encephalomyelopathy

Retinitis pigmentosa

[pig-men-toh-suh, -muhn-]

Retinitis pigmentosa (RP) is a group of genetic eye conditions. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some sight all their life. Others go completely blind from RP, in some cases as early as childhood. Progression of RP is different in each case.

RP is a type of hereditary retinal dystrophy, a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina lead to progressive visual loss. Affected individuals first experience defective dark adaptation or nyctalopia (night blindness), followed by reduction of the peripheral visual field (known as tunnel vision) and, sometimes, loss of central vision late in the course of the disease.

Signs

Mottling of the retinal pigment epithelium with black bone-spicule pigmentation is typically indicative (or pathognomonic) of retinitis pigmentosa. Other ocular features include waxy pallor of the optic nerve head, attenuation (thinning) of the retinal vessels, cellophane maculopathy, cystic macular edema and posterior subcapsular cataract.

Diagnosis

The diagnosis of retinitis pigmentosa relies upon documentation of progressive loss in photoreceptor function by electroretinography (ERG) and visual field testing. The mode of inheritance of RP is determined by family history. At least 35 different genes or loci are known to cause "nonsyndromic RP" (RP that is not the result of another disease or part of a wider syndrome).

DNA testing 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)
(autosomal recessive, RP12)
(autosomal recessive, RP19)
(autosomal recessive, RP20)

For all other genes, molecular genetic testing is available on a research basis only.

RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP can be either recessive, affecting primarily only males, or dominant, affecting both males and females, although females 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.

RP combined with progressive deafness is called Usher syndrome.

Genetics

Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration. This disorder is characterized by the progressive loss of photoreceptor cells and may eventually lead to blindness.

There are multiple genes that, when mutated, can cause the Retinitis pigmentosa 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. Since then, more than 100 mutations have been found in this gene, accounting for 15% of all types of retinal degeneration. Most of those mutations are missense mutations and inherited mostly in a dominant manner.

The rhodopsin gene encodes a principal protein of photoreceptor outer segments. Studies show that mutations in this gene are responsible for approximately 25% of autosomal dominant forms of RP.

Up to 150 mutations have been reported to date in the opsin gene associated with the 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 molecular chaperones have also been involved in RP. It was found that 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 other mutations which also correlate with the disease. These mutations include 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.

Other causes

Some cases of RP are part of a wider syndrome, or come about a result of other diseases such as:

Treatment

There is currently no medical treatment that can completely cure retinitis pigmentosa, although the progression of the disease can be reduced by the daily intake of 15000 IU of vitamin A palmitate. Recent studies have shown that proper vitamin A supplementation can postpone blindness by up to 10 years. Scientists continue to investigate possible treatments. Future treatments may involve retinal transplants, artificial retinal implants, gene therapy, stem cells, nutritional supplements, and/or drug therapies.

In a study published in the journal Nature, researchers working with mice at the University College London Institutes of Ophthalmology and Child Health and Moorfields Eye Hospital, transplanted mouse stem cells which were at an advanced stage of development, and already programmed to develop into photoreceptors, into mice that had been genetically induced to mimic the human conditions of retinitis pigmentosa and age-related macular degeneration. These photoreceptors developed and made the necessary neural connections to the animal's retinal nerve cells, a key step in the restoration of sight. Previously it was believed that the mature retina has no regenerative ability. This research may in the future lead to using transplants in humans to relieve blindness.