Modules:Retinal Degeneration

Photoreceptor degeneration in humans results from retinal diseases such as retinitis pigmentosa and age-related macular degeneration. Photoreceptor cell death is accompanied by changes in the neural retina (Banin et al., 1999; Peng et al., 2000; Strettoi and Pignatelli, 2000; Aleman et al., 2001; Strettoi et al., 2002; Strettoi et al., 2003). The local functional implications are not well understood but could compromise spatial processing and transform the retina into a self-signaling neural assembly(Marc and Jones, 2003), making it difficult to use microelectronic retinal prostheses as a rescue strategy. Genetic rescue techniques have there challenges but have windows of opportunity during the degenerative process (Marc and Jones, 2003).

Robert Marc's Stages of Degeneration

1. Phase I – Rod degeneration; rod photoreceptor outer segments shorten, moving rods through stressed and apoptotic stages. Cone outer segments are truncated as well. Rod neurites sprout and enter the inner retina, extending to the ganglion cell layer. #Stage2 Phase II – Cone degeneration; rhodopsin levels rise in rods and rods die at a faster rate. Cone gene expression levels change. The subretinal space collapses with fibrosis by Muller cells (glial seal). Every bipolar and horizontal cell appears to be remodeled. Though some bipolar cells die at this stage, quantitatively, it’s a relatively small fraction of the whole.

2. Early Phase III – Progressive neurite remodeling; Complete loss of sensory retina and glial seal becomes more compacted. This seal becomes bound to the neural retina and cannot be removed. Neurons of the INL begin to remodel. Global cell death becomes statistically significant.

3. Middle Phase III - Global remodeling; microneuromas (small tumors of abnormal growth) begin to form that include synaptic input from all types of cells. Concurrent and nonbiased neuronal death, cell migration, and rewiring. Rate of death is variable and may depend on the rate of cone cell death. Migration includes bipolar and amacrine cells moving into ganglion cell layer. Movement of amacrine and ganglion cells to the glial seal. Bundles of mixed neurites of all cell types course through the retina. All neurons contain their basic molecular signatures at this point.

4. Late Phase III – Plateau remodeling; Cell death persists, including substantial cell death in the INL and ganglion cell layer. IPL becomes thinner. Optic fiber thins. RPE alterations are evident.

Retinal Degeneration in Humans

There are 161 known gene defects that result in photoreceptor degeneration (Punzo and Cepko, 2007). Rods are primary targets of these mutations (e.g., RP) and different mutations in a single gene can lead to very different progressions of degeneration (Sung et al., 1994). Retinal degeneration can be cone initiated as well (e.g., ARMD). Cone (COD), Cone-Rod Dystrophy (CORD), and Leber’s Congenital Amaurosis (LCA) can all be initiated by defects in the same genes (Wells et al., 1993). RPE gene defects are also known to lead to photoreceptor degeneration (Marc and Jones, 2003).

Animal Models of Retinal Degeneration

> 90% of the human retina is identical to all experimental mammalian retinae in terms of cone density, structure, and molecular signatures of each cell type (Marc and Jones, 2003).

Model	Occurance	Gene	Cellular Phenotype	Human Phenotype
Mouse rd1	Natural	PDE6Brd1	Rod cGMP elevation	arRP
Mouse rd2	Natural	Prph2rd2	Outer segment malformation	RP, AMD
Mouse sh-1	Natural	Myo7a	Usher Syndrome Type B	arRP
Mouse orJ	Natural	Chx10	Retinal Hypcellularity	Microthalmia
Rat RCS	Natural	Mertk	Subretinal space debris stress	arRP
Chicken rd	Natural	Gucy1	Rod/Cone cGMP depression	rLCA type I
Briard Dog	Natural	RPE65	Retinoid metabolism failure	LCA type II This list is far from comprehensive. For example, there is a rd10 mouse and an rcd1 dog.

Retinal Degneration Over Space and Time

Rod diseases begin in the periphery whereas cone-initiated diseases begin in the macula. However, it should be noted that rodent models do not have true foveae and the distribution of rods and cones is even throughout the retina (Euler and Wassle, 1995; Jeon et al., 1998), thus, diseases such as RP will appear pan-retinally in the rodent. However, the circuitry of rodent retina is nearly identical to peripheral primate retina (Euler and Wassle, 1995), suggesting that using a rodent model of retinal degeneration is relevant to the human condition. Degeneration of the neural retina can be very focal, where areas 100-300 μm in diameter die off, surrounded by areas of healthy neural retina (Marc and Cameron, 2001; Jones et al., 2003).

Many retinal degenerative diseases take years to present. Stargardt’s Disease can take years to present and RP can take decades. Disease progression is generally quite heterogeneous (Marc and Cameron, 2001). In fact, it is not uncommon to see “little islands of surviving cones among rivers of degeneration” (Marc and Cameron, 2001). This effect is also seen in rd mouse models (Ogilvie et al., 1997).

Rod-cone dysplasia type 2

• Collie - Rod cell response is nearly absent. Night blindness by six weeks old, blind by one to two years old.

Rod-cone dysplasia type 3

• Cardigan Welsh Corgi

Rod dysplasia

• Norwegian Elkhound - Characterized by dysplasia of the rod cell unit and subsequent degeneration of the cone cell unit. Rod cell response is nearly absent. Night blindness by six months old, blind by three to five years old. Rod dysplasia has now been bred out of this breed.

Early retinal degeneration

• Norwegian Elkhound - Night blindness by six weeks old, blind by twelve to eighteen months old.

Photoreceptor dysplasia

This is caused by an abnormal development of both rod and cone cells. Dogs are initially night blind and then progress to day blindness.

• Miniature Schnauzer - Slowly progressive, not seen until two to five years old.
• Belgian Shepherd Dog - Complete blindness by eight weeks old.

Cone degeneration

• Alaskan Malamute - Temporary loss of vision in daylight (hemeralopia) at eight to ten weeks old. There is a purely rod cell retina by four years old.

Progressive rod-cone degeneration (PRCD)

This is a disease with normal rod and cone cell development but late onset degeneration of the rod cells that progresses to the cone cells. It is inherited as an autosomal recessive trait and has been linked to the ninth canine chromosome.

• Poodle - Night blindness by three to five years old, blind by five to seven years old.
• English Cocker Spaniel - Occurs late in life, usually at four to eight years old.
• American Cocker Spaniel - Night blindness by three to five years old, blind one to two years later.
• Labrador Retriever - Night blindness by four to six years old, blind at six to eight years old.
• Portuguese Water Dog
• Chesapeake Bay Retriever
• Australian Cattle Dog
• Nova Scotia Duck Tolling Retriever

X-linked PRA

This condition is linked to the X chromosome.

• Siberian Husky - Night blindness by two to four years old.
• Samoyed - More severe disease than the Husky.

Dominant PRA

• Bullmastiff - Inherited as an autosomal dominant trait due to a mutation in the gene for rhodopsin.

Feline PRA

• Abyssinian - Two forms exist. One is inherited as an autosomal dominant trait and has an early age onset. The other is inherited as an autosomal recessive trait and has a middle age onset.
• Early onset PRA has also been reported in the domestic shorthaired cat and Persian. The Siamese also likely has a hereditary form of PRA. Despite belief among breeders to the contrary, there is apparently no link between coat color in Persians and the development of PRA.

Central progressive retinal atrophy (CPRA)

CPRA is also known as retinal pigment epithelial dystrophy (RPED). The cause of this condition is the loss of the retinal pigment epithelium's ability to effectively process the photoreceptor outer segment (POS) and subsequent accumulation of POS material in the RPE and loss of function. The loss of function of the RPE leads to photoreceptor degeneration. Vitamin E deficiency may play a role in the development of CPRA. It is characterized by accumulation of pigment spots in the retina surrounded by retinal atrophy and a mottled appearance of the pigmented nontapetal fundus. The pigmented spots eventually coalesce and fade as the atrophy of the retina increases. It is an inherited condition (in the Labrador Retriever it is inherited as an autosomal dominant trait with variable penetrance). CPRA occurs in older dogs. Peripheral vision is retained for a long time. Vision is better in low light and better for moving or distant objects. Not all affected dogs go blind. Secondary cataracts are common.

Commonly affected breeds

• Labrador Retriever
• Golden Retriever
• Border Collie
• Collie
• Shetland Sheepdog
• English Cocker Spaniel
• English Springer Spaniel
• Chesapeake Bay Retriever
• Cavalier King Charles Spaniel
• Briard - has an especially high frequency.
• It can also, but very rarely, be found in the Papillon.Template:Fact

It can also be found in the poodle varieties

Hereditary retinal dysplasia

There is another retinal disease in Briards known as hereditary retinal dysplasia. These dogs are night blind from birth, and day vision varies. Puppies affected often have nystagmus. It is also known as lipid retinopathy.

See also

• Sudden acquired retinal degeneration

References