The causes and treatments of retinitis pigmentosa

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

In RP, loss of rod function dominates early in the clinical course. The first symptom of RP is usually defective dark adaptation or "night blindness." In general, the earlier the age of onset of defective dark adaptation is, the more severe the course of RP is. Although mid-peripheral vision loss occurs early in the disease, it is rarely recognized by the affected individual and isn't considered a presenting symptom. Affected individuals may be considered "clumsy" before constriction of visual fields (i.e., "tunnel vision") is detected.

Despite the fact that sensitive tests of cone function can document early cone association, central visual sharpness is usually maintained until the end stages of RP. Loss of central visual insight over time correlates with the presence of macular lesions early in the course. Most commonly, loss of central sharpness is caused by macular atrophy in advanced RP or less commonly from cystoid macular edema, which occurs in some individuals in the early stages of RP. It was found that there is a general correlation between age-related visual acuity and genetic subtype.

The fundus appearance in RP usually depends on the stage of the retinal degeneration. In the earliest stages, 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. 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 disease process.

Posterior subcapsular cataracts characterized by yellowish crystalline changes in the visual axis of the peripheral 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.

Dust-like particles in the vitreous are present in the great majority of individuals with RP. These are fine, colourless 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 are common and are of no clinical or diagnostic significance.

A rare occurrence in individuals with advanced RP is exudative vasculopathy associated with telangiectatic vessels, serous retinal detachment, and lipid deposition in the retina. The cause of exudative vasculopathy in RP is unknown.

Sector RP is a term used to describe changes in one quadrant or one half of each fundus. Most commonly, the inferonasal 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 usually lack symptoms of defective dark adaptation, although widespread abnormalities of rod and cone function are usually detected by ERG. Information about the natural history of sector RP is conflicting. Sectoral changes have been observed in autosomal dominant RP 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.

Differential Diagnosis:

It should be noted that individuals who suffer from the previous symptoms; photopsia (sensation of lights flashing), abnormal central vision, abnormal colour 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 RP:

Usher syndrome: The three types of Usher syndrome are inherited in an autosomal recessive manner. Individuals with Usher syndrome type 1 have congenital, profound, bilateral sensorineural hearing loss and no intelligible speech. All affected individuals have abnormalities of vestibular nerve function detected on caloric testing and associated mild, non-progressive ataxia. Individuals with Usher syndrome type 2 have a mild-to-profound congenital sensorineural hearing impairment, normal vestibular responses, and late-adolescent-to-young-adult-onset RP. Individuals with Usher syndrome type 3 have bilateral progressive sensorineural hearing loss and RP.

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. 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 midperiphery and gradually coalesce into pale yellow confluent areas.

Cone-rod dystrophy: sometimes called inverse or central RP, is characterized by bilateral and symmetric loss of cone function in the presence of reduced rod function. Like the term RP, the term "cone-rod dystrophy" refers to a group of disorders. In the cone-rod dystrophies, loss of central visual acuity, photoaversion, and color vision defects appear before peripheral visual loss and defective dark adaptation. Cone-rod dystrophies tend to have early onset. The fundus changes may be similar to those of RP. Cone-rod dystrophies are often syndromic; examples include Alström syndrome, Bardet-Beidl syndrome, and the neuronal ceroid lipofuscinoses.

Leber congenital amaurosis (LCA): a severe dystrophy of the retina, typically becomes evident in the first year of life. 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) 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.

Seven genes are currently known to be associated with LCA: CRX, CRB1, GUCY2D, AIPL1, RDH12, RPGRIP1, and RPE65. Together these genes are estimated to account for, depending on the survey, from one-third to one-half of the cases of LCA. Two other disease loci for LCA have been reported. Most often, LCA is inherited in an autosomal recessive manner; rarely, it is inherited in an autosomal dominant manner as a result of mutations within the CRX gene.

Retinal-renal Senior Loken syndrome: Ten% of individuals with nephronophthisis, the most frequent genetic cause of chronic renal failure in children, have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome. Mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), is the most frequent cause of Senior-Loken syndrome.

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.

Unilateral RP: Unilateral RP refers to unilateral functional and ophthalmoscopic changes, which are typical of RP resulting from a variety of causes, some of which may be genetic.

Prevalence:

The prevalence of RP is 19 to 27 per 100,000. The prevalence in the US and Europe is approximately 1/3,500 to 1/4,000. RP shows no ethnic specificity, but RP caused by mutations in particular genes may be more frequent in certain isolated or consanguineous populations.

Causes:

RP is classified as nonsyndromic, or "simple" (not affecting other organs or tissues); syndromic (affecting other systems such as hearing); or systemic (affecting multiple tissues). Nonsyndromic RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner.

Mode of Inheritance

Proportion of All RP

Autosomal dominant RP (adRP)

15-25%

Autosomal recessive RP (arRP)

5-20%

X-linked RP (xlRP)

5-15%

Unknown: Simplex

40-50%

Digenic RP

Very rare

Gene mapping and gene discovery have revealed that the molecular genetic causes of RP are unusually complicated. Genes associated with RP encode proteins that are involved in photo-transduction (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, and photoreceptor cell transcription factors. However, the function of many genes associated with RP remains unknown.

The complexity is clear in genetic heterogeneity; that is, many different genes may cause the same disease. For most RP genes, many different disease-causing mutations have been identified, although in most cases a few specific mutations are "common" among affected individuals. In addition to the multiplicity of mutations, different mutations in the same gene may cause different diseases. For example, different mutations in RHO, the gene encoding rodopsin, may cause autosomal dominant RP, autosomal dominant congenital stationary night blindness, or, rarely, autosomal recessive RP. Mutations in RDS, the gene encoding peripherin, may cause autosomal dominant RP, autosomal dominant macular degeneration, or 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 factors.

Autosomal Dominant RP (adRP):

Three genes; RHO, RP1 and RDS make up approximately 25% to 30%, 5% to 10%, and 5% to 10% of adRP cases, respectively. One RHO mutation of 100, P23H, with distinct sectorial disease, is found in approximately 10% of Americans affected with adRP.

RDS mutations are associated with clinical phenotypes ranging from RP to macular degeneration to complex maculopathies.

From known RP1 mutations; two, Arg677stop and 2280del5, make up half of adRP cases caused by this gene.

Other cloned adRP genes, such as PRPF31, cause a substantial fraction of cases, but the specific occurrence is not yet known.

This table shows genes causing autosomal dominant RP (adRP) (in Chromosomal Order)

Locus Name

Gene Symbol

Chromosomal Locus

Protein Name

Causes

% of adRP

RP18

PRPF3

1q21.2

small nuclear ribonucleoprotein Prp3

 

Several families

RP4

RHO

3q21-q24

Rhodopsin

Recessive RP;  dominant CSNB

25-30%

RP7

RDS

6p21.1-cen

Peripherin

Dominant MD; digenic RP with ROM1

5-10%

RP9

RP9

7p14.2

Retinitis pigmentosa 9 protein

 

Unknown

RP10

IMPDH1

7q31.3-q32

Inosine 5'- 

monophosphate dehydrogenase 1

 

3-5%

RP1

RP1

8q11-q13

Oxygen-regulated protein 1

 

5-10%

 

ROM1

11q13

Rod outer segment membrane protein 1

Digenic RP with RDS

Rare

RP27

NRL

14q11.1-q11.2

Neural retina-specific leucine zipper protein

Autosomal recessive RP

Rare

RP13

PRPF8

17p13.3

Pre-mRNA processing splicing-factor 8

 

Unknown

RP17

CA4

17q23

Carbonic anhydrase IV

 

Unknown

RP30

FSCN2

17q25

Fascin 2

 

3% of Japanese with adRP

 

CRX

19q13.3

Cone-rod homeobox protein

Dominant CORD  3, dominant and recessive LCA 

Rare

RP11

PRPF31

19q13.4

U4/U6 snRNP-associated 61-kD protein

 

15-20%

Where:

CSNB= congenital stationary night blindness

MD= macular dystrophy

CORD= cone rod dystrophy

LCA= Leber congenital amaurosis

Autosomal Recessive RP (arRP):

Most of the arRP genes are rare, causing 1% or fewer cases, but RPE65 (expressed in the RPE), and PDE6A and PDE6B (phosphodiesterase subunits in the phototransduction cascade), cause 2-5% of cases; mutations in USH2A, which can also cause Usher syndrome, may account for up to 5% of arRP cases. Mutations in a few genes are common causes of arRP in specific populations - such as RP25 in Spain - but are rare in a different place. The symptoms of these diseases may overlap with other autosomal recessive retinopathies. In particular, autosomal recessive, early-onset RP and Leber congenital amaurosis (LCA) are very similar.

This table shows genes causing autosomal recessive RP (arRP) (in Chromosomal Order)

Locus Name

Gene Symbol

Chromosomal Locus

Protein Name

Causes

% of arRP

RP20/LCA2

RPE65

1p31

Retinal pigment epithelium-specific 65-kD protein

LCA1 (7-16%)

2%

RP19

ABCA4

1p21-p13

Retinal-specific ATP-binding cassette transporter

Recessive Starga dt disease, and cone-rod dystrophy

~5% 2

RP12

CRB1

1q31-q32.1

Crumbs protein homolog 1

Recessive RP with para-arteriolar preservation of the RPE (PPRPE); LCA (9-13%)

Rare

 

USH2A

1q41

Usher syndrome type IIa protein

Usher syndrome, type 2

4-5%

RP28

 

2p15-p11

Unknown

 

One family

 

MERTK

2q14.1

Proto-oncogene tyrosine-protein kinase MER tyrosine kinase

 

Rare

RP26

CERKL

2q31.2-q32.3

Ceramide kinase-like protein

 

Rare

 

SAG

2q37.1

S-arrestin

Recessive Oguchi disease

Rare

RP4

RHO

3q21-q24

Rhodopsin

Dominant RP; Dominant CSNB  3

Rare

CSNB3

PDE6B

4p16.3

Rod cGMP-specific 3', 5'-cyclic phosphodiesterase beta-subunit

Dominant CSNB

3-4%

 

CNGA1

4p12-cen

cGMP-gated cation channel alpha 1

 

Rare

RP29

 

4q32-q34

Unknown

 

Rare; 4 families

 

LRAT

4q31

Lecithin retinol acyltransferase

 

Unknown

 

PDE6A

5q31.2-q34

Rod cGMP-specific 3', 5'-cyclic phosphodiesterase alpha-subunit

 

3-4%

RP14

TULP1

6p21.3

Tubby-related 

protein 1

 

Rare

RP25

 

6q14-q21

Unknown

 

10-20% of arRP in Spain

 

RGR

10q23

RPE-retinal G protein-coupled receptor

Dominant choroidal sclerosis

Unknown

RP27

NRL

14q11.1-q11.2

Neural retina-specific leucine zipper protein

Dominant RP

 

 

NR2E3

15q23

Photoreceptor-specific nuclear receptor

Recessive enhanced S-cone syndrome

Rare; found in Sephardic Jews in Portugal

 

RLBP1

15q26

Cellular retinaldehyde-binding protein

Recessive Bothnia dystrophy;  recessive retinitis punctata albescans; 

Unknown

RP22

 

16p12.3-p12.1

Unknown

 

Rare

 

CNGB1

16q13

Cyclic-nucleotide-gated cation

 

 

Where:

LCA= Leber congenital amaurosis

CSNB= congenital stationary night blindness

X-Linked RP:

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%, respectively, of X-linked RP. Earlier studies of RPGR failed to find mutations in a majority of families mapped to RP3; however, identification of an additional exon in RPGR (ORF15) has significantly increased the mutation detection rate. ORF15 is also the site of most or all dominant-acting mutations at this locus.

An important diagnostic complication is that carrier females may express mild retinal degeneration. Therefore, families with X-linked inheritance of RP with affected females can be mistaken for families with adRP. Typically, though, retinal disease in affected females with X-linked RP is much less severe than that seen in males, in contrast to adRP, in which males and females are, on average, equally affected.

This table shows Genes Causing X-Linked RP (xlRP) (in Chromosomal Order)

Locus Name

Gene Symbol

Chromosomal Locus

Protein Name

Causes

Percent of arRP

RP20/LCA2

RPE65

1p31

Retinal pigment epithelium-specific 65-kD protein

LCA  1 (7-16%)

2%

RP19

ABCA4

1p21-p13

Retinal-specific ATP-binding cassette transporter

Recessive Stargardt disease, and cone-rod dystrophy

~5%  2

RP12

CRB1

1q31-q32.1

Crumbs protein homolog 1

Recessive RP with para-arteriolar preservation of the RPE (PPRPE); LCA (9-13%)

Rare

 

USH2A

1q41

Usher syndrome type IIa protein

Usher syndrome, type 2

4-5%

RP28

 

2p15-p11

Unknown

 

One family

 

MERTK

2q14.1

Proto-oncogene tyrosine-protein kinase MER tyrosine kinase

 

Rare

RP26

CERKL

2q31.2-q32.3

Ceramide kinase-like protein

 

Rare

 

SAG

2q37.1

S-arrestin

Recessive Oguchi

Rare

RP4

RHO

3q21-q24

Rhodopsin

Dominant RP; Dominant CSNB  3

Rare

CSNB3

PDE6B

4p16.3

Rod cGMP-specific 3', 5'-cyclic phosphodiesterase beta-subunit

Dominant CSNB

3-4%

 

CNGA1

4p12-cen

cGMP-gated cation channel alpha 1

 

Rare

RP29

 

4q32-q34

Unknown

 

Rare; 4 families

 

LRAT

4q31

Lecithin retinol acyltransferase

 

Unknown

 

PDE6A

5q31.2-q34

Rod cGMP-specific 3', 5'-cyclic phosphodiesterase alpha-subunit

 

3-4%

RP14

TULP1

6p21.3

Tubby-related 

protein 1

 

Rare

RP25

 

6q14-q21

Unknown

 

10-20% of arRP in Spain

 

RGR

10q23

RPE-retinal G protein-coupled receptor

Dominant choroidal sclerosis

Unknown

RP27

NRL

14q11.1-q11.2

Neural retina-specific leucine zipper protein

Dominant RP

 

 

NR2E3

15q23

Photoreceptor-specific nuclear receptor

Recessive enhanced S-cone syndrome

Rare; found in Sephardic Jews in Portugal

 

RLBP1

15q26

Cellular retinaldehyde-binding protein

Recessive Bothnia dystrophy;  recessive retinitis punctata albescans

Unknown

RP22

 

16p12.3-p12.1

Unknown

 

Rare

 

CNGB1

16q13

Cyclic-nucleotide-gated cation channel 4

 

 

Digenic RP:

Digenic RP is caused by the simultaneous presence of a mutation in the RDS gene and a mutation in the ROM1 gene.

Risk of Inheritance to Family Members:

Autosomal Dominant RP

Parents of a proband: Most individuals who are suffering from autosomal dominant retinitis pigmentosa will have an affected parent, although occasionally the family history will be 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, reduced penetrance of the mutant allele in an asymptomatic parent, or a de novo mutation for retinitis pigmentosa.

Sibs of a proband: (sibs are people who share at least one parent. A male sibling is called a brother; and a female sibling is called a sister). The risk to sibs depends upon 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%.

Offspring of a proband: Each child of an individual with autosomal dominant RP has a 50% chance of inheriting the mutation.

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 sib 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. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Heterozygotes are asymptomatic.

Offspring of a proband: All offspring are obligate carriers.

Carrier Detection:

Carrier testing for at-risk family members is available on a clinical basis for RLBP1, CRB1, ABCA4, and RPE65 mutations once the disease-causing mutations have been identified in the proband.

X-Linked Recessive RP

Parents of a proband: Women who have an affected son and another affected male relative are obligate heterozygotes. If pedigree analysis reveals that an affected male represents a simplex case, several possibilities regarding his mother's carrier status need to be considered:

He has a de novo disease-causing mutation and his mother is not a carrier.

His mother has a de novo disease-causing mutation either a) as a "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body); or b) as "germline mosaicism" (i.e., present in her germ cells only).

His maternal grandmother has a de novo disease-causing mutation.

Sibs of a proband: The risk to sibs depends upon the genetic status of the proband's mother. A female who is a carrier has a 50% chance of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers and may or may not have symptoms.

Offspring of a proband: All the daughters of an affected male are carriers; none of his sons will be affected.

Digenic Inheritance

Parents of a proband: The parents are obligate heterozygotes; one parent carries an RDS mutation and the other parent carries an ROM1 mutation. Heterozygotes are asymptomatic.

Sibs of a proband: At conception, each sib has a 25% chance of having RP, a 25% chance of being an asymptomatic carrier of the RDS mutation, a 25% chance of being an asymptomatic carrier of the ROM1 mutation, and a 25% chance of being unaffected and not a carrier of either mutation. Once an at-risk sib is known to be hearing, the chance of his/her being a carrier is 2/3. Heterozygotes are asymptomatic.

Offspring of a proband: All offspring are carriers of either the RDS mutation or the ROM1 mutation.

Treatment of Retinitis Pigmentosa:

Vitamin A/beta-carotene: antioxidants may be useful in treating patients with RP, but no clear, prospective evidence in favor of vitamin supplementation yet exists. A recent comprehensive epidemiologic study concluded that very high daily doses of vitamin A palmitate (15,000 U/d) slow the progress of RP by about 2% per year. The effects are modest; therefore, this treatment must be weighed against the uncertain risk of long-term adverse effects from large chronic doses of vitamin A. Annually check liver enzymes and vitamin A levels. Beta-carotene doses of 25,000 IU have been recommended.

Optical aids: 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.

Gene therapy is under investigation, with the hope to replace the defective protein by using DNA vector (e.g., adenovirus, lentivirus). Gene therapy was successful in providing the missing protein to a dog with Leger congenital amaurosis. Using adeno-associated virus (AAV), the Briard dog with RPE65 mutations after treatment had 20% of its RPE cells express the functional protein, thereby allowing the dog to see. This was also effective in a mouse model of Leber congenital amaurosis.

Microchip implants that go inside the retina are in the early stages of development for treating blindness associated with this condition.

Stem cells: UK Researchers working with mice, transplanted mouse stem cells which were at an advanced stage of development, and already programmed to develop into photoreceptor cells, into mice that had been genetically induced to mimic the human conditions of retinitis pigmentosa and age-related macular degeneration. These photoreceptors developed and made the necessary neural connections to the animal's retinal nerve cells, a key step in the restoration of sight. Previously it was believed that the mature retina has no regenerative ability. This research may in the future lead to using transplants in humans to relieve blindness.

Scientists at the Osaka Bioscience Institute have identified a protein, named Pikachurin, which they believe could lead to a treatment for retinitis pigmentosa.

Agents to Avoid:

Vitamin E: 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).

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