Known as RP, it is a genetic eye disorder that causes vision loss.
Symptoms include trouble seeing at night and decreased peripheral vision (side vision).
The onset of symptoms is generally gradual. As peripheral vision worsens, people may experience “tunnel vision.” Complete blindness is rare.
Retinitis pigmentosa is usually inherited from a person’s parents. Mutations in one of more than 50 genes are involved. The underlying mechanism involves the progressive loss of rod photoreceptor cells at the back of the eye.
This is generally followed by the loss of cone photoreceptor cells. Diagnosis is through an examination of the retina finding deposits of dark pigment.
Other supportive tests may include an electroretinogram , visual field tests, or genetic testing.
There is currently no cure for retinitis pigmentosa. Efforts to manage the problem may include the use of low vision aids, portable lighting, or a guide dog.
Vitamin A palmitate supplements may be helpful in delaying the worsening. A visual prosthesis may be an option for certain people with a serious illness.
It is estimated that it affects 1 in 4,000 people. The onset is often in childhood, but some are not affected until adulthood.
Signs and symptoms
The initial retinal degenerative symptoms of retinitis pigmentosa are characterized by decreased night vision (nyctalopia) and loss of the middle peripheral visual field.
Rod photoreceptor cells, which are responsible for low-light vision and are oriented at the periphery of the retina, are the retinal processes first affected during nonsyndromic forms of this disease.
Visual decline progresses relatively rapidly into the far peripheral field, eventually spreading into the central visual field as tunnel vision increases.
Visual acuity and color vision can be compromised due to associated abnormalities in the photoreceptor cells of the cone, which are responsible for color vision, visual acuity, and sight in the central visual field.
The progression of disease symptoms occurs symmetrically, with the left and right eyes experiencing symptoms at a similar rate.
A variety of indirect symptoms characterize retinitis pigmentosa along with the direct effects of degeneration of the initial rod photoreceptor and subsequent descent of the cone photoreceptors.
Phenomena such as photophobia, which describes the event in which light is perceived as an intense glare, and photopsia, the presence of flashing or bright lights within the visual field, often manifest during the later stages of Retinitis pigmentosa.
Findings related to Retinitis pigmentosa have often been characterized in the fundus as the “ophthalmic triad.”
This includes the development of:
- A mottled appearance of the retinal pigment epithelium (RPE) caused by the formation of bone spicules.
- A waxy appearance of the optic nerve.
- The attention of the blood vessels in the retina.
Non-syndromic Retinitis Pigmentosa usually has a variety of the following symptoms:
- Night blindness.
- Tunnel vision (due to loss of peripheral vision).
- Lattice vision.
- Photopsia (flashing / bright lights).
- Photophobia (aversion to bright lights).
- Development of bone spicules in the background.
- Slow adjustment from dark to light environments and vice versa.
- Blurry vision.
- Bad color separation.
- Loss of central vision.
- Eventual blindness.
Retinitis pigmentosa can be:
- Non-syndromic, that is, it occurs alone, without other clinical findings.
- Syndromic, with other neurosensory disorders, developmental abnormalities, or complex clinical findings.
- Secondary to other systemic diseases.
Retinitis pigmentosa combined with deafness (congenital or progressive) is called Usher syndrome.
Alport syndrome is associated with Retinitis pigmentosa and an abnormal glomerular-basement membrane leading to nephrotic syndrome and is inherited as X-linked dominant.
Retinitis pigmentosa combined with ophthalmoplegia, dysphagia, ataxia, and cardiac conduction defects is seen in mitochondrial DNA syndrome Kearns-Sayre syndrome (also known as torn red fiber myopathy)
Retinitis pigmentosa combined with retardation, peripheral neuropathy, acanthotic (stippled) red blood cells, ataxia, steatorrhea, and absence of very low-density lipoprotein are seen in abetalipoproteinemia.
Retinitis pigmentosa is seen clinically in association with other rare genetic disorders (such as muscular dystrophy and chronic granulomatous disease) as part of McLeod syndrome.
This is an X-linked recessive phenotype characterized by a complete absence of XK cell surface proteins and thus markedly reduced expression of all Kell red blood cell antigens.
For transfusion purposes, these patients are considered completely incompatible with all normal and K0 / K0 donors.
Retinitis pigmentosa associated with hypogonadism and developmental delay with an autosomal recessive inheritance pattern is seen with Bardet-Biedl syndrome.
Other conditions include neurosyphilis, toxoplasmosis, and Refsum’s disease.
Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration.
There are multiple genes that, when mutated, can cause the retinitis pigmentosa phenotype.
The inheritance patterns of Retinitis pigmentosa have been identified as autosomal dominant, autosomal recessive, X-linked, and maternally acquired (mitochondrial), and depend on specific mutations of the Retinitis pigmentosa gene present in the parental generation.
In 1989, a gene mutation was identified for rhodopsin, a pigment that plays an essential role in the visual transduction cascade that enables vision in low light conditions.
The rhodopsin gene encodes a major protein for the outer segments of photoreceptors.
Mutations in this gene most often present as missense or misfolded mutations of the rhodopsin protein, and most often follow autosomal dominant inheritance patterns.
Since the discovery of the rhodopsin gene, more than 100 RHO (rhodopsin) gene mutations have been identified, accounting for 15% of all types of retinal degeneration and approximately 25% of the autosomal dominant forms of Retinitis pigmentosa.
To date, up to 150 mutations in the opsin gene associated with Retinitis pigmentosa have been reported since the Pro23 His mutation in the intradiscal domain of the protein was first reported in 1990.
These mutations are found throughout the opsin gene and are distributed throughout the three domains of the protein (the intradiscal, transmembrane, and cytoplasmic domains).
One of the main biochemical causes of Retinitis pigmentosa in the case of rhodopsin mutations is protein misfolding and alteration of molecular chaperones.
The codon 23 mutation in the rhodopsin gene, in which proline is changed to histidine, was found to represent the largest fraction of rhodopsin mutations in the United States.
Several other studies have reported various codon mutations associated with retinitis pigmentosa, including Thr58Arg, Pro347Leu, Pro347Ser, as well as deletion of Ile-255.
In 2000, a rare mutation at codon 23 causing autosomal dominant retinitis pigmentosa was reported, in which proline was converted to alanine.
However, this study demonstrated that the retinal dystrophy associated with this mutation was characteristically mild in presentation and course. Furthermore, there was a greater conservation in electroretinography amplitudes than the more prevalent Pro23His mutation.
Autosomal recessive inheritance patterns of Retinitis pigmentosa have been identified in at least 45 genes.
This means that two unaffected individuals who are carriers of the same genetic mutation that induces Retinitis pigmentosa in dialelic form can produce offspring with the Retinitis pigmentosa phenotype.
A mutation in the USH2A gene is known to cause 10-15% of a syndromic form of Retinitis pigmentosa known as Usher Syndrome when inherited in an autosomal recessive manner.
Mutations in four pre-mRNA splicing factors are known to cause autosomal dominant retinitis pigmentosa. These are PRPF3 (human PRPF3 is HPRPF3, also PRP3), PRPF8, PRPF31, and PAP1.
These factors are expressed ubiquitously and it is proposed that defects in one ubiquitous factor (a protein expressed everywhere) should only cause disease in the retina because retinal photoreceptor cells have a much higher requirement for protein processing (rhodopsin). than any other type of cell.
Somatic or X-linked inheritance patterns of Retinitis pigmentosa are currently identified with mutations of six genes, the most common being at specific loci in the RPGR and RP2 genes.
A variety of defects in the retinal molecular pathway have been combined with multiple known mutations in the Retinitis Pigmentosa gene.
Mutations in the rhodopsin gene, which is responsible for most cases of autosomal dominant retinitis pigmentosa, disrupt the opsin rod protein essential for translating light into decipherable electrical signals within the phototransduction cascade of the central nervous system .
Defects in the activity of this G protein-coupled receptor are classified into different classes depending on the specific folding abnormality and the resulting molecular pathway defects.
The activity of the mutant Class I protein is compromised as specific point mutations in the protein-encoding amino acid sequence affect the transport of the pigment protein to the outer segment of the eye, where the phototransduction cascade is located.
Furthermore, the misfolding of class II rhodopsin gene mutations disrupts the protein’s conjunction with 11-cis-retinal to induce proper chromophore formation.
Additional mutants in this pigment-encoding gene affect protein stability, alter mRNA integrity after translation, and affect transducin and opsin optical protein activation rates.
Furthermore, animal models suggest that the retinal pigment epithelium is unable to engulf the dislodged outer rod segment discs, leading to an accumulation of outer rod segment debris.
In mice that are homozygous recessive for the retinal degeneration mutation, the rod photoreceptors stop developing and undergo degeneration before cell maturation is complete.
A defect in cGMP-phosphodiesterase has also been documented; this leads to toxic levels of cGMP.
An accurate diagnosis of retinitis pigmentosa is based on documentation of progressive loss photoreceptor cell function, confirmed by a combination of visual field and visual acuity tests, fundus, and electroretinography and optical coherence imaging (ERG).
Visual field and visual acuity tests measure and compare the size of the patient’s field of vision and the clarity of their visual perception with standard visual measurements associated with healthy 20/20 vision.
Clinical diagnostic features indicative of retinitis pigmentosa include a substantially small and progressively decreasing visual area on the visual field test, and compromised levels of clarity measured during the visual acuity test.
In addition, optical tomography, such as the fundus and the retina (optical coherence), provide other diagnostic tools to determine the diagnosis of Retinitis pigmentosa.
Photographing the back of the dilated eye allows to confirm the accumulation of bone spicules in the fundus, which occurs during the last stages of retinal degeneration of Retinitis pigmentosa.
Combined with cross-sectional images from optical coherence tomography, it provides clues on:
The thickness of the photoreceptors, the morphology of the retinal layer and the physiology of the retinal pigment epithelium, fundus images can help determine the stage of progression of Retinitis pigmentosa.
Although visual field and acuity test results combined with retinal imaging support the diagnosis of retinitis pigmentosa, additional testing is necessary to confirm other pathologic features of this disease.
Electroretinography (ERG) confirms the diagnosis of retinitis pigmentosa by evaluating the functional aspects associated with photoreceptor degeneration, and can detect physiological abnormalities before the initial manifestation of symptoms.
An electrode lens is applied to the eye as the response of the photoreceptors to varying degrees of fast light pulses is measured.
Patients exhibiting the retinitis pigmentosa phenotype would show a decreased or delayed electrical response in the rod photoreceptors, as well as a possibly compromised cone photoreceptor cellular response.
The patient’s family history is also considered when determining a diagnosis due to the genetic mode of inheritance of retinitis pigmentosa.
At least 35 different genes or loci are known to cause “non-syndromic retinitis pigmentosa” (Retinitis pigmentosa that is not the result of another disease or part of a broader syndrome).
Indications of the type of Retinitis pigmentosa mutation can be determined through DNA tests, which are available on a clinical basis for:
- RLBP1 (Autosomal recessive, Bothnia Retinitis pigmentosa type).
- RP1 (autosomal dominant, RP1).
- RHO (autosomal dominant, RP4).
- RDS (autosomal dominant, RP7).
- PRPF8 (autosomal dominant, RP13).
- PRPF3 (autosomal dominant, RP18).
- CRB1 (autosomal recessive, RP12).
- ABCA4 (autosomal recessive, RP19).
- RPE65 (autosomal recessive, RP20).
For all other genes (eg DHDDS), molecular genetic testing is available for research only.
Retinitis pigmentosa can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
X-linked Retinitis pigmentosa can be recessive, affecting mainly males only, or dominant, affecting both males and females, although males are generally more mildly affected.
Some digestive (controlled by two genes) and mitochondrial forms have also been described.
Genetic counseling depends on an accurate diagnosis, determination of the mode of inheritance in each family, and the results of molecular genetic testing.
There is currently no cure for retinitis pigmentosa, but the efficacy and safety of several prospective treatments are currently being evaluated.
The efficacy of various supplements, such as vitamin A, docosahexaenoic acid (DHA), and lutein, in slowing disease progression remains an unresolved, albeit prospective, treatment option.
Clinical trials investigating optical prosthetic devices, gene therapy mechanisms, and retinal lamina transplants are active areas of study in the partial restoration of vision in patients with retinitis pigmentosa.
Studies have shown delay in rod photoreceptor degeneration by taking 15,000 IU (equivalent to 4.5 mg) of vitamin A palmitate daily; therefore, disease progression stalls in some patients.
Recent research has shown that adequate vitamin A supplementation can postpone blindness for up to 10 years (reducing the loss from 10% pa to 8.3% per year) in some patients at certain stages of the disease.
The Argus retinal prosthesis became the first approved treatment for the disease in February 2011, and is currently available in Germany, France, Italy, and the United Kingdom. Interim results in 30 long-term patients were published in 2012.
The Argus II retinal implant has also received market approval in the US.
The device can help adults with Retinitis pigmentosa who have lost the ability to perceive shapes and movement to be more mobile and perform daily activities.
In June 2013, twelve US hospitals announced that they would soon accept consultation from patients with Retinitis pigmentosa in preparation for the launch of Argus II later that year.
The Alpha-IMS is a subretinal implant that involves the surgical implantation of a small image recording chip under the optic fovea.
Visual enhancement measures in Alpha-IMS studies require demonstration of device safety before proceeding with clinical trials and market approval.
The goal of gene therapy studies is to virally complement retinal cells expressing mutant genes associated with the retinitis pigmentosa phenotype with healthy forms of the gene.
Thus, it enables the repair and proper function of retinal photoreceptor cells in response to the instructions associated with the inserted healthy gene.
Clinical trials investigating the insertion of the healthy RPE65 gene into retinas expressing the LCA2 retinitis pigmentosa phenotype measured modest improvements in vision; however, retinal photoreceptor degradation continued at the disease-related rate.
Gene therapy can probably preserve the remaining healthy retinal cells without repairing the earlier accumulation of damage in the already diseased photoreceptor cells.
The response to gene therapy would theoretically benefit young patients who show the shortest progression of photoreceptor decline; therefore, it correlates with a greater possibility of cell rescue through the healthy inserted gene.
The progressive nature and lack of a definitive cure for retinitis pigmentosa contribute to the inevitably grim outlook for patients with this disease.
Although total blindness is rare, the patient’s visual acuity and field of vision will continue to decline as the rod photoreceptor advances and subsequent cone photoreceptor degradation.
Possible treatments remain in the research and clinical trial stages; however, treatment studies on visual restoration in retinitis pigmentosa hold promise for the future.
Studies indicate that children with the disease genotype benefit from presymptomatic counseling to prepare for the physical and social implications associated with progressive vision loss.
While the psychological prognosis may be slightly alleviated with active counseling, the physical implications and progression of the disease largely depend on the age of initial manifestation of symptoms and the rate of photoreceptor degradation, rather than access to prospective treatments.
Corrective visual aids and personalized vision therapy provided by Low Vision Specialists can help patients correct minor visual acuity disturbances and optimize the remaining visual field.
Support groups, vision insurance, and lifestyle therapy are helpful additional tools for those managing progressive visual impairment.
Retinitis pigmentosa is the leading cause of inherited blindness, with approximately 1 / 4,000 people experiencing the non-syndromic form of their disease in their lifetime. An estimated 1.5 million people worldwide are currently affected.
Early-onset retinitis pigmentosa occurs in the first few years of life and is typically associated with forms of syndromic disease, while late-onset retinitis pigmentosa arises from early to mid-adulthood.
The autosomal dominant and recessive forms of retinitis pigmentosa affect the male and female populations equally.
However, the less common form of the X-linked disease affects male receptors for the X-linked mutation, while females generally remain unaffected carriers of the Retinitis pigmentosa trait.
The X-linked forms of the disease are considered serious and usually lead to total blindness in later stages. On rare occasions, a dominant form of the X-linked gene mutation will affect males and females equally.
Due to the genetic inheritance patterns of Retinitis pigmentosa, many isolated populations exhibit higher disease frequencies or a higher prevalence of a specific Retinitis pigmentosa mutation.
Pre-existing or emerging mutations that contribute to rod photoreceptor degeneration in retinitis pigmentosa are transmitted through family lines.
Therefore, it allows certain cases of Retinitis Pigmentosa to be concentrated in specific geographic regions with an ancestral history of the disease.
Several hereditary studies have been conducted to determine variable prevalence rates in Maine (USA), Birmingham (England), Switzerland (affects 1/7000), Denmark (affects 1/2500), and Norway.
Navajo Indians also show a high inheritance rate for Retinitis pigmentosa, which is estimated to affect 1 in 1878 individuals.
Despite the increased frequency of Retinitis pigmentosa within specific family lines, the disease is considered non-discriminatory and tends to affect all world populations equally.
Future treatments may include retinal transplants, artificial retinal implants, gene therapy, stem cells, nutritional supplements, and / or drug therapies.
2006 : UK researchers transplanted stem cells from mice that were in an advanced stage of development, and already programmed to develop into photoreceptor cells.
In 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 restoring sight.
It was previously believed that the mature retina has no regenerative capacity. This research may lead to the use of human transplants to alleviate blindness in the future.
2008 : Scientists at the Osaka Institute of Biosciences have identified a protein, called Pikachurin, which they believe could lead to a treatment for retinitis pigmentosa.
2008 : An attempt was made to link retinitis pigmentosa with FAM46A gene expression.
2010 : A possible gene therapy appears to work in mice.
2012 : Scientists at Columbia University Medical Center showed in an animal model that gene therapy and induced pluripotent stem cell therapy could be viable options for treating retinitis pigmentosa in the future.
2012 : Scientists from the University of Miami presented data showing the protection of photoreceptors in an animal model when the eyes are injected with neurotrophic factor derived from midbrain astrocytes.
Researchers at the University of California at Berkeley were able to restore sight in blind mice by exploiting a “photo switch” that activates retinal ganglion cells in animals with damaged rod and cone cells.
2015 : a study by Bakondi et al. at Cedars-Sinai Medical Center demonstrated that CRISPR / Cas9 can be used to treat rats with the autosomal dominant form of retinitis pigmentosa.
2016 : RetroSense Therapeutics attempted to inject light-sensitive algae DNA viruses into the eyes of several blind people (who have retinitis pigmentosa). If successful, they will be able to see in black and white.