optical coherence tomography has revealed that patients with little vision may still have some remaining photoreceptor nuclei that might be amenable to treatment. Promising results in restoring retinal

264 Retinitis Pigmentosa ERGs in retinitis pigmentosa over a 10 year interval Blue-green

White

White (30 Hz)

Blue-green

Normal

Normal

VI-92, age 6

VI-92, age 15

VI-90, age 11

VI-90, age 20

VI-86, age 13

VI-86, age 22

VI-84, age 17

VI-84, age 26

a

b

White

White (30 Hz)

Figure 1 ERG responses recorded in 1967 (a) and 1977 (b) from a normal subject and from four affected members of a family with a dominant form of retinitis pigmentosa transmitted over six generations. Pedigree number and age at time of testing are indicated for each patient. One to three responses to same stimulus are represented. For (a) and (b), rod-isolated responses to single flashes of blue-green light are illustrated in the left column; mixed cone–rod responses to single flashes of white light are illustrated in the middle column; and cone-isolated responses to 30 Hz white flickering light are illustrated in the right column. Calibration symbol for 1967 responses designates 50 ms horizontally for columns 1 and 2, 25 ms for column 3, 50 mV vertically for column 1, and 100 mV vertically for columns 2 and 3. Calibration symbol for 1977 responses designates 60 ms horizontally and 100 mV vertically for all tracings. Reproduced from Berson EL and Simonoff EA (1979) Dominant retinitis pigmentosa with reduced penetrance: Further studies of the electroretinogram. Archives of Ophthalmology 97: 1286–1291, with permission from American Medical Association. Copyright ã (1979) American Medical Association.

function have been achieved with a viral-mediated subretinal injection of the RPE65 gene in a canine model and the RPGRIP gene in a murine model of this group of diseases when treatment is initiated at a time when these models have remaining photoreceptors. It remains to be established whether viral-mediated gene therapy is safe and effective in humans with the early stages of Leber congenital amaurosis. Retinitis pigmentosa has been associated not only with hearing loss but also with polydactyly, mental retardation, truncal obesity, and hypogonadism (Laurence–Moon–Bardet–Biedl syndrome). Some clinicians have subdivided this syndrome into two disorders; polydactyly is found primarily in patients with the Bardet–Biedl form, and neurological abnormalities are found usually in patients with the Laurence–Moon form. Variability of clinical expression is well known and some patients may have this condition without mental retardation or polydactyly. Mutations in at least nine genes have so far been identified (i.e., BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, and PHTB1). Renal disease occurs in some cases; therefore, patients should have their blood pressure and urine checked periodically. No treatment is known for the retinal degeneration observed in some 90% of patients with this syndrome.

Retinitis pigmentosa is also found in association with anosmia, ataxia, dry skin, and EKG abnormalities with elevated serum phytanic acid (Refsum disease); malabsorption, acanthocytosis, ataxia, and abetalipoproteinemia (Bassen–Kornzweig syndrome); and adult-onset ataxia, dysarthria, hyporeflexia, decreased proprioception, decreased vibration sense, and low serum vitamin E levels (Friedreich-like ataxia with retinitis pigmentosa). These uncommon recessively inherited conditions are treatable as follows: a low phytol/low phytanic acid diet (excluding animal fats, milk products, and dark green leafy vegetables) in the case of Refsum disease; a low-fat diet plus supplementation with vitamin A, vitamin E, and vitamin K in the case of Bassen–Kornzweig syndrome, and vitamin E supplementation in the case of Friedreichlike ataxia associated with retinitis pigmentosa. The common forms of retinitis pigmentosa have also yielded to treatment. In a randomized, controlled double-masked trial among 601 patients aged 18–49, the course of retinal degeneration as monitored by the ERG was slower on average among patients taking a daily supplement of vitamin A palmitate, 15 000 IU day
1, than among those not on this dose. Furthermore, the course appeared to be faster on average among patients taking a daily supplement of 400 IU day
1 of vitamin

Retinitis Pigmentosa 265

Table 1 Estimated proportions of cases of retinitis pigmentosa (RP) caused by Identified genes (excluding syndromic RP except for Usher syndrome) Inheritance pattern/gene

Percent of all RP (including Usher syndrome)

Autosomal dominant (40% of all cases of retinitis pigmentosa) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

RHO (rhodopsin) (3q) RP1 (8q) PRPF31 (19q) PRPF3 (1q) peripherin/RDS (6p) FSCN2 (fascin) (17q) PRPF8 (17p) IMPDH1 (7q) NRL (14q) CRX (19q) CA4 (carbonic anhydrase) (17q) PAP1 (7p) SEMA4A (semaphorin) (1q)

10% 2.2% 2.0% 1.6% 1% 1% 0.8% 0.8% 0.4% 0.4% ? frequency in USA (2% in UK) <1% <1%

Autosomal recessive (50% of all cases of retinitis pigmentosa, including isolates) 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

usherin (1q) rod PDEb (4p) rod PDEa (5q) CNGA1 (rod channel a (4p) RPE65 (1p) myosin VIIa (11q) LRAT (4q) NR2E3 (15q) MERTK (2q) harmonin (11p) CDH23 (10q) PCDH15 (10q) MASS1 (5q) clarin-1 (3q) SAG (arrestin) (2q) CRALBP (15q) RHO (rhodopsin) (3q) TULP1 (6q) ABCA4 (i.e., ABCR) (1p) RGR (10q) CRB1 (1q) CERKL (2q) CNGB1 (rod channel b) (16q) SANS (17q) RP1 (8q)

10% (Usher IIA) 2% 1.5% 1% 1% 1% (Usher IB) <1% <1% <1% <1% (Usher IC) <1% (Usher ID) <1% (Usher IF) <1% (Usher IIC) <1% (Usher IIIA) 0.5% 0.5% 0.5% 0.5% <1% <1% <1% <1% <1% <1% (Usher 1G) <1%

X-linked (10% of all cases of retinitis pigmentosa) 39. RPGR (Xp21.1) 40. RP2 (Xp11.3)

8% (RPGR and RP2 combined account for 1% 90% of XLRP)

Digenic (only a few families) 41. ROM1 (11q) and peripherin/RDS (6p)

<1%

Mitochondrial (only one family) 42. MTTS2

<1%

Percentages are approximate and are based on the breakdown of RP cases according to genetic type reported by Fishman (Archives of Ophthalmology 96: 822–826, 1978), Macrae (Birth Defects: Original Article Series 18: 175–185, 1982), and Bunker et al. (American Journal of Ophthalmology 97: 357–365, 1984) and on the assumptions that all isolate cases are autosomal recessive and that about one-third of cases of Usher syndrome type I (approximately 6% of all cases of RP) are caused by defects in myosin VIIa. The values are calculated based on frequency of cases in a published series multiplied by the proportion of RP with that inheritance pattern (e.g., dominant rhodopsin mutations were found in 90/363 cases of ADRP; ADRP accounts for about 40% of all cases of RP; accordingly, the percentage of cases caused by dominant rhodopsin mutations is 90/363 ¼ 24.8%  0.4 ¼ 9.92  10%). A current referenced list of genes causing retinitis pigmentosa and allied retinal diseases can be accessed on the world wide web at: http:// www.sph.uth.tmc.edu/Retnet/sum-dis.htm.

266 Retinitis Pigmentosa

Pigment epithelium

Photoreceptor outer segment Photon

IRBP Retinal

Retinal Retinol

Retinol

Recoverin Rhodopsin 11-cis-retinal

CRBP CRALBP

Guanylate cyclase

Transducin Alpha, beta, gamma cGMP-PDE * cGMP

Arrestin

5⬘GMP Rhodopin * 11-trans-retinal

Rhodopsin kinase

Transducin *

cGMP-PDE alpha, beta, gamma

*Activated Peripherin

ROM-1

cGMPgated channel

Figure 2 Schematic representation of some proteins normally found in the rod photoreceptor outer segment, interphotoreceptor matrix, and retinal pigment epithelium. Genes encoding these proteins are considered candidate genes that could cause retinitis pigmentosa because mutations in them could result in compromise of the phototransduction cascade or the mechanism by which vitamin A is transported between the photoreceptors and the pigment epithelium with consequent photoreceptor cell degeneration. IRBP, interphotoreceptor retinoid binding protein; CRBP, cellular retinol-binding protein; CRALBP, cellular retinal-binding protein; PDE, phosphodiesterase; ROM1, rod outer segment membrane protein 1; cGMP, cyclic guanosine monophosphate. Reproduced from Berson EL (1993) Retinitis pigmentosa: The Friedenwald lecture. Investigative Ophthalmology & Visual Science 34: 1659–1676, with permission from Association for Research in Vision and Ophthalmology.

E than those not on this dose. This has led to the recommendation that most adult patients with the common forms of retinitis pigmentosa should take a daily supplement of 15 000 IU of vitamin A in the palmitate form under the supervision of their physician and avoid high-dose supplementation with vitamin E. Since doses of >25 000 IU day
1 of preformed vitamin A can be associated with liver disease when taken over the long term, patients should have a fasting serum vitamin A and liver function profile before commencing this treatment and measures of these parameters annually thereafter while on this supplement. Betacarotene is not predictably converted to preformed vitamin A and therefore should not be considered as a substitute for treatment with vitamin A palmitate. Sources of the appropriate dose of vitamin A palmitate are maintained on the website of the Foundation Fighting Blindness. No toxic effects have been observed in adults with retinitis pigmentosa in good general health on this supplement of vitamin A who have been followed for up to 12 years. Because of the increased risk of birth defects associated with high-dose vitamin A supplementation, women who are pregnant or planning to become pregnant should not take this supplement. Long-term vitamin A supplementation has

been associated with a decrease in bone density and up to a 1% increase in risk of hip fracture; therefore, postmenopausal women and men aged 49 and above with retinitis pigmentosa taking vitamin A should have their bone health monitored periodically by their family doctor. Since patients under age 18 were not included in this trial, no formal recommendation can be made for patients with retinitis pigmentosa under this age. A second randomized, controlled, double-masked trial for retinitis pigmentosa revealed that docosahexaenoic acid (DHA) supplementation in a dose of 1200 mg day
1 did not, on average, provide benefit for adults also taking vitamin A 15 000 IU day
1. However, a subgroup analysis revealed that those taking vitamin A who ate two or more 3-ounce servings of oily fish per week (i.e., salmon, tuna, herring, mackerel, or sardines) of which DHA is a major constituent showed a 40–50% slowing of annual decline in visual field sensitivity. It has been estimated that the combination of vitamin A palmitate 15 000 IU day
1 and a diet rich in oily fish could result in almost 20 years of additional visual preservation. The average patient who starts this regimen in his or her thirties would be expected to retain some useful vision until about age 80 in contrast to an

Retinitis Pigmentosa 267

untreated patient who would be expected to be virtually blind by age 60. Night vision devices are available that amplify light and thereby allow patients with retinitis pigmentosa and night blindness to use their remaining cones to function under dim daylight, moonlight, or even starlight conditions. The best candidates for these devices are patients with best corrected vision of better than 20/200 in at least one eye and a central visual field diameter of >20 in that eye. For patients with reduced visual acuity, a closed circuit television for reading is helpful in some instances. Patients with retinitis pigmentosa should avoid exposure to bright sunlight outdoors until more is known about whether exposure to sunlight affects the course of this condition. Since no particular type of sunglass has been shown to alter the course of retinal degeneration, patients should select sunglasses for outdoor use that provide maximal protection from sunlight without compromising vision. The precise cellular mechanisms that lead to photoreceptor cell death are under study. Among the questions remaining to be answered are why rod-specific gene defects lead to cone photoreceptor cell death and whether the process of apoptosis (or genetically programmed cell death) can help to explain pathogenesis. Efforts to replace degenerated photoreceptor cells through transplantation of healthy photoreceptor cells in the subretinal space have so far proved unsuccessful as the implanted photoreceptors have not formed functional connections with the proximal retina necessary for the transmission of visual information to the brain. Light-sensitive microchips implanted on or under the retina are under study but their value remains to be established. Studies are in progress to rescue remaining photoreceptor cells with ciliary neurotrophic factor (CNTF), gene therapy, or other nutritional supplements. A multidisciplined approach combining biochemistry, electrophysiology, molecular and cell biology, and ophthalmology would appear to have the greatest chance of making new discoveries that will benefit patients with this group of diseases. See also: Animal Models of Inherited Retinal Degenerations; Cone Photopigment Evolution; Electroretinography; Photoreceptor Adaptation; Photoreceptors: Physiology; Retinal Color Mechanisms; Retinal Development: An Overview; Vision: Light and Dark Adaptation.

Further Reading Acland GM, Aguirre GD, Ray J, et al. (2001) Gene therapy restores vision in a canine model of childhood blindness. Nature Genetics 28: 92–95.

Andre´asson SOL, Sandberg MA, and Berson EL (1987) Narrowband filtering for monitoring low-amplitude cone electroretinograms in retinitis pigmentosa. American Journal of Ophthalmology 105: 500–503. Apfelstedt-Sylla E, Theischen M, Ruther K, Wedemann H, Gal A, and Zrenner E (1995) Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystropy and mutations in the human RDS/peripherin gene. British Journal of Ophthalmology 79: 28–34. Ben-Arie-Weintrob Y, Berson EL, and Dryja TP (2005) Histopathologic–genotypic correlations in retinitis pigmentosa and allied diseases. Ophthalmic Genetics 26: 91–100. Berson EL (1993) Retinitis pigmentosa: The Friedenwald lecture. Invest Ophthalmology & Visual Science 34: 1659–1676. Berson EL (1998) Treatment of retinitis pigmentosa with vitamin A. Proceedings of the Fernstro¨m Symposium on Tapetoretinal Degenerations, Lund, Sweden. Digital Journal of Ophthalmology 4(7). http://www.djo.harvard.edu (accessed by August 2008). Berson EL (2007) Long-term visual prognoses in patients with retinitis pigmentosa: The Ludwig von Sallmann Lecture. Experimental Eye Research 85: 7–14. Berson EL, Rosner B, Sandberg MA, et al. (1993) A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Archives of Ophthalmology 111: 761–772. Berson EL, Rosner B, Sandberg MA, et al. (2004) Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Archives of Ophthalmology 122: 1297–1305. Berson EL, Rosner B, Sandberg MA, et al. (2004) Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: Subgroup analyses. Archives of Ophthalmology 122: 1306–1314. Berson EL and Simonoff EA (1979) Dominant retinitis pigmentosa with reduced penetrance: Further studies of the electroretinogram. Archives of Ophthalmology 97: 1286–1291. Bishara S, Merin S, Cooper M, Azizi E, Delpre G, and Deckelbaum RJ (1982) Combined vitamin A and E therapy prevents retinal electrophysiological deterioration in abetalipoproteinemia. British Journal of Ophthalmology 66: 767–770. Feskanich D, Singh V, Willett WC, and Colditz GA (2002) Vitamin A intake and hip fractures among postmenopausal women. Journal of the American Medical Association 287: 47–54. Gouras P, Carr RE, and Gunkel RD (1971) Retinitis pigmentosa in abetalipoproteinemia: Effects of vitamin A. Investigative Ophthalmology & Visual Science 10: 784–793. Hartong DT, Berson EL, and Dryja TP (2006) Retinitis Pigmentosa. Lancet 368: 1795–1809. Michaelsson K, Lithell H, Vessby B, and Melhus H (2003) Serum retinol levels and the risk of fracture. New England Journal of Medicine 348: 287–294. Pawlyk BS, Smith AJ, Buch PK, et al. (2005) Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Investigative Ophthalmology & Visual Science 46: 3039–3045. Refsum S (1981) Heredopathia atactica polyneuritiformis, phytanic acid storage disease Refsum’s disease: A biochemically well-defined disease with a specific dietary treatment. Archives of Neurology 38: 605–606. Sibulesky L, Hayes KC, Pronczuk A, Weigel-Di Franco C, Rosner B, and Berson EL (1999) Safety of <7500 RE (<25 000 IU) vitamin A daily in adults with retinitis pigmentosa. American Journal of Clinical Nutrition 69: 656–663.

268 Retinitis Pigmentosa Sieving P, Caruso RC, Tao W, et al. (2006) Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proceedings of the National Academy of Sciences of the United States of America 103: 3896–3901. Yokota T, Shiohiri T, Gotoda T, et al. (1997) Friedreich-like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the a-tocopherol transfer protein gene. Annals of Neurology 41: 826–832.

Relevant Websites http://www.sph.uth.tmc.edu – RetNet: Summaries of Genes and Loci Causing Retinal Diseases, The University of Texas School of Public Health (for a current referenced list of genes causing retinitis pigmentosa). http://www.blindness.org – The Foundation Fighting Blindness (for a list of sources of the appropriate dose of vitamin A palmitate).