Retinitis pigmentosa (RP) is a member of a group of genetic disorders 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 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. The underlying mechanism involves the progressive loss of rod photoreceptor cells that line the retina of the eyeball. The rod cells secrete a neuroprotective substance (rod-derived cone viability factor, RdCVF) that protects the cone cells from apoptosis. 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 (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 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 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 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 Photopsia (Spontaneously occurring flashes/blinking/swirling/shimmering lights) Photophobia (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. 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 (congenital 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, ataxia, and cardiac conduction defects is seen in the mitochondrial DNA disorder Kearns–Sayre syndrome (also known as Ragged Red Fiber Myopathy). RP combined with intellectual disability, peripheral neuropathy, acanthotic (spiked) RBCs, ataxia, steatorrhea, and absence of VLDL is seen in abetalipoproteinemia. RP is seen clinically in association with several other rare genetic disorders (including 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 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, and developmental delay with an autosomal recessive inheritance 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, 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.Adamus, G., Ren, G. & Weleber, R.G. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 4, 5 (2004). https://doi.org/10.1186/1471-2415-4-5Bastek JV, Foos RY, Heckenlively J. Traumatic pigmentary retinopathy. Am J Ophthalmol. 1981 Nov;92(5):621-4. doi: 10.1016/s0002-9394(14)74652-5. PMID 7304688.
Genetics Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration.
There are multiple genes that code for proteins needed in the visual pathway that, when mutated, can cause the retinitis pigmentosa phenotype. 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 of the gene for rhodopsin, a pigment 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 forms of RP.
Over 100 mutations have been reported to date in the opsin 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, and cytoplasmic domains). One of the main biochemical 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, accounts for 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 in codon 23 was reported causing autosomal dominant retinitis pigmentosa, in which proline changed to alanine. 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 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 ubiquitously expressed and it is proposed that defects in a ubiquitous factor (a protein expressed everywhere) should only cause disease in the retina because the retinal photoreceptor cells have a far greater requirement for protein processing (rhodopsin) 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: OMIM Gene Type RPY Retinitis pigmentosa Y-linked RP1 Retinitis pigmentosa-1 RP2 Retinitis pigmentosa-2 RPGR Retinitis pigmentosa-3 RHO Retinitis pigmentosa-4 / Retinitis pigmentosa-6 PRPH2 Retinitis pigmentosa-7 RP9 Retinitis pigmentosa-9 IMPDH1 Retinitis pigmentosa-10 PRPF31 Inheritance can be either phenotypic or genotypic. Retinitis pigmentosa-11 Autosomal Dominant CRB1 Retinitis pigmentosa-12, autosomal recessive PRPF8 Retinitis pigmentosa-13 TULP1 Retinitis pigmentosa-14 CA4 Retinitis pigmentosa-17 HPRPF3 Retinitis pigmentosa-18 ABCA4 Retinitis pigmentosa-19 RPE65 Retinitis pigmentosa-20 / Retinitis pigmentosa-22 OFD1 Retinitis pigmentosa-23 / Retinitis pigmentosa-24 EYS Retinitis pigmentosa-25 CERKL Retinitis pigmentosa-26 NRL Retinitis pigmentosa-27 FAM161A Retinitis pigmentosa-28 FSCN2 Retinitis pigmentosa-30 TOPORS Retinitis pigmentosa-31 CLCC1 Retinitis pigmentosa-32 SNRNP200 Retinitis pigmentosa-33 /