Available RPE65 Genetic Test for enrollment in Retinitis Pigmentosa Genetic Therapy.
RP is an inherited disorder that results from harmful changes in any one of more than 50 genes. These genes carry the instructions for making proteins that are needed in cells within the retina, called photoreceptors. Some of the changes, or mutations, within genes are so severe that the gene cannot make the required protein, limiting the cell's function. Other mutations produce a protein that is toxic to the cell. Still other mutations lead to an abnormal protein that doesn't function properly. In all three cases, the result is damage to the photoreceptors.
Photoreceptors are cells in the retina that begin the process of seeing. They absorb and convert light into electrical signals. These signals are sent to other cells in the retina and ultimately through the optic nerve to the brain where they are processed into the images we see. There are two general types of photoreceptors, called rods and cones. Rods are in the outer regions of the retina, and allow us to see in dim and dark light. Cones reside mostly in the central portion of the retina, and allow us to perceive fine visual detail and color.
Image courtesy of Robert N. Fariss, Ph.D., chief of the NEI Biological Imaging Core, and Ann H. Milam, Ph.D., former professor in the Department of Ophthalmology at the University of Washington.
In the early stages of RP, rods are more severely affected than cones. As the rods die, people experience night blindness and a progressive loss of the visual field, the area of space that is visible at a given instant without moving the eyes. The loss of rods eventually leads to a breakdown and loss of cones. In the late stages of RP, as cones die, people tend to lose more of the visual field, developing ìtunnel vision.î They may have difficulty performing essential tasks of daily living such as reading, driving, walking without assistance, or recognizing faces and objects.
To understand how RP is inherited, it's important to know a little more about genes and how they are passed from parent to child. Genes are bundled together on structures called chromosomes. Each cell in your body contains 23 pairs of chromosomes. One copy of each chromosome is passed by a parent at conception through egg and sperm cells. The X and Y chromosomes, known as sex chromosomes, determine whether a person is born female (XX) or male (XY). The 22 other paired chromosomes, called autosomes, contain the vast majority of genes that determine non-sex traits. RP can be inherited in one of three ways:
Autosomal recessive Inheritance
In autosomal recessive inheritance, it takes two copies of the mutant gene to give rise to the disorder. An individual with a recessive gene mutation is known as a carrier. When two carriers have a child, there is a:
Autosomal dominant Inheritance
In this inheritance pattern, it takes just one copy of the gene with a disorder-causing mutation to bring about the disorder. When a parent has a dominant gene mutation, there is a 1 in 2 chance that any children will inherit this mutation and the disorder.
In this form of inheritance, mothers carry the mutated gene on one of their X chromosomes and pass it to their sons. Because females have two X chromosomes, the effect of a mutation on one X chromosome is offset by the normal gene on the other X chromosome. If a mother is a carrier of an X-linked disorder there is a:
RP is considered a rare disorder. Although current statistics are not available, it is generally estimated that the disorder affects roughly 1 in 4,000 people, both in the United States and worldwide.
A scene as it might be viewed by someone with normal vision and someone with advanced RP.
The symptoms of RP typically appear in childhood. Children often have difficulty getting around in the dark. It can also take abnormally long periods of time to adjust to changes in lighting. As their visual field becomes restricted, patients often trip over things and appear clumsy. People with RP often find bright lights uncomfortable, a condition known as photophobia. Because there are many gene mutations that cause the disorder, its progression can differ greatly from person to person. Some people retain central vision and a restricted visual field into their 50s, while others experience significant vision loss in early adulthood. Eventually, most individuals with RP will lose most of their sight.
RP is diagnosed in part through an examination of the retina. An eye care professional will use an ophthalmoscope, a tool that allows for a wider, clear view of the retina. This typically reveals abnormal, dark pigment deposits that streak the retina. These pigment deposits are in part why the disorder was named retinitis pigmentosa. Other tests for RP include:
Living with vision loss
A number of services and devices are available to help people with vision loss carry out daily activities and maintain their independence. In addition to an eye care professional, it's important to have help from a team of experts, which may include occupational therapists, orientation and mobility specialists, certified low vision therapists, and others. NEI has more information on living with low vision.
Children with RP may benefit from low vision aids that maximize existing vision. For example, there are special lenses that magnify central vision to expand visual field and eliminate glare. Computer programs that read text are readily available. Closed circuit televisions with a camera can adjust text to suit one's vision. Portable lighting devices can adjust a dark or dim environment. Mobility training can teach people to use a cane or a guide dog, and eye scanning techniques can help people to optimize remaining vision. Once a child is diagnosed, he or she will be referred to a low vision specialist for a comprehensive evaluation. Parents may also want to meet with the child's school administrators and teachers to make sure that necessary accommodations are put in place.
For parents of children with RP, one challenge is to determine when a child might need to learn to use a cane or a guide dog. Having regular eye examinations to measure the progress of the disorder will help parents make informed decisions regarding low vision services and rehabilitation.
Targeted therapies for RP
An NEI-sponsored clinical trial found that a daily dose of 15,000 international units of vitamin A palmitate modestly slowed the progression of the disorder in adults. Because there are so many forms of RP, it is difficult to predict how any one patient will respond to this treatment. Talk to an eye care professional to determine if taking vitamin A is right for you or your child.
An artificial vision device called the Argus II has also shown promise for restoring some vision to people with late-stage RP. The Argus II, developed by Second Sight with NEI support, is a prosthetic device that functions in place of lost photoreceptor cells. It consists of a light-sensitive electrode that is surgically implanted on the retina. A pair of glasses with a camera wirelessly transmits signals to the electrode that are then relayed to the brain. Although it does not restore normal vision, in clinical studies, the Argus II enabled people with RP to read large letters and navigate environments without the use of a cane or guide dog. In 2012, the U.S. Food and Drug Administration (FDA) granted a humanitarian device exemption for use of the Argus II to treat late-stage RP. This means the device has not proven effective, but the FDA has determined that its probable benefits outweigh its risks to health. The Argus II is eligible for Medicare payment.
NEI supports research to develop a variety of treatments to prevent vision loss and restore sight. Gene therapy for several different types of RP has shown promise in the laboratory. In a landmark clinical trial, gene therapy for a retinal disorder called Leber congenital amaurosis (LCA) led to improved vision for people with that disorder. This and other gene therapy clinical trials for LCA are ongoing to establish a maximally safe dosage and determine the long-term benefits of treatment. Stem cells have also shown promise in the lab. Thanks in part to basic research supported by NEI, the company Advanced Cell Technologies is conducting a clinical trial to test the safety of stem cell treatments for a type of retinal disorder called macular degeneration. Other researchers, including a team at NEI, are gearing up for similar trials. NEI researchers are also evaluating various drug and nutritional therapies in the lab. See the list of clinical trials on RP(link is external).
Last Reviewed: December 2015
The National Eye Institute (NEI) is part of the National Institutes of Health (NIH) and is the Federal government’s lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness.
E.L. Berson, in Encyclopedia of Neuroscience, 2009
Retinitis pigmentosa is also found in association with anosmia, ataxia, dry skin, and EKG abnormalities with elevated serum phytanic acid (Refsum disease); malabsorption, acanthocytosis, ataxia, and abetalipoproteinemia (Bassen–Kornzweig syndrome); and adult-onset ataxia, dysarthria, hyporeflexia, decreased proprioception, decreased vibration sense, and low serum vitamin E levels (Friedreich-like ataxia with retinitis pigmentosa). These uncommon recessively inherited conditions are treatable as follows: a low phytol/low phytanic acid diet (excluding animal fats, milk products, and dark green leafy vegetables) in the case of Refsum disease; a low-fat diet plus supplementation with vitamin A, vitamin E, and vitamin K in the case of Bassen–Kornzweig syndrome, and vitamin E supplementation in the case of Friedreich-like ataxia associated with retinitis pigmentosa.
Shilpa Desai, A. Yasin Alibhai, in Atlas of Retinal OCT: Optical Coherence Tomography, 2018
Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited disorders that are characterized by loss of retinal cell function, preferentially in the peripheral retina. RP can have varying severity, age of onset, mode of inheritance, and systemic associations. RP may be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive fashion. The X-linked form of the disease is typically the most severe. The disease is often secondary to mutations in the rhodopsin gene, though some forms have been linked to mutations in the RDS gene (Anasagasti et al., 2012). Generally, RP is characterized by a slowly progressive loss of night vision (nyctalopia) along with contraction of the visual field. In later stages of the disease central acuity is affected, which may cause profound vision loss. Typical fundus abnormalities include waxy pallor of the optic nerve, a tapetal-like reflex resulting from changes in the retinal pigment epithelium (RPE), narrowing of the peripheral retinal vasculature, and bone-spicule changes in the mid-peripheral retina (Fig. 1). Definitive diagnosis requires electrophysiologic testing. Computed tomography is useful to aid in the initial diagnosis and detecting associated macular abnormalities such as cystoid macular edema (Fig. 2). Treatment of RP is limited at this time, although retinal prosthetic implants are available for extremely severe cases (Farrar et al., 2012).
T.J. Hollingsworth, Alecia K. Gross, in International Review of Cell and Molecular Biology, 2012
Retinitis pigmentosa is a retinal degeneration transmitted by varied modes of inheritance and affects approximately 1 in 4000 individuals. The photoreceptors of the outer retina, as well as the retinal pigmented epithelium which supports the outer retina metabolically and structurally, are the retinal regions most affected by the disorder. In several forms of retinitis pigmentosa, the mislocalization of the rod photoreceptor protein rhodopsin is thought to be a contributing factor underlying the pathophysiology seen in patients. The mutations causing this mislocalization often occur in genes coding proteins involved in ciliary formation, vesicular transport, rod outer segment disc formation, and stability, as well as the rhodopsin protein itself. Often, these mutations result in the most early-onset cases of both recessive and dominant retinitis pigmentosa, and the following presents a discussion of the proteins, their degenerative phenotypes, and possible treatments of the disease.
Fayçal Hentati, ... Rim Amouri, in Handbook of Clinical Neurology,2012
Retinitis pigmentosa is more frequently reported in patients from Japan. It seems to be more frequently associated with the H101Q mutation in the α-TTP gene (Gotoda et al., 1995; Yokota et al., 1997; Hoshino et al., 1999). It is rarely observed in patients with the 744delA mutation and has been reported in one patient from Tunisia and three patients from Morocco (Gabsi et al., 2001; Benomar et al., 2002). Clinically, retinitis pigmentosa is characterized by progressive impairment of visual acuity with night blindness, and is similar in clinical and pathological findings to the common autosomal recessive retinitis pigmentosa sine pigmento type. The fundus displays a tigroid feature with paramacular granular hyperfluorescence at fluorescein angiography; ring scotomata are seen by Goldman's perimetry and reduced A and B waves and reduction of oscillatory potentials in electroretinograms (Yokota et al., 2000).
Douglas R. Fredrick, in Swaiman's Pediatric Neurology (Sixth Edition),2017
In retinitis pigmentosa, abnormalities of the retinal pigment epithelium can lead to photoreceptor dysfunction and death. Retinitis pigmentosa typically affects rods before affecting cones. This process leads to initial symptoms of night blindness and constriction of the peripheral visual field, eventually affecting cones and central visual acuity. A typical bone spicule pattern of the retinal pigment epithelium is diagnostic. Electrodiagnostic tests, such as electroretinography, may be helpful. Retinitis pigmentosa has been characterized as involving rods or cones, or both. All modes of inheritance patterns have been described, and there may be variations of phenotypic expression within families.
T.P. Sakmar, T. Huber, in Encyclopedia of Neuroscience, 2009
Retinitis pigmentosa is a group of hereditary progressive blinding diseases with variable clinical presentations. One form of the disease, autosomal dominant retinitis pigmentosa (ADRP), was linked to a mutation in the gene for rhodopsin. More than 70 different rhodopsin gene mutations have been reported in patients with ADRP. The mutations reported would result in alterations in all domains of rhodopsin: extracellular, membrane-embedded, and cytoplasmic. ADRP is characterized by a progressive death of rod and, sometimes, cone cells, resulting in gradual vision loss. The molecular pathophysiology of ADRP, namely how a defect in rhodopsin leads to rod cell death, remains to be fully elucidated.
John V. Forrester MB ChB MD FRCS(Ed) FRCP(Glasg) (Hon) FRCOphth(Hon) FMedSci FRSE FARVO, ... Eric Pearlman BSc PhD, inThe Eye (Fourth Edition), 2016
Retinitis pigmentosa is the term used to describe a heterogeneous group of rod–cone dystrophies that have a variety of clinical appearances by virtue of varying inheritance patterns. Studies have documented the frequencies of the various modes of inheritance. Approximately 43% are inherited by autosomal transmission, 20% by autosomal recessive transmission, and between 8% and 25% by X-linked recessive transmission. Figures again vary, but approximately 20–25% of cases of retinitis pigmentosa appear to be isolated, or at least have unidentifiable patterns of inheritance. As the disease may be classified according to Mendelian inheritance patterns, the possibility of single-gene defects is high and this has prompted an energetic search for the isolation of such genes.
Patients with this form of retinitis pigmentosa present with symptoms of night blindness from childhood; they have progressive constriction of visual fields and loss of vision in mid-life, although the severity of the disease does vary. The gene for this condition has been mapped to Xp11.3 (short arm of the X chromosome). Further evidence also maps the X-linked gene to Xp21, particularly in families where the female carrier demonstrates the golden tapetoretinal reflex. Recently these gene loci have been designated RP2 (Xp11.3) and RP3 (Xp21.1). Currently, probes are available for identifying both loci and may be used for prenatal diagnosis and genetic counselling.
Several mutations have been found in candidate genes in up to 30% of patients with autosomal dominant retinitis pigmentosa. Mutations in two genes have been studied in particular. These are the rhodopsin gene on chromosome 3q (accounting for 20% of all cases) and the peripherin gene on chromosome 6p. The rhodopsin molecule, composed of 348 amino acids, exists as a seven-loop transmembrane protein in the rod outer segment. The C-terminus of the protein is in the cytoplasm and the N-terminus of rhodopsin is in the intradiscal space. Throughout the protein, several regions are affected by mutations, which fall into three main groups: (1) mutations affecting amino acids in the intradiscal space; (2) mutations affecting amino acids in the transmembrane domain; and (3) mutations affecting amino acids in the cytoplasm. Most of these mutations probably destroy the three-dimensional (tertiary) conformation of the protein and in some way affect protein function. To date, over 150 different mutations have been reported, the majority of which are point mutations, although deletions have also been discovered.
The peripherin gene codes for the retinal degeneration show (RDS) protein found in rodents (see Ch. 9, p. 515), which is a component of the rod outer segment disk membranes. More than 20 mutations have been discovered in this gene in association with autosomal dominant retinitis pigmentosa and other retinopathies, for example retinitis pigmentosa albescens and hereditary maculopathies. Recently, other genes have been identified in autosomal dominant retinitis pigmentosa, and these include one at the centromere of chromosome 8 and both the long and short arms of chromosome 7.
Autosomal recessive forms of retinitis pigmentosa have been less well studied; to date, only one gene mutation has been identified in a rhodopsin gene. Recently there has been a report that certain patients with autosomal dominant retinitis pigmentosa have defects in the gene coding for cyclic guanosine monophosphate phosphodiesterase (see Ch. 4, p. 261) (Box 3-14).
Examples of photoreceptor degeneration are via genetic mutations that lead to cell functional deficits. It was thought that the rate of cell death or dysfunction increases over time. However, mathematical modelling has determined that it is not a cumulative damage that occurs but that the risk of cell death remains constant and the genetic mutation results in random cell death over time – ‘one-hit’ biochemical model. Such examples of neuronal degeneration are photoreceptor degenerations.
Ciliopathies define a dysfunction of cilia function in retinal photoreceptors.
Mutations, for example, that may occur in genes such as CEP290 and RPGR give rise to photoreceptor dysfunction and degeneration as well as being ubiquitous in many cells for centrosome function.
Retinitis pigmentosa related to ciliary dysfunction can be an isolated feature or a part of a syndrome such as Bardet–Biedl syndrome (BBS).
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