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Classification and Genetics of IRD’s

Classification of IRD’s

IRDs can be clinically classified according to the regions of the retina or cell types they primarily affect, their pattern of progression (progressive or stationary), or whether they occur as part of a syndrome (syndromic or non-syndromic).

The initial degeneration of either rod or cone cells is the first form of classifying IRD’s.

In some disorders, such as cone-rod dystrophy and Stargardt disease, cones start to degenerate first, followed by rods. As cones are primarily located in the centre of the retina, people affected by cone-rod dystrophy or Stargardt disease will initially experience deterioration of their central vision, that over time will gradually spread out to affect their peripheral vision.

Retinitis pigmentosa (RP), on the other hand, is a rod-cone dystrophy where rods start to die first followed by cones later. People affected by RP will initially experience night blindness and tunnel vision (due to loss of rods). As the disease progresses, and cones start to die, their central vision can become affected and this can result in legal blindness.

Leber congenital amaurosis (LCA) is the most severe form of IRD. LCA has one of the earliest onset of the diseases that typically appears in the first few months of life. In LCA, cones and rods start to degenerate at the same time and the supporting layer behind the photoreceptors, the retinal pigment epithelium (RPE), may also be affected.

In diseases where both cones and rods eventually degenerate late in the disease, such as cone-rod dystrophy, RP and Stargardt disease, the loss of both photoreceptor types can make an accurate diagnosis difficult.

In the above examples, the photoreceptor cells progressively degenerate and die. In some types of IRDs, the affected cells do not degenerate and appear intact, however, they do not function correctly. One example is congenital stationary night blindness (CSNB) which is caused by a defect in the rods or cones which affects their ability to transmit signals to neighbouring ganglion cells within the retina. Another example, is Achromatopsia (ACHM), or colour blindness, where one or more of the three types of colour-vision cone cells are dysfunctional but remain intact.

The pattern of disease progression is a second way that IRDs can be classified. IRDs can be progressive (the vision loss begins with few symptoms that get worse over time), or stationary (the visual impairment does not get better or worse over time). RP, cone-rod dystrophy and Stargardt disease are examples of progressive diseases, where vision loss worsens over time due to the progressive degeneration of photoreceptor cells in the retina. Achromatopsia and congenital stationary night blindness are examples of IRDs where the visual impairment does not change over time.

IRDs can also be classified as syndromic or non-syndromic. Non-syndromic vision loss is not associated with other signs and symptoms; vision loss is the only symptom of the disease. An example of non-syndromic vision loss is LCA. In contrast, syndromic vision loss occurs with other symptoms in other parts of the body. An example of syndromic vision loss is Usher syndrome, where both hearing and vision are affected.

Genetics of IRD’s

IRDs are caused by a gene mutation that is inherited from a parent. This led to the title of “Inherited Retinal Disease”. In the case of IRDs, the mutation affects genes that play an essential role in normal retinal development and functioning, leading to the degeneration of photoreceptors and other retinal cells and associated vision loss.

Scientific research has shown that IRDs are genetically diverse, with over 260 disease-related genes identified to date. In some cases the genes or mutations responsible are not yet known or not understood. However, ongoing research and genetic testing is advancing our knowledge of such genetic changes in order to find cures.

Genetic testing is of utmost importance for many IRDs due to their genetic origin. Genetic testing can aid in diagnosis and, critically, it can determine if individuals have a specific mutation that may be treatable by specific gene therapies. You can learn more about how genetic testing works, and what it can do, at our toolkit ‘SENDING A RED ALERT!’, intended to inform those with rare eye diseases about genetic testing services: https://www.retina-international.org/toolkit-redalert

You can learn more about inheritance patterns here: https://www.retina-international.org/patients/your-eyes/inheritance-patterns

Watch this short video from the National Eye Institute/National Institutes of Health (NEI/NIH) about vision in families: https://youtu.be/Gz_rAMF7ZHA

Genetic complexity of Inherited Retinal Diseases

A small number of IRDs are caused by mutations in one single gene. For example, Choroideremia (CHM), a progressive condition where vision loss primarily affects males, is caused by a mutation in a gene called CHM. Stargardt disease is caused by a mutation in a gene called ABCA4.

For most other IRDs, affected people may have the same symptoms and the same disease but each person could have mutations in different genes. This is because mutations in many different genes can all have the same end result. For example, RP can be caused by mutations in one of 84 different genes, while cone-rod dystrophy can be caused by mutations in one of 33 different genes. Mutations in 20 different genes can lead to macular dystrophies (MD) and another 15 different genes can be responsible for congenital stationary night blindness.

While mutations in different genes can result in the same disease, different changes in just one gene can sometimes result in different diseases in individuals. For example, different mutations in the GUCY2D gene can result in either cone-rod dystrophy or in LCA. Cone-rod dystrophy can be caused in some individuals by autosomal dominant (ad) variants of GUCY2D while autosomal recessive (ar) variants of the same gene can lead to LCA in other people.

In some instances, the severity of the disease can be affected by different combinations of different types of mutations. A person who has two non-functioning copies of ABC4A will have early-onset cone-rod dystrophy while another person with a combination of two severe and mild variants of ABC4A may have intermediate or late-onset Stargardt disease.

Autosomal recessive retinal dystrophies (arRDs) can be syndromic or non-syndromic. Non-syndromic vision loss is not associated with other signs and symptoms. In contrast, syndromic vision loss involves loss that also occurs with symptoms in other parts of the body. Different mutations in the USH2A gene can cause Usher syndrome type 2 or non-syndromic arRP.

Figure: Genetic diversity of the six major inherited retinal diseases (IRDs). The numbers outside of the ellipses correspond to the number of IRD genes responsible for the specific disease, while numbers within the ellipses correspond either to disease-specific genes or to genes mutated in two or more diseases. RP: retinitis pigmentosa; LCA: Leber congenital amaurosis; CD/CRD: cone dystrophy/cone-rod dystrophy; CSNB: congenital stationary night blindness; MD: macular dystrophy; EVR: exudative vitreoretinopathy.
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