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Retinitis Pigmentosa Overview

, MD, PhD, , PhD, and , MD, DABMG, FACMG.

Author Information
, MD, PhD
Kellogg Eye Center
University of Michigan Medical School
Ann Arbor, Michigan
, PhD
Professor, Human Genetics Center
School of Public Health
University of Texas Health Science Center
Houston, Texas
, MD, DABMG, FACMG
Professor, Director, Oregon Retinal Degeneration Center
Casey Eye Institute
Oregon Health Sciences University
Portland, Oregon

Initial Posting: ; Last Update: March 21, 2013.

Summary

Disease characteristics. Retinitis pigmentosa (RP) is a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina lead to progressive visual loss. Affected individuals first experience defective dark adaptation or "night blindness," followed by constriction of peripheral visual fields and, eventually, loss of central vision late in the course of the disease.

Diagnosis/testing. The diagnosis of RP relies on documentation of progressive loss in photoreceptor function by electroretinography (ERG) and visual field testing. Mutations in more than 50 different genes or loci are known to cause nonsyndromic RP.

Genetic counseling. The mode of inheritance of RP is determined by family history and, in some instances, by molecular genetic testing. RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Females with an X-linked RP mutation may be unaffected or may show clinical symptoms. Such affected females are usually (but not always) less severely affected than males of the same age. Some digenic and mitochondrial forms have also been described. Genetic counseling depends on an accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing.

Management. Treatment of manifestations: Therapy with vitamin A palmitate may slow retinal degeneration but is not recommended for those under age 18 years and should be routinely monitored in women of childbearing age because of potential teratogenic effects in exposed fetuses. Long-term increased intake of vitamin A, of the level recommended for RP, has been reported to increase several fold the risk of osteoporosis. Accordingly, bone density should be monitored with such supplementation. Oral acetazolamide (Diamox) or topical dorzolamide therapy may reduce cystoid macular edema. In those with a visual field of less than 10° who have cataracts, lens extraction should be considered to improve visual function. Because of the concern of acceleration of retinal degeneration from short wave-length light exposure, use of UV-A and UV-B blocking sunglasses is recommended. CPF 550 lenses may increase eye comfort by reducing glare and adaptation time from light to dark. Other optical aids include magnifiers, closed-circuit television, and high-intensity, wide-beam flashlights. In the US, publicly funded agencies at the state level provide services (e.g., vocational training, mobility training, and skills for independent living) for the blind or those with progressive eye disorders.

Surveillance: Goldmann visual field perimeter and full ophthalmoscopic examination with dilation on an annual or biannual basis, with more frequent follow-up for active complications.

Agents/circumstances to avoid: High-dose supplements of vitamin E, which may adversely affect the course of RP; vitamin A palmitate during pregnancy because of potential teratogenic effects.

Definition of Retinitis Pigmentosa

Retinitis pigmentosa (RP) refers to a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) of the retina lead to progressive visual loss.

Clinical Manifestations

Night blindness. In RP, loss of rod function predominates early in the clinical course. The initial symptom of RP is usually defective dark adaptation (i.e., nyctalopia or "night blindness"). If individuals with RP do not volunteer a history of faulty dark adaptation, detailed questioning about activities at dusk or with minimal lighting often elicits such a history starting in childhood or adolescence. In general, the earlier the age of onset of defective dark adaptation, the more severe the course of RP. Although mid-peripheral vision loss occurs early in the disease, it is rarely recognized by the affected individual and is usually not a presenting symptom. Affected individuals may be considered "clumsy" before constriction of visual fields (i.e., "tunnel vision") is detected.

Visual acuity. Despite the fact that sensitive tests of cone function can document early cone involvement, central visual acuity is usually preserved until the end stages of RP. Loss of central visual acuity over time correlates with the presence of macular lesions early in the course [Flynn et al 2001]. Central acuity loss can occur at all ages from cystoid macular edema (CME), which is estimated to occur in approximately 10%-50% of individuals with RP, depending on the study, the genetic type, and the diagnostic tool. Estimates of CME incidence have been higher when optical coherence tomography (OCT) is used compared to fluorescein angiography (FA), which may not demonstrate leakage in affected individuals [Hajali et al 2008].

Some investigators have found a general correlation between age-related visual acuity and mode of inheritance. Fishman [1978] found that individuals with autosomal dominant RP had the best prognosis, with a visual acuity of 20/30 or better in the majority of individuals younger than thirty years of age. Males with X-linked RP had the worst prognosis, with a visual acuity worse than 20/200 in all individuals older than age fifty years. Individuals with autosomal recessive and simplex RP (i.e., single occurrence in the family) were intermediate in severity.

Fundus appearance. The fundus appearance in RP usually depends on the stage of the retinal degeneration. In the earliest stages when electroretinography reveals defective rod responses in individuals who may not yet have appreciated symptoms, the fundus usually appears normal. The term retinitis pigmentosa sine pigmento has been used to refer to a normal appearance of the retina despite documented abnormalities of photoreceptor function.

The earliest observed changes in the fundus are arteriolar narrowing, fine dust-like intraretinal pigmentation, and loss of pigment from the pigment epithelium. As photoreceptor deterioration progresses, there is increasing loss of pigment from the pigment epithelium with intraretinal clumping of melanin, appearing most often as coarse clumps in a "bone spicule" configuration.

Moderate to severe retinal vessel attenuation and waxy pallor of the optic nerve become apparent in individuals with advanced RP. The cause of the retinal vessel attenuation is unknown, but it appears to be a secondary change and not the primary cause of disease.

Posterior subcapsular cataracts characterized by yellowish crystalline changes in the visual axis of the posterior lens cortex are common in all forms of RP. Severity of the cataract correlates with the age of the affected individual. The cause of cataract formation in RP is unknown. Approximately half of individuals with RP eventually require (and usually benefit from) cataract surgery.

Dust-like particles in the vitreous are present in the great majority of individuals with RP. These are fine, colorless particles comprising free melanin pigment granules, pigment epithelium, uveal melanocytes, and macrophage-like cells, which are evenly distributed throughout the vitreous. Observation of these particles can be helpful in the diagnosis of early RP before fundus changes are apparent.

White dots deep in the retina at the level of the pigment epithelium are believed to be a nonspecific manifestation of pigment epithelial degeneration and may account for the retinal appearance termed "retinitis punctata albescens," which is considered a manifestation of RP.

Hyaline bodies (drusen) of the optic nerve head occur frequently in RP, may be associated with arcuate visual field loss, and are not diagnostic of a specific subtype.

Exudative vasculopathy, often called Coats-like disease, is the rare occurrence in individuals with severe or advanced RP of telangiectatic vessels, lipid deposition in the retina, and serous retinal detachment [Khan et al 1988]. The cause of exudative vasculopathy in RP is unknown. However, mutations in CRB1, a cause of Leber congenital amaurosis and autosomal recessive RP, have been associated with Coats-like exudative vasculopathy [den Hollander et al 2001]. When seen in children or young adults, Coats-like vascular changes should be monitored for progression and may require treatment.

Sector RP is a term that has been used to describe changes in one quadrant or one half of each fundus. Most commonly, the inferior and nasal quadrants are symmetrically involved. The visual field defects are less severe than those of typical RP and correspond to the ophthalmoscopically abnormal retina. Individuals with sector RP may lack symptoms of defective dark adaptation, although widespread abnormalities of rod and cone function are usually detected by ERG. The incidence of true sector RP is infrequent. Many forms of RP can present initially with a sectorial distribution that, when followed over decades, develops into a widespread, diffuse disease.

Sectoral changes have been observed in autosomal dominant RP, e.g., in people with the common p.Pro23His mutation of RHO, and in females heterozygous for X-linked RP.

The incidence of sector RP is low, either because it is uncommon or because mild symptoms result in infrequent diagnosis.

RP during pregnancy. Five to ten percent of women with RP report decreased vision during pregnancy that frequently did not recover postpartum; however, no objective data are available [Heckenlively et al 1988, Sunness 1988].

Physiologic changes during pregnancy, such as increased thickness and curvature of the cornea and changes in the accommodative power of the lens, can alter a woman’s refractive state.

Pregnant women are at increased risk for central serous retinopathy, progression of preexisting diabetic retinopathy, and other conditions that can affect vision.

Some woman with poor nutritional intake may be at increased risk for vitamin A deficiency and nyctalopia during pregnancy (for review see Garg & Aggarwal [2012]).

Establishing the Diagnosis

A consensus conference [Marmor et al 1983] suggested that the diagnosis of retinitis pigmentosa (RP) is established when the following are present:

  • Rod dysfunction as measured by
    • Dark adaptation (elevated rod final threshold)

      OR
    • Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
  • Progressive loss in photoreceptor function
  • Loss of peripheral vision that often is greater superiorly but can involve other regions as well
  • Bilateral involvement that has a high degree of symmetry, with respect to both the severity and the pattern of visual field loss and retinal changes

The retina is assessed through the following:

  • Ophthalmoscopy
  • Functional assessment of vision (e.g., visual acuity, visual fields, and color vision)
  • Electrophysiologic testing (electroretinography)
  • Structural assessment of the retina (spectral ocular coherence tomography [OCT]; adaptive optics [AO])
  • Fluorescein angiography, when warranted

Ophthalmoscopy of the retina in individuals with advanced RP is characterized by the presence of intraretinal clumps of black pigment, markedly attenuated retinal vessels, loss of retinal pigment epithelium (RPE), and pallor of the optic nerve. These changes reflect longstanding retinal degeneration and need not be present to make the diagnosis of RP. The fundus findings are, however, instrumental in distinguishing RP from other retinal dystrophies that have similar clinical findings but distinctive retinal changes.

Recent advances in adaptive optics allow highly detailed imaging of the retina with a resolution of two microns, potentially allowing clinicians and investigators to follow photoreceptor degeneration in individuals with RP at the cellular level [Duncan et al 2007, Yoon et al 2009]. However, this technology is not in widespread clinical use.

Functional assessment of vision

  • Visual field testing, also called perimetry, is the mapping of subjectively perceived test objects, which are ellipses of light varying in brightness and in size from 1/16 mm to 64 mm, projected on a uniformly illuminated background. Symptomatic defective dark adaptation in individuals with RP is usually accompanied by peripheral visual field defects or mid-peripheral scotomas (blind spots). In early RP, a ring scotoma often is present in the mid-periphery of the visual field approximately 20-25° from fixation. As the RP progresses, the outer edge of the ring expands toward the periphery, while the inner margin contracts slowly toward the central field (producing "tunnel vision"). Islands of vision may persist for years in the far periphery, most often temporally and inferiorly. Long after the entire peripheral field is gone, a small oval of intact central field typically remains. Individuals with RP may qualify as legally blind by visual field criteria (horizontal diameter of field 20 degrees or less to a size III4e test target in the better eye) before visual acuity drops to the level established for legal blindness (20/200). Hence, visual field testing is useful not only for diagnosis, but also for staging of the disease, for qualifying affected individuals to drive, for assessment of disability, and for establishing legal blindness.
  • Visual acuity (VA) is measured in individuals age five years and older using the Snellen charts, for assessment of macular (central) vision both at distance (20’) and at near (14”).
  • Color vision, which can be assessed subjectively by the affected individual or by objective testing

Electroretinography (ERG) determines objectively the functional status of the photoreceptors. ERG measures an electrical potential that arises in the retina after light stimulation and represents a composite response of millions of retinal cells. The measurement is made with a contact lens electrode placed on the cornea, the output of which is amplified electronically and recorded. Responses obtained under dark-adapted conditions with stimluli that are dim or blue generally reflect rod function, and responses obtained under light-adapted conditions or with 30 Hz flicker stimuli generally reflect cone function. Rod responses can be separated from cone responses, permitting definition of the type and extent of rod and/or cone involvement. Early and severe impairment of isolated rod responses is a characteristic feature in RP and its documentation is important to the diagnosis in young individuals. In more severe or advanced forms of RP, cone loss occurs and eventually the ERG is nondetectable above noise.

Full-field ERG, which stimulates the full visual field and records responses from the entire retina, has traditionally been used to follow disease progression in people with retinitis pigmentosa.

Multifocal ERG allows recording of local responses across the macula and can detect residual macular function in individuals with advanced disease. Therefore, it is useful in long-term follow-up as well as monitoring visual function in clinical trials involving advanced RP [Hood et al 2003, Nagy et al 2008].

Optical coherence tomography (OCT) captures micron-resolution images of the retina. It can be used to demonstrate outer retinal degeneration, measure retinal thickness, and diagnose and follow cystoid macular edema [Hajali et al 2008, Hood et al 2009].

Differential Diagnosis

It should be noted that individuals who present with initial symptoms of photopsia (sensation of lights flashing), abnormal central vision, abnormal color vision, or marked asymmetry in ocular involvement may not have RP, but another retinal degeneration or retinal disease.

Some disorders to consider in the differential diagnosis of typical retinitis pigmentosa (RP) are listed below. In many cases, they are caused by mutations in the same genes implicated in RP.

  • Usher syndrome. The three types of Usher syndrome are inherited in an autosomal recessive manner.
    • Usher syndrome type 1. Congenital, profound, bilateral sensorineural hearing loss and lack of development of speech. All affected individuals have abnormalities of vestibular nerve function detected on caloric testing and associated mild, non-progressive ataxia. Symptoms of typical RP are usually noted in late childhood to early adolescence and are slowly progressive.
    • Usher syndrome type 2. Mild-to-profound congenital sensorineural hearing impairment, normal vestibular responses, and late-adolescent-to-young-adult-onset RP
    • Usher syndrome type 3. Bilateral variable sensorineural hearing loss, vestibular dysfunction, and RP – all of which are slowly progressive.
  • Gyrate atrophy of the choroid and retina, an autosomal recessive disorder, can be distinguished from RP by the appearance of the fundus and by appropriate laboratory tests [Hayasaka et al 1985]. Early in the disease, circumscribed, discrete round patches of choroidal and retinal atrophy occur in the midperiphery. As the disease progresses these areas coalesce to form the sharply defined, scalloped defects of the pigment epithelium and choroid to which the term "gyrate" has been assigned. Ten- to 20-fold elevation of plasma ornithine concentration is caused by deficiency of the enzyme ornithine-ketoacid aminotransferase, which can be assayed in skin fibroblasts.
  • Choroideremia, an X-linked disorder, can be distinguished by the fundus appearance. The early stage consists of fine pigmentary stippling and atrophy of the posterior pole and mid-periphery of the fundus. In later stages, patchy retinal pigment epithelial and choroidal atrophy appear in the mid-periphery and gradually coalesce.
  • Cone or cone-rod dystrophy, sometimes called inverse or central RP, refers to a group of disorders characterized by bilateral and symmetric loss of cone function in the presence of reduced rod function. Loss of central visual acuity, photoaversion, and color vision defects appear before peripheral visual loss and defective dark adaptation. The fundus changes may be similar to those of RP. Cone-rod dystrophies tend to demonstrate early onset and are often syndromic; examples include Alström syndrome, Bardet-Beidl syndrome, the neuronal ceroid lipofuscinoses, and Joubert syndrome and related disorders (JSRD). Note that the “oculorenal” phenotype is included in the spectrum of JSRD, which encompasses Senior-Løken syndrome (retinopathy and juvenile-onset nephronophthisis) and Dekaban-Arima syndrome (retinopathy and cystic dysplastic kidneys).
  • Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Most forms are autosomal recessive. Visual function is usually poor and accompanied by nystagmus, sluggish pupillary responses, photophobia, and hyperopia. The oculo-digital sign (repeated eye rubbing, poking, and pressing to elicit retinal stimulation) is characteristic. The appearance of the fundus is extremely variable. While initially the retina may appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal.
  • Congenital disorders of glycosylation (CDG) type 1a. The congenital disorders of glycosylation encompass several multisystem syndromic disorders caused by defective protein glycosylation. Affected individuals present with developmental delay, dysmorphic features, and neurologic findings. CDG 1a, the most common and well-characterized subtype, includes ophthalmologic findings (e.g., strabismus, progressive myopia, and retinal degeneration) in 50%-70% of cases [De Lonlay et al 2001]. Individuals may display attenuated retinal vessels, pallor of the optic disc, restricted visual fields, and diminished rod function on ERG [Jensen et al 2003, Morava et al 2009]. (See also Congenital Disorders of Glycosylation Overview.)
  • Mitochondrial disorders. Mutations in mitochondrial DNA (mtDNA) cause a range of neurologic findings including dementia, stroke-like episodes, and peripheral neuropathy, as well as retinal dystrophy, Leber hereditary optic neuropathy, hearing loss, and diabetes mellitus. See MELAS, MERRF, Mitochondrial DNA Deletion Syndromes, and Mitochondrial Diseases Overview.
  • Unilateral RP refers to unilateral functional and ophthalmoscopic changes; the underlying etiology and mechanism remain unknown. Many non-genetic causes of retinopathy may masquerade as unilateral RP and should be excluded (see Non-inherited retinopathies below). Although some have proposed skewed X-chromosome inactivation in female carriers of X-linked RP as one mechanism of unilateral RP, to date there have been no published reports of unilateral X-linked RP and most cases of unilateral RP are either simplex or autosomal dominant [Farrell 2009]. Typically other affected family members have bilateral RP, indicating that unilateral involvement itself is not necessarily heritable.
  • Treatable disorders. It is important to note the three inherited disorders with retinal degeneration and systemic manifestations for which treatment exists.
    • Bassen-Kornzweig disease (abetalipoproteinemia) presents with acanthocytosis and malabsorption, and is treated with vitamins A and E.
    • Ataxia with vitamin E deficiency (AVED) with ataxia and neuropathy is caused by mutations in TTPA, encoding alpha-tocopherol transfer protein, and is treated with vitamin E.
    • Refsum disease (phytanic acid oxidase deficiency) presents with neuropathy, ataxia, deafness, and cardiac arrhythmia, and is treated with dietary reduction of phytanic acid.
  • Non-inherited retinopathies. Many non-inherited causes of retinal inflammation can present with fundus findings similar to retinitis pigmentosa, including trauma, infection, autoimmune retinopathy, and drug toxicity [Hamel 2006].

Prevalence

The prevalence of RP is 1:3000 to 1:7000 persons, or 14 to 33 per 100,000 [Haim 2002]. The prevalence in the US and Europe is approximately 1:3,500 to 1:4,000. Haim [2002] reported that in Denmark the lifetime risk of developing RP is 1:2500. Similar frequencies are expected in other populations but have not been documented.

RP shows no ethnic specificity; however, the spectrum of mutations within a given gene may vary between populations. This is especially true for certain isolated populations or those with a high rate of consanguinity. Furthermore, the frequency of a specific dominant or recessive mutant allele may be common in a particular population as a result of a founder effect or may change due to genetic drift. For example, the NM_000539.3:c.68C>A (NP_000530.1:p.Pro23His) mutation in RHO, which accounts for 12%-14% of all adRP in Americans of European origin, is otherwise rare [Sullivan et al 2006].

Causes

Retinitis pigmentosa (RP) is classified as nonsyndromic, or "simple" (not affecting other organs or tissues); syndromic (affecting other neurosensory systems such as hearing); or systemic (affecting multiple tissues). This overview focuses on nonsyndromic forms of RP. Nonsyndromic RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Rare digenic forms also occur. Digenic RP occurs in individuals who are heterozygous for both a ROM1 mutation and a PRPH2 mutation [Kajiwara et al 1994].

Table 1 summarizes the relative proportion of probands with RP by mode of inheritance.

Table 1. Causes of Nonsyndromic Retinitis Pigmentosa by Mode of Inheritance

Mode of InheritanceProportion of All RP Probands
Autosomal dominant RP (adRP)15%-25%
Autosomal recessive RP (arRP)5%-20%
X-linked RP (xlRP)5%-15%
Unknown: Simplex 140%-50%
Digenic RPVery rare

Daiger et al [2007]

1. Single occurrence of RP in a family

Gene mapping and gene discovery have revealed unusually complicated molecular genetic causes of RP [Daiger et al 2007]. Many of the genes associated with RP encode proteins that are involved in phototransduction (the process by which the energy of a photon of light is converted in the photoreceptor cell outer segment into a neuronal signal), the visual cycle (production and recycling of the chromophore of rhodopsin), photoreceptor structure, or photoreceptor gene transcription [Hims et al 2003]. However, the function of many genes in which mutations cause RP remains unknown.

The complexity of RP is evident in:

  • Locus heterogeneity: mutations in many different genes cause the same phenotype [Daiger et al 2007].
  • Allelic heterogeneity: many different disease-causing mutations occur within the same gene; however, a few specific mutations may be "common" among affected individuals.
  • Allelic disorders: different mutations in the same gene may cause different phenotypes. For example, different mutations in RHO, the gene encoding rhodopsin, may cause autosomal dominant RP, autosomal dominant congenital stationary night blindness, or, rarely, autosomal recessive RP. Mutations in PRPH2 (previously known as RDS), the gene encoding peripherin, may cause autosomal dominant RP, autosomal dominant macular degeneration, or, with a mutation in ROM1, digenic RP.
  • Clinical severity and disease phenotype often differ among individuals with the same mutation, most likely as the result of genetic and/or environmental modifying factors.

Autosomal Dominant RP

  • RHO. More than 100 RHO mutations have been reported; one, NM_000539.3:c.68C>A (NP_000530.1:p.Pro23His) associated with distinct sectorial disease, is found in approximately 12%-14% of Americans of European origin who have adRP [Sullivan et al 2006].
  • RP1. Of the RP1 mutations known, two account for half of adRP caused by an RP1 mutation: c.2029C>T (p.Arg677Ter) and c.2285_2289delTAAAT (p.Leu762TyrfsTer17); reference sequences NM_006269.1 NP_006260.1.
  • PRPH2 (RDS) mutations are associated with clinical phenotypes ranging from RP to macular degeneration to complex maculopathies.
  • PRPF31. Mutation of PRPF31, previously thought to account for 5%-6% of adRP, is now known to account for 8% of adRP, because 2.5% of adRP is caused by genomic rearrangements of this gene that are detected using deletion/duplication analysis rather than sequence analysis.

Table 2. Genes Associated with Autosomal Dominant Retinitis Pigmentosa (adRP)

GeneEstimated Proportion of adRP Attributed to Mutations in This GeneProteinOMIMLinks to RetNet Database 1
RHO20%-30% 2Rhodopsin180380, 613731RetNet
PRPF315%-10% 2U4/U6 small nuclear ribonucleoprotein Prp31600138, 606419RetNet
PRPH25%-10% 2Peripherin-2179605, 608133 RetNet
RP13%-4% 2Oxygen-regulated protein 1 180100, 603937RetNet
IMPDH12%-3% 2Inosine-5'-monophosphate dehydrogenase 1146690, 180105, RetNet
PRPF82%-3% 2Pre-mRNA-processing-splicing factor 8600059, 607300RetNet
KLHL71%-2%Kelch-like protein 7611119, 612943RetNet
NR2E31%-2% 2Photoreceptor-specific nuclear receptor 604485, 611131RetNet
CRX1% 2Cone-rod homeobox protein 120970, 602225, RetNet
PRPF31% 2U4/U6 small nuclear ribonucleoprotein Prp3601414, 607301RetNet
TOPORS1% 3E3 ubiquitin-protein ligase Topors609507, 609923RetNet
CA4Rare 2Carbonic anhydrase 4600852, 114760RetNet
NRLRare 2Neural retina-specific leucine zipper protein162080, 613750RetNet
ROM1Rare 2Retinal outer segment membrane protein 1180721RetNet
RP9Rare 2Retinitis pigmentosa 9 protein180104, 607331RetNet
RDH12UnknownRetinol dehydrogenase 12608830, 612712RetNet
SNRNP200UnknownU5 small nuclear ribonucleoprotein 200 kDa helicase601664, 610359RetNet
AIPL1Rare 4Aryl-hydrocarbon-interacting protein-like 1604392RetNet
BEST1Rare 5Bestrophin- 1607854, 613194RetNet
PRPF6Rare 6Pre-mRNA-processing factor 6613979, 613983RetNet
RPE65Rare 7Retinoid isomerohydrolase180069, 613794RetNet
linked to 6q23; gene not identified Linkage in one familynot identified614494RetNet
GUCA1B4%-5% in Japan; rare in UKGuanylyl cyclase-activating protein 2602275, 613827RetNet
FSCN23% of Japanese with adRP; otherwise rare 2Fascin-2 607643, 607921RetNet
SEMA4A3%-4% in PakistanSemaphorin-4A607292, 610282 RetNet

Data are compiled from the following standard references: gene symbol from HGNC; OMIM numbers from OMIM; protein name from UniProt.

See Retinitis Pigmentosa: Phenotypic Series to view genes associated with this phenotype in OMIM.

1. For additional information including allelic disorders (i.e., other phenotypes associated with mutation in a given gene) see RetNet.

2. Daiger et al [2008]

3. Bowne et al [2008]

4. Sohocki et al [2000]

5. Davidson et al [2009]

6. Tanackovic et al [2011]

7. Bowne et al [2011]

Autosomal Recessive RP

Mutations in one gene, USH2A (which can also cause Usher syndrome type 2), may account for 10%-15% of arRP.

The symptoms of autosomal recessive RP may overlap with other autosomal recessive retinopathies. In particular, autosomal recessive early-onset RP and Leber congenital amaurosis (LCA) are very similar.

Table 3. Genes Associated with Autosomal Recessive Retinitis Pigmentosa (arRP)

GeneEstimated Proportion of arRP Attributed to Mutations in This GeneProtein OMIMLinks to RetNet Database 1
USH2A10%-15%Usherin608400, 613809RetNet
ABCA42%-5% 2Retinal-specific ATP-binding cassette transporter601691, 601718 RetNet
PDE6A2%-5%Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha180071, 613801RetNet
PDE6B2%-5%Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta180072, 613801RetNet
RPE652%-5%Retinoid isomerohydrolas180069, 613794 RetNet
CNGA11%-2%cGMP-gated cation channel alpha-1123825, 613756RetNet
BEST1≤1%Bestrophin-1607854, 613194RetNet
C2ORF71≤1%Uncharacterized protein C2orf71613425, 613428RetNet
C8ORF37≤1%Uncharacterized protein C8orf37614477, 614500RetNet
CLRN1≤1%Clarin-1606397, 614180RetNet
CNGB1≤1%Cyclic nucleotide-gated cation channel beta-1600724, 613767RetNet
DHDDS≤1%Dehydrodolichyl diphosphate synthetase608172, 613861RetNet
FAM161A≤1%Protein FAM161A606068, 613596RetNet
IDH3B≤1%Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial604526, 612572RetNet
IMPG2≤1%Interphotoreceptor matrix proteoglycan 2607056, 613581RetNet
LRAT≤1%Lecithin retinol acyltransferase604863, 613341RetNet
MAK≤1%Serine/threonine-protein kinase MAK154235, 614181RetNet
MERTK≤1%Tyrosine-protein kinase Mer604705, 613862RetNet
NRL≤1%Neural retina-specific leucine zipper protein162080, 613750RetNet
PDE6G≤1%Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamm180073, 613582RetNet
PRCD≤1%Progressive rod-cone degneration protein610598, 610599RetNet
PROM1≤1%Prominin-1604365, 612095RetNet
RBP3≤1%Retinol-binding protein 3180290RetNet
RGR≤1%RPE-retinal G protein-coupled receptor600342, 613769RetNet
RHO≤1%Rhodopsin180380, 613731RetNet
RLBP1≤1%Retinaldehyde-binding protein 1180090, 607475RetNet
RP1≤1%Oxygen-regulated protein 1180100, 603937RetNet
SPATA7≤1%Spermatogenesis-associated protein 7604232, 609868RetNet
TTC8≤1%Tetratricopeptide repeat domain 8608132, 613464RetNet
TULP1≤1%Tubby-related protein 1600132, 602280RetNet
ZNF513≤1%Zinc finger protein 513613598, 613617RetNet
ARL6≤1%ADP-ribosylation factor-like protein 6608845, 613575RetNet
NR2E3Rare; found in Sephardic Jews in Portugalnuclear receptor subfamily 2 group E3604485, 611131RetNet
EYS10%-30% in Spain; common in China 3Protein eyes shut homolog602772, 612424RetNet
CRB16%-7% in Spain 4Crumbs homolog 1600105, 604210RetNet
CERKL3%-4% in Spain 5Ceramide kinase-like protein608380, 608381RetNet
SAG2%-3% in JapanS-arrestin181031, 613758RetNet

Data are compiled from the following standard references: gene symbol from HGNC; OMIM numbers from OMIM; protein name from UniProt. See RetNet for mapped loci for which no gene has yet been identified.

See Retinitis Pigmentosa: Phenotypic Series to view genes associated with this phenotype in OMIM.

1. For additional information including allelic disorders (i.e., other phenotypes associated with mutation in a given gene) see RetNet.

2. Klevering et al [2004]

3. Ruiz et al [1998], Abd El-Aziz et al [2006]

4. Vallespin et al [2007]

5. Avila-Fernandez et al [2008]

X-Linked RP

In general, the close proximity of multiple RP-related genes on the X chromosome makes gene mapping and mutation detection difficult.

Typically retinal disease in females with xlRP is less severe than that seen in males; in contrast, in adRP males and females are, on average, equally affected. Because females heterozygous for a mutation in an X-linked RP-related gene may be unaffected or express mild to severe retinal degeneration [Souied et al 1997, Grover et al 2000], families with xlRP in which some females are affected can be mistaken for families with adRP. For example, in a cohort of 215 families with apparent adRP, three families (1.4%) had xlRP caused by mutations in RPGR [Daiger et al 2008]. Nonetheless, this observation likely underestimates the actual frequency of RPGR mutations in pedigrees consistent with adRP.

Table 4. Genes Associated with X-Linked RP (xlRP)

GeneEstimated Proportion of xlRP Attributed to Mutations in This Gene Protein OMIMLinks to RetNet Database 1
RPGR70%-90% 2X-linked retinitis pigmentosa GTPase regulator300029, 312610RetNet
RP210%-20% 2, 3Protein XRP2300757, 312600RetNet

Data are compiled from the following standard references: gene symbol from HGNC; OMIM numbers from OMIM; protein name from UniProt. See RetNet for mapped loci for which no gene has yet been identified.

See Retinitis Pigmentosa: Phenotypic Series to view genes associated with this phenotype in OMIM.

1. For additional information including allelic disorders (i.e., other phenotypes associated with mutation in a given gene) see RetNet.

2. Mutations in RPGR (also called RP3) and RP2 are the most common causes of xlRP. Linkage studies suggest that they account for 70%-90% and 10%-20% of xlRP, respectively [Vervoort et al 2000]. Note: Earlier studies of RPGR failed to find mutations in a majority of families that mapped to RP3; however, identification of an additional exon in RPGR (ORF15) substantially increased the mutation detection rate [Bader et al 2003]. ORF15 is the site of many of the dominant-acting mutations at this locus [Rozet et al 2002, Bader et al 2003, Sharon et al 2003].

3. Bader et al [2003], Sharon et al [2003]

Digenic RP

Digenic RP is caused by the simultaneous presence of a mutation in PRPH2 and a mutation in ROM1 [Dryja et al 1997]. Although the same PRPH2 mutation (NM_000322.4:c.554T>C; NP_000313.2:p.Leu185Pro) was found in all cases reported, three different ROM1 mutations were identified in these families. In a cohort of 215 families with apparent adRP, one family (0.5%) had digenic RP [Daiger et al 2008].

Evaluation Strategy

Determining the mode of inheritance is critical to establishing the genetic cause of RP in an individual with nonsyndromic disease. This information allows the clinician to counsel affected individuals regarding the risk to relatives of developing RP. Molecular genetic testing is often required to confirm the diagnosis and may be needed to aid in determining the mode of inheritance.

Determining the Mode of Inheritance

Family history. A three-generation family history with attention to all first-degree relatives and their immediate descendants should be obtained to help determine the mode of inheritance. Documentation of relevant findings in family members can be accomplished either through direct examination of those individuals or through review of their medical records including ERG testing, visual field testing, and ophthalmologic examination.

Simplex cases (i.e., a single occurrence in a family) represent 10%-40% of all individuals with RP. Possible explanations for a simplex case include the following:

However, an individual who represents an apparent simplex case may have affected relatives either unknown to the proband or so mildly affected as to have escaped detection. Because other family members may be affected unbeknownst to the person providing the family history, clinical examination of first-degree relatives is often valuable.

Ophthalmologic evaluation of the mothers and daughters of males representing simplex cases may clarify the mode of inheritance in some families through detection of females who are carriers of xlRP. In some cases, xlRP may be misdiagnosed as adRP on the basis of affected females and multiple affected generations. In such families, females with xlRP may have less severe disease than males. Furthermore, lack of male-to-male transmission supports X-linked inheritance.

For most simplex cases the mode of inheritance must be determined by molecular genetic testing. Furthermore, it is important to stress that simplex cases of RP are not necessarily autosomal recessive and caution should be used in predicting recurrence risk when molecular genetic testing has been uninformative.

Molecular Genetic Testing

To identify the molecular basis of RP single gene testing or a RP multi-gene panel may be used.

Single gene testing. Molecular genetic testing for mutations in many RP-related genes is possible. Testing of single genes is most efficient if the mode of inheritance is known and testing is prioritized based on the proportion of mutations in each gene as a cause of RP.

Note: In any family with a PRPH2 mutation or a ROM1 mutation in which inheritance appears non-Mendelian, digenic inheritance should be considered and the other gene should be sequenced.

Multi-gene panels. Consider using a multi-gene panel that includes a number of genes associated with RP.

Note: (1) The genes included in a multi-gene panel will vary between laboratories and over time within the same laboratory. (2) Selection of a multi-gene panel for testing an individual may be influenced by reimbursement issues relating to a third-party (i.e., insurance) payer.

Research molecular genetic testing. Because new technologies may facilitate gene identification in the near future, participation in research studies may be useful for individuals in whom a specific mutation cannot be identified.

Interpretation of molecular genetic test results. The average likelihood of finding a disease-causing mutation in any given individual is approximately 50% with genetic testing [Daiger et al 2007, Berger et al 2010]. Given the complexity of RP, the correct interpretation of molecular genetic test results and effective patient counseling on the implications of test results are substantial challenges [Daiger et al 2007].

Follow up may involve performing additional clinical genetic testing of a family member with RP to ascertain their risks. For those families in which the underlying molecular basis is not identified, additional testing may be warranted when testing for mutations in newly identified genes is available.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Retinitis pigmentosa (RP) may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Rare digenic and mitochondrial forms also occur. For discussions about how to establish the mode of inheritance see Evaluation Strategy.

Risk to Family Members – Autosomal Dominant RP

Parents of a proband

  • Most individuals diagnosed as having autosomal dominant retinitis pigmentosa have an affected parent, although occasionally the family history is negative.
  • Family history may be "negative" because of early death of a parent, failure to recognize retinitis pigmentosa in family members, late onset in a parent, incomplete penetrance of the mutant allele in an asymptomatic parent, or a de novo mutation.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's parents.
    • If one of the proband's parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%.
    • If the mutation is not identified in a parent, the risk to sibs is reduced, but greater than that of the general population because of the possibility of incomplete penetrance or germline mosaicism in a parent.

Offspring of a proband

Risk to Family Members – Autosomal Recessive RP

Parents of a proband

  • The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each child of carrier parents has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes for a mutation causing autosomal recessive RP are asymptomatic in most cases.

Offspring of a proband. All offspring are obligate carriers.

Other family members of a proband. The sibs of obligate heterozygotes are at a 50% risk of being heterozygotes.

Carrier Detection – Autosomal Recessive RP

Carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing.

Risk to Family Members – X-Linked RP

Parents of a male proband

  • Women who have an affected son and another affected male relative are obligate heterozygotes.
  • Females with a disease-causing mutation may be asymptomatic, or have mild, moderate, or severe disease. Such affected females are usually (but not always) less severely affected than males of the same age.
  • If pedigree analysis reveals that an affected male represents a simplex case, several possibilities regarding his mother's carrier status need to be considered:
  • No data are available on the occurrence or frequency of de novo mutations for most genes associated with RP. Although Chang et al [2007] and Mears et al [2000] reported de novo mutations in RPGR causing X-linked RP and X-linked cone-rod-dystrophy, the frequency of such mutations is unknown.
  • No data are available on the possibility or frequency of germline mosaicism in the mother as an etiology for RP.
  • The father of an affected male is not affected.

Sibs of a male proband

Offspring of a male proband. All the daughters of an affected male inherit the mutation and are carriers; none of his sons inherit the mutation.

Other family members of a male proband. The maternal aunts of an affected male, and their offspring, may be at risk of being carriers or being affected (depending on their gender, family relationship, and the carrier status of the proband's mother). In addition, the maternal uncles and the maternal grandfather of an affected male may be affected, again depending on the carrier status of the proband’s mother.

Carrier Detection – X-Linked RP

Carrier testing for at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

Digenic and Mitochondrial Inheritance

Digenic RP is caused by the simultaneous presence of mutations in PRPH2 (previously known as RDS) and ROM1 [Dryja et al 1997].

Related Genetic Counseling Issues

Because of the many potential complications in interpreting the family history, in some families the only reliable indication of mode of inheritance is identification of the underlying molecular cause. See Evaluation Strategy

Clinical severity (which can range from mild to severe) and disease phenotype often differ among individuals with the same mutation; thus, age of onset and/or disease progression cannot be predicted based on the mode of inheritance or the underlying mutation alone.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for diseases such as RP are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which a/the disease-causing mutation(s) have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Retinitis Pigmentosa International
    PO Box 900
    Woodland Hills CA 91365
    Phone: 818-992-0500
    Fax: 818-992-3265
    Email: info@rpinternational.org
  • American Council of the Blind (ACB)
    2200 Wilson Boulevard
    Suite 650
    Arlington VA 22201
    Phone: 800-424-8666 (toll-free); 202-467-5081
    Fax: 202-467-5085
    Email: info@acb.org
  • Foundation Fighting Blindness
    11435 Cronhill Drive
    Owings Mills MD 21117-2220
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-568-0150
    Email: info@fightblindness.org
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jerigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • Retina International
    Retina Suisse
    Ausstellungsstrasse 36
    Zurich CH-8005
    Switzerland
    Phone: +41 (0) 44 444 1077
    Fax: +41 (0) 44 444 1070
    Email: christina.fasser@retina-international.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with retinitis pigmentosa (RP) the following evaluations are recommended:

  • Goldmann visual field perimetery (GVF)
  • Full ophthalmoscopic examination with dilation
  • Medical genetics consultation

Treatment of Manifestations

Retinitis pigmentosa. Vitamin A palmitate (15,000 IU per day) has been recommended for most forms of RP [Berson et al 1993]; however, this study and its recommendations remain controversial (see Therapies Under Investigation). High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [Radu et al 2008].

Increased intake of docosohexanoic acid (DHA) and lutein-zeaxanthin have been recommended on the basis of two studies [Berson et al 2010, Berson et al 2012] (see Therapies Under Investigation).

Cystoid macular edema. Some therapeutic success has been reported with both systemic and topical carbonic anhydrase inhibitors (oral acetazolamide [Diamox] or topical dorzolamide); however, rebound edema can occur with continued use [Fishman & Apushkin 2007].

Cataracts. Most affected individuals with a visual field of greater than 10° are not incapacitated by posterior subcapsular cataracts. Those with a visual field of less than 10° usually report significant improvement in visual function following lens extraction [Jackson et al 2001].

Optical aids. Because of the concern of acceleration of retinal degeneration from short wave-length light exposure, use of UV-A and UV-B blocking sunglasses is recommended. Use of CPF 550 lenses (Corning Photochromatic Filter manufactured by Corning Glass Works), which filter out 97%-99% of the spectral and ultraviolet energy below 550 nm wavelength, has been promoted for individuals with RP to increase eye comfort by reducing glare and internal light scatter, to improve contrast, and to reduce adaptation time from light to dark and vice versa.

Various optical aids have been proposed for individuals with peripheral visual loss and preserved central vision, although all have drawbacks.

Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.

Wide-field, high-intensity flashlights produce a bright wide beam of light and improve the nighttime mobility of individuals with RP. They are inexpensive and allow binocular viewing, but are large, heavy, and conspicuous.

Agencies for the visually impaired. In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.

Surveillance

Generally Goldmann visual field perimetry (GVF) and a full ophthalmoscopic examination with dilation are performed on an annual or biannual basis, with more frequent follow-up for active complications such as cystoid macular edema.

Agents/Circumstances to Avoid

Because vitamin E may adversely affect the course of RP, it is recommended that individuals with RP avoid high-dose supplements (e.g., 400 IU/d) [Berson 2000].

Vitamin A palmitate should be avoided during pregnancy because of potential teratogenic effects to the developing fetus.

Evaluation of Relatives at Risk

See Related Genetic Counseling Issues for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate (see Therapies Under Investigation) to the developing fetus. See Clinical Manifestations for further information about possible progression of disease during pregnancy.

Therapies Under Investigation

Supplementation. Several trials of nutritional supplements to treat retinitis pigmentosa have been conducted with varying success; the results are often controversial [Massof & Fishman 2010].

  • Vitamin A
    • Therapy with 15,000 IU per day of vitamin A palmitate possibly slows changes in retinal function detected by ERG [Berson et al 1993, Massof & Finkelstein 1993]. However, clinical measures such as visual acuity and visual field appear unaffected by vitamin A. Of note, the only preparation tested has been vitamin A palmitate.
    • Vitamin A palmitate therapy is not recommended for those under age 18 years.
    • Although toxicity with long-term use has not been noted [Sibulesky et al 1999], routine monitoring of serum vitamin A concentration and liver function has been recommended for any individual on vitamin A palmitate therapy.
    • Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
    • Because long-term high intake of vitamin A daily has been reported to increase several fold the risk of osteoporosis, bone density should be monitored with such supplementation [Melhus et al 1998, Feskanich et al 2002, Michaelsson et al 2003].
  • Docosahexaenoic acid (DHA)
    • DHA therapy (1200 mg/day) showed no effect on disease course in patients receiving vitamin A palmitate [Berson et al 2004a], although high RBC concentration of DHA correlated with slower decline in visual field sensitivity [Berson et al 2004b].
    • DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [Hoffman et al 2004].
    • A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [Hodge et al 2006].
  • Lutein
    • One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [Aleman et al 2001].
    • A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [Bahrami et al 2006].
    • A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of midperipheral visual field than in untreated individuals [Berson et al 2010].

Other

  • Triamcinolone injection. A recent study demonstrated a short-term benefit which was lost after a few months [Scorolli et al 2007].
  • Intravitreal VEGF inhibitors bevacizumab and ranibizumab. Preliminary data show some success in reducing macular edema and improving visual acuity [Artunay et al 2009, Yuzbasioglu et al 2009].
  • Hyperbaric oxygen therapy was shown to preserve visual acuity, visual field, and ERG response in people with RP as compared to vitamin A therapy over a ten-year period [Vingolo et al 2008].
  • Retinal cell transplant. Multiple studies have investigated the in vitro differentiation of embryonic and adult stem cells into retinal cell types and the in vivo transplantation of these cells, as well as fetal retinal cells, into animal retinas. Of several studies implanting fetal retinal cells into individuals with RP, two studies have shown variable improvement in visual function [Radtke et al 2004, Radtke et al 2008].
  • The bionic eye. Several prototypes of prostheses that electrically stimulate the inner retina have been tested in persons with RP who are blind. These devices have demonstrated the ability to induce posphenes as well as improve performance on some tests of visual function [Flynn et al 2001, Mokwa et al 2008].
  • Neurotrophic factors have shown promise in treating several animal models of RP. An intraocular implant which secretes ciliary neurotrophic factor (CNTF) has demonstrated safety in Phase I trials and is currently in Phase II/III trials for both RP and age-related macular degeneration [Dandekar et al 2004, Emerich & Thanos 2008].
  • Prolonged light deprivation has not been demonstrated to be effective in altering the progression of RP.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008;358:2231–9. [PubMed: 18441371]
  2. Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19:979–90. [PMC free article: PMC2940541] [PubMed: 18774912]
  3. Jin ZB, Gu F, Matsuda H, Yukawa N, Ma X, Nao-I N. Somatic and gonadal mosaicism in X-linked retinitis pigmentosa. Am J Med Genet A. 2007;143A:2544–8. [PubMed: 17935240]
  4. Lee SH, Yu HG, Seo JM, Moon SW, Moon JW, Kim SJ, Chung H. Hereditary and clinical features of retinitis pigmentosa in Koreans. J Korean Med Sci. 2010;25:918–23. [PMC free article: PMC2877238] [PubMed: 20514315]
  5. Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, Testa F, Mingozzi F, Bennicelli JL, Ying GS, Rossi S, Fulton A, Marshall KA, Banfi S, Chung DC, Morgan JI, Hauck B, Zelenaia O, Zhu X, Raffini L, Coppieters F, De Baere E, Shindler KS, Volpe NJ, Surace EM, Acerra C, Lyubarsky A, Redmond TM, Stone E, Sun J, McDonnell JW, Leroy BP, Simonelli F, Bennett J. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374:1597–605. [PubMed: 19854499]
  6. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358:2240–8. [PMC free article: PMC2829748] [PubMed: 18441370]
  7. Sandberg MA, Rosner B, Weigel-DiFranco C, McGee TL, Dryja TP, Berson EL. Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations. Invest Ophthalmol Vis Sci. 2007;48:1298–304. [PubMed: 17325176]
  8. Wright AF, Chakarova CF, Abd El-Aziz MM, Bhattacharya SS. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet. 2010;11:273–84. [PubMed: 20212494]

Chapter Notes

Author History

Stephen P Daiger, PhD (2000-present)
Abigail Fahim, MD, PhD (2013-present)
Roberta A Pagon, MD; University of Washington (2000-2013)
Richard G Weleber, MD, DABMG, FACMG (2013-present)

Revision History

  • 21 March 2013 (me) Comprehensive update posted live
  • 16 September 2005 (me) Comprehensive update posted to live Web site
  • 21 October 2004 (bp) Revision: PRPF3 added
  • 7 July 2004 (bp) Revision: Table 6; change in test availability
  • 19 April 2004 (bp) Revision: Clinical testing for PRPF8 available
  • 23 June 2003 (me) Comprehensive update posted to live Web site
  • 4 August 2000 (bp, me) Overview posted to live Web site
  • November 1997 (bp, sd) First draft
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