Age-Related Macular Degeneration

Age-Related Macular Degeneration

Observed genes

Polygenic score

Influential genes: CFH, ARMS2, HTRA

Variations in CFH gene can sometimes incorrectly target the body's healthy cells, including cells in the retina.

Mutations in the ARMS2 gene have been associated to both the development of AMD and its progression to advanced stages.

Mutations in the HTRA gene have also been connected to the development of AMD and its progression.

Overview

Age-related macular degeneration (AMD) is a disease that affects a person's central vision. There are two types: dry (atrophic or nonexudative) and wet (neovascular and exudative) macular degeneration. The dry type is more common (80%) and has a characteristic of slower progression, whereas the wet type is more aggressive and can progress to a loss of central vision in a period of a few days to a few weeks. The symptoms (in both types) include blurry vision, inability to recognize faces, blind spots, difficulties reading, distorted lines, etc. 

170 million people worldwide suffer from AMD and it is a leading cause of adult blindness in developed countries.[1] The risk factors for AMD development are genes, race, ethnicity, age, a family history of AMD, smoking, alcohol consumption, unhealthy diet, chronic medical conditions, cataract surgery, and certain medications. The diagnosis is based on the history and various examination methods (visual acuity test, retina examination, etc.). The treatment consists of smoking cessation, blood pressure control, and vitamin and zinc supplements. Additionally, for the treatment of wet-type AMD, we can use VEGF (vascular endothelial growth factor) inhibitors. 

You can prevent AMD development and progression through some lifestyle modifications (smoking cessation, healthy diet, and physical activity). 

Prevalence & Risk factors

The global prevalence of AMD is estimated to be 170 million. [1] Age-related macular degeneration is a leading cause of adult blindness in developed countries. It varies among racial and ethnic groups (more prevalent in White than Black persons, the intermediate prevalence in Hispanic and Chinese). It also increases with age (after 50 years of age) and becomes more pronounced after age 65. People with a family history of AMD typically have an early-onset and more severe disease. Other risk factors for developing AMD are smoking, alcohol consumption, unhealthy diet, chronic medical conditions (stroke, CAD, hypertension, AIDS, myeloproliferative diseases), cataract surgery, and some medications (aspirin, nitroglycerin, beta-blockers). 

   

Genetics

Age-related macular degeneration is a complex disease that results from both genetic and environmental factors. Examples of well-known environmental risk factors contributing to disease development are age and the habit of smoking, however, gender, race, the health of the cardiovascular system, and diet are also associated with this condition. About half of AMD cases are caused by genetics, with the CFH and ARMS2/HTRA1 genes being the most well-known and described. It is important to consider all the factors when you want to take some preventive steps.

Technological advances allowing the analysis of whole genomes and underlying molecular pathways, instead of just individual genes, have facilitated and accelerated the process of discovering new genetic associations with many common complex diseases, not just AMD. Genetics is estimated to contribute to approximately 50% of AMD cases. Results from previous family studies, twin studies, and segregation analyzes were examined by the researchers, and in the case of an affected first-degree relative, a higher risk was found than in controls without a positive family history - resp. 23.7% vs 11.6%. 

Specifically, imbalance and dysregulation of the complement system (CFH gene on chromosome 1) appear to play an important role in the development of AMD. However, genes not involved in complement pathways have also been identified, e.g. the ARMS2/HTRA1 locus on chromosome 10. This locus is thought to be associated with a population risk of up to 57%.[2-4]

Genetic testing allows us to detect whether you have the predisposition to develop this disease. In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

Signs & Symptoms

There are 2 types of AMD: dry (atrophic or nonexudative) and wet (neovascular and exudative).

Dry AMD is the most common and comprises around 80% of cases. The loss of vision in this case is usually slow. Early AMD is often asymptomatic, then there is a gradual loss of vision in one or both eyes. It can present as blurry vision, inability to recognize faces, blind spots, and difficulties reading. 

Wet AMD is less common but it accounts for 80% of cases with severe visual loss or blindness. It is characterized by rapid distortion and loss of central vision over a period of a few days days to weeks. It usually appears in one eye, although the disease is often present in both eyes. Distortion of straight lines (metamorphopsia) is one of the earliest changes seen in wet AMD.  Patients may also present with complaints of a dark patch in their central vision (scotoma). Most patients with advanced AMD lose central vision, but they rarely lose their peripheral vision.

In a minority of patients, dry AMD can progress to wet. 

Diagnosis

The diagnosis is based on the history and various examination methods. The doctor can perform a visual acuity test to measure the vision ability at various distances. Pupil dilation can be induced pharmacologically to allow a close-up examination of the retina. Other tests that can be done include fluorescein dye retinal angiography, optical coherence tomography, and fundus autofluorescence. 

Patients should test each eye daily and immediately report line distortions or scotomas to their clinician.

Therapy

The treatment varies depending on the type of AMD. For the dry type, the recommendations are cessation of smoking, blood pressure control, and supplementation with antioxidative vitamins (A, C, E) and zinc. These are also used for the treatment of the wet type. Furthermore, wet AMD can be treated with intravitreal (inside an eye) injections of VEGF (vascular endothelial growth factor) inhibitors, for example, ranibizumab.

Prevention

Healthy lifestyle habits may be helpful in preventing AMD. These include smoking cessation, physical activity, and a healthy diet. The diet should include fruits, green leafy vegetables, fish, and nuts. Nutritional and vitamin supplements (B, E, C, A) should be used as well. 

Prognosis

Significant loss of vision has a great impact on the functional status and quality of life of a person. It limits the ability to safely drive a car and is associated with increased rates of falls and hip fractures. Also, it results in disability and clinical depression in over one-third of patients, but with early and appropriate treatment most adverse outcomes can be prevented.

Recommendations

  • If you experience any symptoms, visit your doctor.  
  • Improve your health by smoking cessation and physical activity.
  • Keep a healthy diet that includes fruit, green leafy vegetables, fish, and nuts.
  • Take nutritional and vitamin supplements. 
  • Patients should test each eye daily and immediately report line distortions or scotomas to their clinician.

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Recommendations

  • If you experience any symptoms, visit your doctor.  
  • Improve your health by smoking cessation and physical activity.
  • Keep a healthy diet that includes fruit, green leafy vegetables, fish, and nuts.
  • Take nutritional and vitamin supplements. 
  • Patients should test each eye daily and immediately report line distortions or scotomas to their clinician.

Sources

  1. Pennington, K. L., & DeAngelis, M. M. (2016). Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye and Vision (London, England), 3, 34. https://doi.org/10.1186/s40662-016-0063-5
  2. Warwick A, Lotery A. Genetics and genetic testing for age-related macular degeneration. Eye. 2017;32(5):849-857. doi:10.1038/eye.2017.245
  3. Ratnapriya R, Chew EY. Age-related macular degeneration—clinical review and genetics update. Clin Genet. 2013;84(2):160-166. doi:10.1111/cge.12206
  4. Swaroop A, Chew EY, Bowes Rickman C, Abecasis GR. Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration. Annu Rev Genom Hum Genet. 2009;10(1):19-43. doi:10.1146/annurev.genom.9.081307.164350
  5. Genetics and Age-Related Macular Degeneration - American Academy of Ophthalmology, https://www.aao.org/eye-health/diseases/age-related-macular-degeneration-amd-genetics
  6. Pennington, K. L., & DeAngelis, M. M. (2016). Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye and vision (London, England), 3, 34. https://doi.org/10.1186/s40662-016-0063-5
  7. Arroyo J. G., (2020), Age-related macular degeneration: Clinical presentation, etiology, and diagnosis, UptoDate, https://www-uptodate-com.ezproxy.is.cuni.cz/contents/age-related-macular-degeneration-clinical-presentation-etiology-and-diagnosis?search=age%20related%20macular%20degeneration&source=search_result&selectedTitle=2~76&usage_type=default&display_rank=2#H11
  8. Arroyo J. G., (2022), Age-related macular degeneration: Treatment and prevention, UptoDate, https://www-uptodate-com.ezproxy.is.cuni.cz/contents/age-related-macular-degeneration-treatment-and-prevention?search=amd%20treatment%20adult&source=search_result&selectedTitle=1~76&usage_type=default&display_rank=1#H20

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