Inherited Retinal Diseases

What is the retina?

The retina is a thin layer of tissue located at the back of the eye that plays a crucial role in vision. It contains millions of light-sensitive cells known as photoreceptors, as well as other nerve cells that receive and organize visual information.

Genetic Etiology of Inherited Retinal Diseases

The genetic etiology of inherited retinal diseases (IRDs) is highly complex, with mutations in over 280 genes identified as causative factors. These genes encode proteins with diverse retinal functions, therefore these mutations can affect various aspects of retinal function, including photoreceptor structure, phototransduction  pathways, and the retinoid cycle.

The genetic inheritance of IRDs in most cases follows simple inheritance patterns, such as:

• autosomal dominant;
• autosomal recessive, as in Achromatopsia;
• X-linked, as in Blue Cone Monochromacy; or
• mitochondrial.

List of Inherited Retinal Diseases

Inherited Retinal Diseases encompass a diverse range of diseases, each characterized by specific clinical features and genetic mutations. Here some of them:

• Blue Cone Monochromacy and Achromatopsia;

• Retinitis Pigmentosa (RP): characterized by the gradual deterioration of photoreceptor cells, initially rods, typically leading to symptoms such as night blindness and peripheral vision loss; diagnosed in childhood or adolescence, RP is an inherited retinal disease that often leads to legal and sometimes complete blindness. RP itself is highly heterogeneous: mutations in more than 50 genes are known to cause non-syndromic RP and nearly 3100 mutations have been reported in these genes [11]. Syndromic forms of RP are equally heterogeneous: mutations in 12 genes cause Usher syndrome and 17 genes are associated with Bardet-Biedl syndrome; together these two diseases account for another 1200 pathogenic mutations . Usher syndrome combines retinitis [11] with congenital deafness, highlighting the multi-systemic nature of some IRDs. RP is also known as rod-cone dystrophy (RCD).

• Leber Congenital Amaurosis (LCA): is a group of inherited retinal diseases characterized by severe impairment vision or blindness at birth or in early infancy. Various phenotypes (from LCA1 to LCA19) with at least 29 genotypes have been identified that account for around 70-80% of cases, with thereby genes yet to be identified [12]. Some retinal experts consider LCA to be a severe form of Retinitis Pigmentosa (RP). The condition is caused by degeneration and/or dysfunction of photoreceptors, the cells in the retina that make vision possible. The estimated birth prevalence of LCA – all genetic causative mutations -is two to three per 100,000 births [12]. 

• Stargardt Disease: characterized by progressive loss of central vision, typically beginning in childhood or adolescence, due to the degeneration of cones in the macula. Stargardt disease is an inherited form of macular degeneration sometimes referred to as juvenile or early onset macular degeneration. Stargardt disease is usually an autosomal recessive condition caused by mutations in the gene ABCA4, but there are also rarest causative mutations on the gene ELOVL4  through the autosomal dominant inheritance pattern. Stargardt is the most commonly [Mendelian] inherited childhood and adulthood maculopathy. It has a prevalence of 1 in 10,000. Stargardt is the second most common cause of blindness in the pediatric population, after Leber Congenital Amaurosis  [14].

Diagnosis

Accurate clinical diagnosis is very important. Clinical care of patients has evolved over the past decade with improved diagnostic tools (e.g., genetic testing, novel noninvasive visual function testing, and imaging studies) [9]. See for example: DNA test for Blue Cone Monochromacy.

It is very important to establish a clinical diagnosis so the patient receives appropriate care (prognosis, monitoring for co-morbidities, and assessment of other organs that may be affected in syndromic conditions). It is also important to drawn a pedigree, documenting family history of eye disease, providing. information on the genetic nature and inheritance of the disease and communicate the implications to other relevant family members [9], and to help the patient and family cope with and prepare for progressive visual impairment (low vision consultation, employment accommodations, and emotional support).

A very important step in the diagnosis is the molecular genetic testing (genotyping or DNA test) of the patient that can be valuable to confirm the diagnosis and optimize management.

Methods for identifying the genetic cause of IRDs have advanced significantly in recent years, and  next generation sequencing NGS testing, using a retinal dystrophy panel, provides an efficient first step for genetic testing. However, Blue Cone Monochromacy is rarely included on retinal dystrophy panels, then if you want to test your DNA for Blue Cone Monochromacy, please refer to the BCMFF no-cost DNA Test program.

Management, Treatment and Research of Inherited Retinal Diseases

Devices such as magnifiers, screen readers, and specialized software can help individuals with IRDs manage their vision loss.

Recent years have also seen the number of therapeutic trials grow exploring novel treatments for inherited retinal diseases, with a particular focus on gene therapy, which involves delivering a normal copy of the defective gene to retinal cells. Treatments target specific genetic causes of disease and stages of the degenerative process. 

Other strategies, including retinal prostheses, stem cell therapies, optogenetics gene therapies [8], and gene editing, are also under investigation.

 The FDA (in 2017), the EMA (in 2018), and Health Canada and the Therapeutic Goods Administration of Australia (2020) approved voretigene neparvovec-rzyl for Leber Congenital Amaurosis RPE65-related IRD to specifically treat patients in countries where it is approved.

External Resources

1. https://preventblindness.org/wp-content/uploads/2024/04/Inherited-Retinal-Diseases-Factsheet.pdf

2. https://onlinelibrary.wiley.com/doi/10.1111/ceo.13917

3. https://preventblindness.org/inherited-retinal-diseases/

4. https://www.childrenshospital.org/conditions/inherited-retinal-disorders

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9654499/

6. https://www.nature.com/articles/s41598-022-24636-1

7. https://www.fightingblindness.org/

8. https://nanostherapeutics.com/technology-2/

9. https://www.aao.org/education/clinical-statement/guidelines-on-clinical-assessment-of-patients-with

10. https://www.retina.janssen.com/inherited-retinal-diseases

11. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013 Aug;84(2):132-41. doi: 10.1111/cge.12203. Epub 2013 Jun 19. PMID: 23701314; PMCID: PMC3856531.

12. https://eyewiki.aao.org/Leber_Congenital_Amaurosis

13. https://www.fightingblindness.org/diseases/retinitis-pigmentosa

14. https://www.aao.org/education/disease-review/stargardt-disease-stgd

15. Hanany M, Shalom S, Ben-Yosef T, Sharon D. Comparison of Worldwide Disease Prevalence and Genetic Prevalence of Inherited Retinal Diseases and Variant Interpretation Considerations. Cold Spring Harb Perspect Med. 2024 Feb 1;14(2):a041277. doi: 10.1101/cshperspect.a041277. PMID: 37460155; PMCID: PMC10835612.