Retinitis pigmentosa (RP) is a member of a group of
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
s called inherited retinal dystrophy (IRD) that cause
loss of vision.
[ Symptoms include trouble seeing at night and decreasing peripheral vision (side and upper or lower visual field).][ As peripheral vision worsens, people may experience " tunnel vision".][ Complete ]blindness
Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...
is uncommon. Onset of symptoms is generally gradual and often begins in childhood.[
Retinitis pigmentosa is generally inherited from one or both parents.] It is caused by genetic variants in nearly 100 genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.[ The underlying mechanism involves the progressive loss of rod ]photoreceptor cell
A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light (visible electromagnetic radiation ...
s that line the retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
of the eyeball.[ The ]rod cell
Rod cells are photoreceptor cells in the retina of the eye that can function in lower light better than the other type of visual photoreceptor, cone cells. Rods are usually found concentrated at the outer edges of the retina and are used in ...
s secrete a neuroprotective substance (rod-derived cone viability factor, RdCVF) that protects the cone cells from apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. When these rod cells die, this substance is no longer provided. This is generally followed by the loss of cone photoreceptor cells.[ Diagnosis is through eye examination of the retina finding dark pigment deposits caused by the rupture of the underlying retinal pigmented epithelial cells, given that these cells contain melanin.][ Other supportive testing may include the electroretinogram (ERG), visual field testing (VFT), ocular coherence tomography (OCT) and DNA testing to determine the gene responsible for a person's particular type of RP.][
There is currently no cure for retinitis pigmentosa.][ Efforts to manage the problem may include the use of low vision aids, portable lighting, or orientation and mobility training.][ Vitamin A palmitate supplements may be useful to slow progression.][ A visual prosthesis may be an option for people with severe symptoms.][
There is only one FDA-approved gene therapy that is commercially available to RP patients with Leber congenital amaurosis type 2. It replaces the miscoded RPE65 protein that is produced within the retinal pigmented epithelium. It has been found to be effective in approximately 50% of the patients who receive the therapy. The earlier a child receives the RPE65 therapy, the better their chances are for a positive outcome. There are many other therapies being researched at this time, with the goal of being approved in the next few years.
It is estimated to affect 1 in 4,000 people.]
Signs and symptoms
The initial retinal degenerative symptoms of retinitis pigmentosa are characterized by decreased night vision
Night vision is the ability to see in low-light conditions, either naturally with scotopic vision or through a night-vision device. Night vision requires both sufficient spectral range and sufficient intensity range. Humans have poor night v ...
( nyctalopia) and the loss of the mid-peripheral visual field. The rod photoreceptor cells, which are responsible for low-light vision and are orientated mainly in the retinal periphery, are the retinal processes affected first during non-syndromic (without other conditions) forms of this disease. Visual decline progresses relatively quickly to the far peripheral field, eventually extending into the central visual field as tunnel vision increases. Visual acuity
Visual acuity (VA) commonly refers to the clarity of visual perception, vision, but technically rates an animal's ability to recognize small details with precision. Visual acuity depends on optical and neural factors. Optical factors of the eye ...
and color vision can become compromised due to accompanying loss of the cone photoreceptor cells, which are responsible for color vision, visual acuity, and sight in the central visual field. The progression of disease occurs in both eyes in a similar but not identical pattern. A variety of indirect symptoms characterize retinitis pigmentosa along with the direct effects of the initial rod photoreceptor degeneration and later cone photoreceptor decline. Phenomena such as photophobia
Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence o ...
in which light is perceived as an intense glare, and photopsia, the presence of blinking, swirling or shimmering lights spontaneously occurring within the visual field, often manifest during the later stages of RP.
Findings related to RP have often been characterized in the fundus (back layer) of the eye as the "ophthalmic triad". This includes the development of (1) a mottled appearance of the retina and retinal pigment epithelium (RPE) that gives the same visual appearance of bone spicule patterns (but are not bone spicules), (2) a waxy yellow appearance of the optic disk, and (3) the attenuation
In physics, attenuation (in some contexts, extinction) is the gradual loss of flux intensity through a Transmission medium, medium. For instance, dark glasses attenuate sunlight, lead attenuates X-rays, and water and air attenuate both light and ...
of blood vessels in size and arterial/venous ratio as they enter and exit the optic disk of the retina and transverse it.
Non-syndromic RP (RP appears alone without other co-morbidities) usually presents a variety of the following symptoms:
* Night blindness
* Tunnel vision (due to loss of peripheral vision)
* Latticework vision (due to patchy loss of peripheral vision)
* loss of depth perception
Depth perception is the ability to perceive distance to objects in the world using the visual system and visual perception. It is a major factor in perceiving the world in three dimensions.
Depth sensation is the corresponding term for non-hum ...
* Photopsia (Spontaneously occurring flashes/blinking/swirling/shimmering lights)
* Photophobia
Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence o ...
(aversion to bright lights)
* Development of the appearance of melanin pigment in a bone spicule pattern in the fundus (not bone tissue)
* Slow adjustment from dark to light environments and vice versa
* Blurring of vision
* Poor color separation
* Central vision towards the end of progression, because this is a disease of the rods, and the cones are mostly responsible for central vision ( macula and fovea)
* Eventual partial or total blindness
Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...
. The majority of patients do not become totally blind, often retaining limited or non-functional vision.
Causes
RP may be:
(1) non-syndromic, that is, it occurs alone, without any other clinical findings,
(2) syndromic, with other neurosensory disorders, developmental abnormalities, or complex clinical findings, or
(3) secondary to other systemic diseases.
* RP combined with deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...
(congenital
A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
or progressive) is called Usher syndrome.
* Alport's syndrome is associated with RP and an abnormal glomerular-basement membrane leading to nephrotic syndrome. It is inherited as X-linked dominant.
* RP combined with ophthalmoplegia, dysphagia
Dysphagia is difficulty in swallowing. Although classified under " symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right.
It may be a sensation that suggests difficulty in the passage of solids or l ...
, ataxia
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
, and cardiac conduction defects is seen in the mitochondrial DNA
Mitochondrial DNA (mtDNA and mDNA) is the DNA located in the mitochondrion, mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the D ...
disorder Kearns–Sayre syndrome (also known as Ragged Red Fiber Myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...
).
* RP combined with intellectual disability, peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
, acanthotic (spiked) RBCs, ataxia, steatorrhea
Steatorrhea (or steatorrhoea) is the presence of excess fat in Human feces, feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incon ...
, and absence of VLDL is seen in abetalipoproteinemia.
* RP is seen clinically in association with several other rare genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
s (including muscular dystrophy
Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...
and chronic granulomatous disease) as part of McLeod syndrome. This is an X-linked recessive phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
characterized by a complete absence of XK cell surface proteins, and therefore 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.
* RP associated with hypogonadism
Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...
, and developmental delay with an autosomal recessive inheritance
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
pattern is seen with Bardet–Biedl syndrome.
Other conditions include neurosyphilis, toxoplasmosis and Refsum's disease.
Acquired conditions resulting in ophthalmoscopic findings resembling RP include eye inflammation associated with infection in early age ( rubella, syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
, toxoplasmosis, herpesvirus), autoimmune paraneoplastic retinopathy, drug toxicity ( phenothiazines and chloroquine, less commonly with thioridazine and hydroxychloroquine), diffuse unilateral subacute neuroretinitis and eye trauma. Acquired conditions may be unilateral or bilateral, and static or progressive.
Genetics
Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration.
There are multiple genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
that code for proteins needed in the visual pathway that, when mutated
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral rep ...
, can cause the retinitis pigmentosa phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
. Inheritance patterns of RP have been identified as autosomal dominant, autosomal recessive, X-linked, and maternally ( mitochondrially) acquired, and are dependent on the specific RP gene mutations present in the parental generation. Autosomal Dominant RP Type 11 (PRPF-31) can be inherited as a genotype only because of incomplete penetrance, and is thus coded for in the DNA but does not manifest the disease as a phenotype. In 1989, a mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
of the gene for rhodopsin
Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...
, a pigment
A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), chemically unreactive in water or another medium; in contrast, dyes are colored sub ...
that plays an essential part in the visual transduction cascade enabling vision in low-light conditions, was identified. The rhodopsin gene encodes a principal protein of photoreceptor outer segments. Mutations in this gene most commonly presents as missense mutations or misfolding of the rhodopsin protein, and most frequently follow autosomal dominant inheritance patterns. Since the discovery of the rhodopsin gene, more than 100 RHO mutations have been identified, accounting for 15% of all types of retinal degeneration, and approximately 25% of autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
forms of RP.
Over 100 mutations have been reported to date in the opsin
Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become retinylidene proteins, but are usually still called opsins regardless. Most pro ...
gene associated with RP since the Pro23His mutation in the intradiscal domain of the protein was first reported in 1990. These mutations are found throughout the opsin gene and are distributed along the three domains of the protein (the intradiscal, transmembrane
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
, and cytoplasmic
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...
domains). One of the main biochemical
Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...
causes of RP in the case of rhodopsin mutations is protein misfolding, and the disruption of molecular chaperones. The mutation of codon 23 in the rhodopsin gene, in which proline is changed to histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
, accounts for the largest fraction of rhodopsin mutations in the United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
. 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 in codon 23 was reported causing autosomal dominant retinitis pigmentosa, in which proline changed to alanine
Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...
. However, this study showed that the retinal dystrophy associated with this mutation was characteristically mild in presentation and course. Furthermore, there was greater preservation in electroretinography amplitudes than the more prevalent Pro23His mutation.
Autosomal recessive inheritance patterns of RP have been identified in at least 45 genes. This means that two unaffected individuals who are carriers of the same RP-inducing gene mutation in diallelic form can produce offspring with the RP phenotype. A mutation on the USH2A gene is known to cause 10-15% of a syndromic form of RP known as Usher's Syndrome when inherited in an autosomal recessive fashion.
Mutations in four pre-mRNA
A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by Transcription (genetics), transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcript ...
splicing factors are known to cause autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
retinitis pigmentosa. These are PRPF3 (human PRPF3 is HPRPF3; also PRP3), PRPF8, PRPF31 and PAP1. These factors are ubiquitously expressed and it is proposed that defects in a ubiquitous factor (a protein expressed everywhere) should only cause disease in the retina
The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...
because the retinal photoreceptor cells have a far greater requirement for protein processing (rhodopsin
Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...
) than any other cell type.
The somatic, or X-linked inheritance patterns of RP are currently identified with the mutations of six genes, the most common occurring at specific loci in the RPGR and RP2 genes.
Types include:
Pathophysiology
A variety of retinal molecular pathway defects have been matched to multiple known RP gene mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s. Mutations in the rhodopsin
Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...
gene (''RHO''), which is responsible for the majority of autosomal-dominantly inherited RP cases, disrupts the rhodopsin protein essential for translating light into decipherable electrical signals within the phototransduction cascade of the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
. Defects in the activity of this G-protein-coupled receptor are classified into distinct classes that depend on the specific folding abnormality and the resulting molecular pathway defects. The Class I mutant protein's activity is compromised as specific point mutations in the protein-coding amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
sequence affect the pigment protein's transport to the outer segment of the eye, where the phototransduction cascade is localized. Additionally, the misfolding of Class II rhodopsin gene mutations disrupts the protein's conjunction with 11-cis-retinal to induce proper chromophore
A chromophore is the part of a molecule responsible for its color. The word is derived .
The color that is seen by our eyes is that of the light not Absorption (electromagnetic radiation), absorbed by the reflecting object within a certain wavele ...
formation. Additional mutants in this pigment-encoding gene affect protein stability, disrupt mRNA integrity post-translationally, and affect the activation rates of transducin
Transducin (Gt) is a protein naturally expressed in vertebrate retina rods and cones and it is very important in vertebrate phototransduction. It is a type of heterotrimeric G-protein with different α subunits in rod and cone photoreceptors.
...
and opsin
Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become retinylidene proteins, but are usually still called opsins regardless. Most pro ...
optical proteins.
Additionally, animal models suggest that the retinal pigment epithelium fails to phagocytose the outer rod segment discs that have been shed, leading to an accumulation of outer rod segment debris. In mice that are homozygous recessive for retinal degeneration mutation, rod photoreceptors stop developing and undergo degeneration before cellular maturation completes. A defect in cGMP-phosphodiesterase has also been documented; this leads to toxic levels of cGMP.
Oxidative damage associated with lipid peroxidation is a potential cause of cone cell death in retinitis pigmentosa.
Diagnosis
An accurate diagnosis
Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...
of retinitis pigmentosa relies on the documentation of the progressive loss of photoreceptor cell
A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light (visible electromagnetic radiation ...
function, confirmed by a combination of visual field and visual acuity
Visual acuity (VA) commonly refers to the clarity of visual perception, vision, but technically rates an animal's ability to recognize small details with precision. Visual acuity depends on optical and neural factors. Optical factors of the eye ...
tests, fundus and optical coherence imagery, and electroretinography (ERG).
Visual field and acuity tests measure and compare the size of the patient's field of vision and the clarity of their visual perception with the 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 in the visual field test, and compromised levels of clarity measured during the visual acuity test. Additionally, optical tomography such as fundus and retinal (optical coherence) imagery provide further diagnostic tools when determining an RP diagnosis. Photographing the back of the dilated eye allows the confirmation of bone spicule accumulation in the fundus, which presents during the later stages of RP retinal degeneration. Combined with cross-sectional imagery of optical coherence tomography, which provides clues into photoreceptor thickness, retinal layer morphology, and retinal pigment epithelium physiology, fundus imagery can help determine the state of RP progression.
While visual field and acuity test results combined with retinal imagery support the diagnosis of retinitis pigmentosa, additional testing is necessary to confirm other pathological features of this disease. Electroretinography (ERG) confirms the RP diagnosis by evaluating 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 photoreceptor response to varying degrees of quick light pulses is measured. Patients exhibiting the retinitis pigmentosa phenotype would show decreased or delayed electrical response in the rod photoreceptors, as well as possibly compromised cone photoreceptor cell 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 gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s or loci are known to cause nonsyndromic RP. Indications of the RP mutation type can be determined through DNA testing, which is available on a clinical basis for:
* (autosomal recessive, Bothnia type RP)
* (autosomal dominant, RP1)
* (autosomal dominant, RP4)
* (autosomal dominant, RP7)
* (autosomal dominant, RP13)
* (autosomal dominant, RP18)
* CRB1 (autosomal recessive, RP12)
* (autosomal recessive, RP19)
* (autosomal recessive, RP20)
For all other genes (e.g. DHDDS), molecular genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
is available on a research basis only.
RP can be inherited in an autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
, autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
, X-linked or Y-linked manner. X-linked RP can be either recessive, affecting primarily only males, or dominant, affecting both males and females, although males are usually more mildly affected. Some digenic (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 results of molecular genetic testing.
Treatment
There is currently no cure for retinitis pigmentosa, but the efficacy and safety of various prospective treatments are currently being evaluated. The efficiency of various supplements, such as vitamin A, DHA, NAC, and lutein, in delaying disease progression remains an unresolved, yet prospective treatment option. Clinical trials investigating optic prosthetic devices, gene therapy mechanisms, and retinal sheet transplantations are active areas of study in the partial restoration of vision in retinitis pigmentosa patients.
Stalling of disease
Studies have demonstrated the delay of rod photoreceptor degeneration by the daily intake of 15000 IU (equivalent to 4.5 mg) of vitamin A palmitate; thus, stalling disease progression in some patients. Recent investigations have shown that proper vitamin A
Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...
supplementation can postpone blindness by up to 10 years (by reducing the 10% loss pa to 8.3% pa) in some patients in certain stages of the disease.
Bone marrow derived stem cells (BMSC)
MD Stem Cells, a clinical research company using autologous bone marrow derived stem cells (BMSC) in the treatment of retinal and optic nerve disease, published results from the Retinitis Pigmentosa cohort within their ongoing NIH registered Stem Cell Ophthalmology Study II (SCOTS2) clinical trial (NCT 03011541). Outcomes were encouraging with 45.5% of eyes showing an average of 7.9 lines of improvement (40.9% LogMAR improvement over baseline) and 45.5% of eyes showing stable acuity over the follow-up. Results were statistically significant(p=0.016). Retinitis Pigmentosa continues to be treated and evaluated in the study.
Argus retinal prosthesis
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 UK. Interim results on 30 patients long term trials were published in 2012. The Argus II retinal implant has also received market approval in the US. The device may help adults with RP who have lost the ability to perceive shapes and movement to be more mobile and to perform day-to-day activities. In June 2013, twelve hospitals in the US announced they would soon accept consultation for patients with RP in preparation for the launch of Argus II later that year. The Alpha-IMS is a subretinal implant involving the surgical implantation of a small image-recording chip beneath the optic fovea. Measures of visual improvements from Alpha-IMS studies require the demonstration of the device's safety before proceeding with clinical trials and granting market approval.
Gene therapy
The goal of gene therapy studies is to virally supplement retinal cells expressing mutant genes associated with the retinitis pigmentosa phenotype with healthy forms of the gene; thus, allowing the repair and proper functioning 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 in retinas expressing the LCA2 retinitis pigmentosa phenotype measured modest improvements in vision; however, the degradation of retinal photoreceptors continued at the disease-related rate. Likely, gene therapy may preserve remaining healthy retinal cells while failing to repair the earlier accumulation of damage in already diseased photoreceptor cells.[ Response to gene therapy would theoretically benefit young patients exhibiting the shortest progression of photoreceptor decline; thus, correlating to a higher possibility of cell rescue via the healthy inserted gene.
]
Drugs
One study at UC Berkeley found that disulfiram, a drug used to treat alcoholism in humans, had potential to partially restore vision loss in rats with retinitis pigmentosa, even during late stages of the disease. Efforts to continue research in humans is ongoing.
Prognosis
The progressive nature of and lack of a definitive cure for retinitis pigmentosa contribute to the inevitably discouraging outlook for patients with this disease. While complete blindness is rare, the person's visual acuity and visual field will continue to decline as initial rod photoreceptor and later cone photoreceptor degradation proceeds.
Studies indicate that children carrying the disease genotype benefit from presymptomatic counseling in order to prepare for the physical and social implications associated with progressive vision loss. While the psychological prognosis can be slightly alleviated with active counseling the physical implications and progression of the disease depend largely on the age of initial symptom manifestation and the rate of photoreceptor degradation, rather than access to prospective treatments. Corrective visual aids and personalized vision therapy provided by Low Vision Specialists may help patients correct slight disturbances in visual acuity and optimize their remaining visual field. Support groups, vision insurance, and lifestyle therapy are additional useful tools for those managing progressive visual decline.
Epidemiology
Retinitis pigmentosa is the leading cause of inherited blindness, with approximately 1/4,000 individuals experiencing the non-syndromic form of their disease within their lifetime. It is estimated that 1.5 million people worldwide are currently affected. Early onset RP occurs within the first few years of life and is typically associated with syndromic disease forms, while late onset RP emerges from early to mid-adulthood.
Autosomal dominant and recessive forms of retinitis pigmentosa affect both male and female populations equally; however, the less frequent X-linked form of the disease affects male recipients of the X-linked mutation, while females usually remain unaffected carriers of the RP trait. The X-linked forms of the disease are considered severe, and typically lead to complete blindness during later stages. In rare occasions, a dominant form of the X-linked gene mutation will affect both males and females equally.
Due to the genetic inheritance patterns of RP, many isolate populations exhibit higher disease frequencies or increased prevalence of a specific RP mutation. Pre-existing or emerging mutations that contribute to rod photoreceptor degeneration in retinitis pigmentosa are passed down through familial lines; thus, allowing certain RP cases to be concentrated to specific geographical regions with an ancestral history of the disease. Several hereditary studies have been performed to determine the varying prevalence rates in Maine (USA), Birmingham (England), Switzerland (affects 1/7000), Denmark (affects 1/2500), and Norway. Navajo Indians display an elevated rate of RP inheritance as well, which is estimated as affecting 1 in 1878 individuals. Despite the increased frequency of RP within specific familial lines, the disease is considered non-discriminatory and tends to equally affect all world populations.
Research
Future treatments may involve retinal transplants, artificial retinal implants, gene therapy, stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
s, nutritional supplements, and/or drug therapies.
2012: Scientists at the University of Miami Bascom Palmer Eye Institute presented data showing protection of photoreceptors in an animal model when eyes were injected with mesencephalic astrocyte-derived neurotrophic factor ( MANF). Researchers at the University of California, Berkeley were able to restore vision to blind mice by exploiting a "photoswitch" 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
Cedars-Sinai Medical Center is a non-profit, Tertiary referral hospital, tertiary, 915-bed teaching hospital and multi-specialty academic health science centre, academic health science center located in Los Angeles, California. Part of the Cedars ...
showed that CRISPR/Cas9 can be used to treat rats with the autosomal dominant form of retinitis pigmentosa. Researchers find that two molecules, rod-derived cone viability factor (RdCVF) and Nrf2, can protect cone photoreceptors in mouse models of retinitis pigmentosa.
2016: RetroSense Therapeutics aimed to inject viruses with DNA from light-sensitive algae into the eyes of several blind people (who have retinitis pigmentosa). If successful, they will be able to see in black and white.
In 2017 the FDA approved the gene therapy voretigene neparvovec to treat people with biallelic RPE65 mutation-associated retinal dystrophy.
In 2020, a literature review estimated the experimental therapeutic technique called transcorneal electrical stimulation as "probably effective" (level B) in retinitis pigmentosa, based on the evidence available at that time.
In 2021 an optogenetics
Optogenetics is a biological technique to control the activity of neurons or other cell types with light. This is achieved by Gene expression, expression of Channelrhodopsin, light-sensitive ion channels, Halorhodopsin, pumps or Photoactivated ade ...
application of the protein Channelrhodopsin in a human patient was reported with partial recovery of non-functional vision in a series of one patient only. They did not use standard protocol to measure visual improvement, but created their own criteria. The serendipitous discovery of the novel algal channelrhodopsin used came out of the 1000 Plant Genomes Project.
Notable cases
* Jennifer L. Armentrout, American author of YA paranormal and Science Fiction
* Walt Bodine. American broadcaster, Kansas City
* Willie Brown, 41st Mayor of San Francisco, California
* Alex Bulmer, Canadian playwright
* Molly Burke, Canadian YouTuber and motivational speaker
* Mark Erelli, American singer/songwriter, guitarist for Lori McKenna
Lorraine McKenna ( Giroux; born December 22, 1968) is an American folk, Americana, and country music singer-songwriter. In 2016, she was nominated for the Grammy Award for Song of the Year and won Best Country Song for co-writing the hit singl ...
* Neil Fachie, British paralympic cyclist
* William (Bill) Fulton, urban planner, author, and former Mayor of Ventura, California
* Gordon Gund, American businessman and professional sports team owner
* Rigo Tovar, Mexican musician, singer and actor
* Lindy Hou, Australian tandem cyclist and triathlete
* Amar Latif, entrepreneur, television personality and professional traveller
* Rachael Leahcar, Australian singer/songwriter, actress and motivational speaker
* Steve Lonegan, Mayor of Bogota, New Jersey; Republican candidate for U.S. Senate
* Chris McCausland, British stand-up comedian and actor
* Robin Millar, English record producer, musician and businessman
* Woody Shaw
Woody Herman Shaw Jr. (December 24, 1944 – May 10, 1989) was an American jazz trumpeter, flugelhornist, cornetist, composer, arranger, band leader, and educator. Shaw is widely known as one of the 20th century's most important and influentia ...
, American jazz trumpeter
* Regina Sorenson, Australian television personality
* Shel Talmy, American record producer, songwriter and arranger
* Sabriye Tenberken, German Tibetologist and developer of Tibetan Braille
* Danelle Umstead, American Paralympic alpine skier, '' Dancing with the Stars'' contestant
* Jon Wellner, American actor
* Steve Wynn, American business magnate and Las Vegas casino developer
* Sheena Iyengar, S.T. Lee Professor of Business in the Management Department at Columbia Business School
See also
* Cone dystrophy
* List of eye diseases and disorders
* Progressive retinal atrophy for the condition in dogs
* Retinal degeneration (rhodopsin mutation)
* Retinitis pigmentosa GTPase regulator
* Retinitis Pigmentosa International
References
External links
GeneReviews/NCBI/NIH/UW entry on Retinitis Pigmentosa Overview
NCBI/Molecular diagnosis of retinitis pigmentosa
{{Authority control
Channelopathies
Blindness
Disorders of choroid and retina
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