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What are inherited retinal diseases?

What are inherited retinal diseases?

Inherited retinal diseases defined

Inherited retinal diseases are a group of rare eye disorders that can lead to serious vision impairment or loss. They are sometimes also referred to as inherited retinal dystrophies or disorders. These conditions can occur when one or more of your genes are not working properly.

You are not alone

Approximately 1 in 2,000 people have inherited retinal diseases based on global estimates*

*Prevalence may vary by region, locality or subpopulation.

What are genes and gene variants?

Genes

Genes can be considered the great blueprint for life. Genes are stored in nearly every cell of your body and contain DNA, also known as deoxyribonucleic acid, which carries instructions for how you look and everything that makes you unique. As the body’s instruction manual, genes tell parts of your body how to grow and function.

Gene variants

A “gene variant” is a change in one or more of the DNA sequences that make up your genes. A change means something was added, missing, or replaced in the DNA sequence.

How do inherited retinal diseases happen?

The video breaks down what genes are and how gene variants can impact our vision

Hi, I’m Elena the genetic counselor, here to help you find more answers. You might be wondering, “How do inherited retinal diseases happen?” To find the answer, let’s take a closer look at our genes.

Genes are often called the great blueprint for life. As the body's instruction manual, our genes tell all parts of our body, including our eyes, how to grow and function.1,2

Humans have approximately 25,000 genes.1 Genes are stored in nearly every cell of our body, housed in small threadlike structures called chromosomes.3 We have 23 pairs of chromosomes.4 For each pair, we inherit one chromosome from our mother and one from our father.

Within each of our chromosomes are strands of deoxyribonucleic acid, commonly known as DNA.2 If genes are the blueprint for life, think of DNA as the instructions within those blueprints. They carry very specific instructions for how tall we can grow, the color of our hair, and the many characteristics that make us unique.2

Each DNA sequence is made up of thousands of building blocks that are abbreviated as As, Cs, Gs, and Ts.2 These letters are strung together in long strands. The order of these letters provides specific instructions to our body.2 When the inherited DNA sequence contains a slight change—like a missing letter, or a letter is replaced by another, or there are a few added letters—that's when we inherit a gene variant from our parents and can potentially pass it to future generations.5

Most gene variants are considered benign, which means they aren’t believed to have a serious impact on our health.5,6 However, some gene variants can affect how our bodies function, including our eyes.6 This could result in vision loss or impairment from an inherited retinal disease.7,8

A genetic test is the only way to precisely identify the genetic cause of vision loss or impairment.8,9 With the evolution of genetic testing comes the ability to potentially find the genetic cause of inherited retinal diseases in even more people.10,11 Just in the past 10 years alone, nearly 100 new genes related to inherited retinal diseases have been discovered, bringing the total identified to over 270 genes.12 And science continues to advance.

So, if you’ve never had a genetic test, or a prior test showed negative or inconclusive results, talk to your eye specialist or genetic counselor about genetic testing or retesting.10,11,13 Move forward with more answers, and stay tuned for my next video about the different ways retinal diseases can be inherited at EyesOnGenes.com.

References

1 MedlinePlus Genetics. National Institutes of Health. What is a gene? 2021. Available at: https://medlineplus.gov/genetics/understanding/basics/gene. Last accessed: January 2024.

2 MedlinePlus Genetics. National Institutes of Health. What is DNA? 2021. Available at: https://medlineplus.gov/genetics/understanding/basics/dna/. Last accessed: January 2024.

3 MedlinePlus Genetics. National Institutes of Health. What is a chromosome? 2021. Available at: https://medlineplus.gov/genetics/understanding/basics/chromosome/ Last accessed: January 2024.

4 MedlinePlus Genetics. National Institutes of Health. How many chromosomes do people have? 2021. Available at: https://medlineplus.gov/genetics/understanding/basics/howmanychromosomes/ Last accessed: January 2024.

5 MedlinePlus Genetics. National Institutes of Health. What is a gene variant and how do variants occur? 2021. Available at: https://medlineplus.gov/genetics/understanding/mutationsanddisorders/genemutation/#:~:text=A%20gene%20variant%20is%20a,is%20a%20more%20accurate%20term. Last accessed: January 2024.

6 MedlinePlus Genetics. National Institutes of Health. How can gene variants affect health and development? 2021. Available at: https://medlineplus.gov/genetics/understanding/mutationsanddisorders/mutationscausedisease/ Last accessed: January 2024.

7 Cremers FP, et al. Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype–Phenotype Correlations, and Inheritance Models. Genes. 2018; 9(4):215

8 Ziccardi L, et al. Gene Therapy in Retinal Dystrophies. Int J Mol Sci. 2019; 20(22):5722.

9 Tatour Y, et al. Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects. Diagnostics (Basel). 2020;10(10):779

10 Lee K, et al. Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies. Genet Med. 2015; 17(4):245-252

11 Méjécase C, et al. Practical guide to genetic screening for inherited eye diseases. Ther Adv Ophthalmol. 2020; 12:1S28.

12 Ben-Yosef, T. Inherited Retinal Diseases. Int J Mol Sci. 2022 Nov; 23(21): 13467.

13 Birtel J et al. Diagnosis of Inherited Retinal Diseases. Klin Monbl Augenheilkd. 2021; 238(3):249–259.

Let’s take a closer look inside the eye:

Image showing a side view of an eye with light coming in from the left with cones and rods at the back of the eye

How are retinal diseases inherited?

Narrated by Elena, this animated video brings to life 3 ways inherited retinal diseases can occur

Hi, I’m Elena. As a genetic counselor, I’m often asked about how changes within our genes, or “gene variants,” can be inherited. Understanding key information about inherited retinal diseases is how we can start to take control.1,2,3

Today, I’m going to walk us through 3 different ways retinal diseases can be passed down from our parents. The first is autosomal dominant inheritance.4 Whoa, that’s a mouthful! Here’s what it means: You might remember from the Genes 101 video that our genes are housed inside our chromosomes.5 We have 23 pairs of chromosomes.6 For each pair, we receive one chromosome from each parent. To explain how this inheritance pattern works, it helps to imagine two butterflies—one representing a mother, and one representing a father. In this case, the butterfly with the gene variant has an added spot. This spot represents inherited retinal disease in humans. For autosomal dominant inheritance, the child would only need to inherit a single gene variant to be affected by the condition.4,7 So, in the case where a single parent has the gene variant, there’s a 50% chance that the child will inherit that parent’s retinal disease.7 This is represented by the added spot.

Next, we have autosomal recessive inheritance.4 Here, even if our parents don’t have an inherited retinal disease, they can still be “carriers.”4 A carrier is someone who carries the gene variant, but most of the time does not have symptoms.4 In rare cases, a “carrier” may experience symptoms. In either case, carriers can pass down the gene variant to their children.4 Unlike autosomal dominant inheritance, the child would have to inherit 2 copies of a gene variant, 1 from their mother and 1 from their father, to be affected by the condition.4,8 What that means is, in the cases where both parents are carriers but are not affected by the condition, there’s a 25% chance that the child will inherit both copies of the gene variant and inherit a retinal disease, and a 50% chance that the child will inherit a single copy and only be a carrier.4

Now let’s examine X-linked recessive inheritance. For X-linked conditions, we need to take a closer look into the chromosomes of each parent because in this pattern, gene variants are passed through the X chromosome.4 Females have 2 X chromosomes, and males have 1 X and 1 Y.9 So, if a female were to inherit an X chromosome with a gene variant, she still has another healthy X chromosome that could act as a backup and function properly. However, males only inherit 1 X chromosome, and if that happens to have a variant, he doesn’t have that backup healthy chromosome.4,9 This leaves them more at risk of being affected by an X-linked recessive condition.4,9 In the case where the mother is a carrier, and the father is unaffected by the condition, if they have a son, there’s a 50% chance that he will be affected.10 However, if they have a daughter, there’s a 50% chance that she will be a carrier of the gene variant.10 It's important to remember that these outcomes can change depending on which parent possesses the gene variant.10

Now, we know that’s a whole lot to take in. Understanding inheritance patterns plays a big role in understanding how these conditions are passed down. It’s important to know that family history is only one of the pieces we use to solve the diagnosis puzzle. You can still inherit genes that cause retinal diseases with no known family history of these diseases.11 A genetic test, along with the correct eye exams, may give us more answers.2,12 Move forward with more answers and stay tuned for more episodes at EyesOnGenes.com.

References

1 Branham K et al. Am J Med Genet C Semin Med Genet. 2020; 184(3):571–577.

2 Lee K et al. Genet Med. 2015; 17(4):245–252.

3 Lam B.L et al. Orphanet J Rare Dis. 2021; 16,514.

4 Prevent Blindness.org. Inherited Retinal Diseases Factsheet. Available at: Inherited-Retinal-Diseases-Factsheet.pdf (preventblindness.org) Last accessed: October 2023.

5 MedlinePlus Genetics. National Institutes of Health. What is a chromosome? 2021. Available at: https://medlineplus.gov/genetics/understanding/basics/chromosome/ Last accessed: October 2023.

6 MedlinePlus Genetics. National Institutes of Health. How many chromosomes do people have? 2021. Available at: https://medlineplus.gov/genetics/understanding/basics/howmanychromosomes/ Last accessed: October 2023.

7 National Human Genome Research Institute. Autosomal Dominant Disorder. Available at: Autosomal Dominant Disorder (genome.gov) Last accessed: October 2023.

8 National Human Genome Research Institute. Autosomal Recessive Disorder. Available at: Autosomal Recessive Disorder (genome.gov) Last accessed: October 2023.

9 National Human Genome Research Institute. X-linked. Available at: X-Linked (genome.gov) Last accessed: October 2023.

10 Gocuk SA, et al. Female carriers of X-linked inherited retinal diseases – Genetics, diagnosis, and potential therapies. 2023; 96:101190.

11 Moore A.T. Genetic Testing for Inherited Retinal Disease. Ophthalmology. 2017;124(9):1254-1255.

12 Zanolli M et al. Genetic testing for inherited ocular conditions in a developing country. Ophthalmic Genet. 2020; 41(1):36.

Family history alone doesn’t tell the full story

Family history can reveal a lot about inherited retinal diseases, but it’s just one of the pieces that genetic experts and eye specialists use to try to solve the diagnosis puzzle.

Nearly 50%

of people with an inherited retinal disease called retinitis pigmentosa have no knowledge of previous family history.

If you do not have any known family history but have been suspected of having an inherited retinal disease, it’s still important to ask your eye specialist about genetic testing or retesting.

It’s hard to distinguish one inherited retinal disease from another

Overlapping symptoms can make diagnosing inherited retinal diseases challenging. Therefore, genetic testing has become the benchmark to uncover a genetic diagnosis for your vision loss or impairment.

Each inherited retinal disease is different and can have one or more of these common symptoms:1617

  • Difficulty seeing at night
  • Sensitivity to light
  • Blind spots
  • Uncontrolled eye movements
  • Loss of central and/or peripheral vision
  • Farsightedness
  • Colour blindness

There are many different types of inherited retinal diseases. Some include:

Disclaimer: All prevalence rates are global estimates and may vary across regions.

Retinitis pigmentosa (RP)
  • RP is one of the most common inherited retinal diseases18
  • Symptoms may begin in childhood or adulthood
  • Up to 1 in 3,000 people have RP worldwide18
  • Approximately 15% of RP can be inherited in an X-linked pattern and can result in X-linked retinitis pigmentosa (XLRP).19 X-linked refers to the linkage to the X chromosome, one of the sex chromosomes in the human genome. This type of RP is typically more severe in males than females and can result in severe vision impairment or loss20
  • Approximately 30% to 40% of all RP patients have autosomal dominant RP (ADRP), and approximately 50% to 60% have autosomal recessive RP (ARRP), regardless of gender21
  • Variants in more than 100 genes are known to cause a form of retinitis pigmentosa that only affects the eyes
  • Some symptoms include:
    • Progressive vision loss
    • Difficulty seeing at night
    • Blind spots that progress into loss of peripheral vision
    • Loss of central vision over time, which makes it difficult to read, drive, or recognise faces
  • A systemic disease that also affects other organs22
  • There are 3 types of Usher syndrome (USH1, USH2, USH3)22
  • Hearing symptoms usually appear at birth in USH1 and USH2, while hearing loss symptoms usually appear by late childhood or adolescence in USH3. Vision loss appears in childhood in USH1, and usually in adolescence in USH2 and USH322
  • Globally, up to 1 in 6,000 people have USH22
  • Variants in 10 genes are known to cause Usher syndrome22
  • Some symptoms include22:
    • Hearing loss
    • Loss of night vision, the first visual symptom
    • Blind spots that progress into loss of peripheral vision
  • There is differentiation between onset in childhood, early adulthood, and late adulthood, when the average age at onset of symptoms is approximately 55 years2324
  • Up to 1 in 8,000 people have Stargardt disease worldwide23
  • Variants in 2 genes are known to cause Stargardt disease23
  • Some symptoms include:25
    • Loss of central vision over time
    • Night blindness
    • Colour blindness
    • Symptoms and progression vary widely
  • Symptoms usually begin during childhood and worsen over time26
  • Globally, up to 1 in 40,000 people have CRD26
  • Variants in more than 30 genes are known to cause cone-rod dystrophy26
  • Some symptoms include26:
    • Decreased sharpness of vision
    • Sensitivity to light
    • Problems recognising colours
    • Blind spots
    • Loss of peripheral vision over time
    • Blindness by mid-adulthood
  • Symptoms develop in the first few months of life27
  • Up to 1 in 30,000 people have achromatopsia worldwide27
  • Variants in 6 genes are known to cause achromatopsia27
  • Some symptoms include27:
    • Partial or total loss of colour vision
    • Can only see black, white and shades of grey
    • Increased sensitivity to light
    • Involuntary eye movements
    • Reduced sharpness of vision
    • Farsightedness, or less commonly, nearsightedness
  • Symptoms usually appear during infancy28
  • Up to 1 in 33,000 people have LCA worldwide28
  • Variants in at least 38 genes are known to cause Leber congenital amaurosis28
  • Some symptoms include28:
    • Night blindness
    • Vision loss at infancy
    • Increased sensitivity to light
    • Involuntary eye movements
    • Extreme farsightedness
    • Pupils not reacting normally to light
  • Symptoms usually begin in early childhood29
  • Up to 1 in 50,000 males have CHM worldwide29
  • More males are affected by CHM than females29
  • Variants in the CHM gene cause choroideraemia29
  • Some symptoms include29:
    • Night blindness in early childhood
    • Loss of peripheral vision
    • Less ability to see details over time
    • Blindness, most commonly in late adulthood
  • A systemic disease that also affects other organs30
  • Symptoms begin early- to mid-childhood30
  • Up to 1 in 100,000 – 1 in 140,000 people in North America and 1 in 125,000 – 1 in 160,000 people in Europe have BBS31
  • Variants in at least 26 genes are known to cause Bardet-Biedl syndrome30
  • Some symptoms include30:
    • Night vision loss
    • Progressive peripheral vision loss
    • Issues with colour discrimination
    • Overall loss of visual acuity
    • Problems with kidneys and eyes
    • Obesity
    • Born with extra fingers or toes
    • Learning disabilities31
    • Developmental delays
More answers lie in our genes

While you can’t change what you inherit, you may find answers that can help put you in control of your future.3233

Microscope icon
5 simple steps to test

Know what to expect before, during and after your genetic test or retest.

References

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Myasthenia Gravis Foundation of America (MGFA). A Manual for the Healthcare Provider. Available at: https://myasthenia.org/Portals/0/Provider%20Manual_ibook%20version.pdf Last accessed: June 2024.
[2]
National Institute of Neurological Disorders and Stroke (NINDS). Myasthenia Gravis. Available at: https://www.ninds.nih.gov/health-information/disorders/myasthenia-gravis Last accessed: June 2024.
[3]
Dewilde S, et al. People Diagnosed with Myasthenia Gravis have Lower health-related quality of life and Need More Medical and Caregiver Help in Comparison to the General Population: Analysis of Two Observational Studies. Adv Ther. Vol 40, 4377–4394 (2023). Available at: https://doi.org/10.1007/s12325-023-02604-z Last accessed: June 2024.
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Mahic, et al. Healthcare resource use in myasthenia gravis: a US health claims analysis. Ther Adv Neurol Disorders (2023). Available at: https://doi.org/10.1177/17562864221150327 Last accessed: June 2024.
[5]
Daum P et al. Perioperative management of myasthenia gravis. BJA Education (2021) 21(11): 414e419
[6]
John Hopkins Medicine. Myasthenia Gravis. Available at: https://www.hopkinsmedicine.org/health/conditions-and-diseases/myasthenia-gravis Last accessed: June 2024.
[7]
Mishra A, et al. Myasthenia Gravis: A Systematic Review. Cureus (2023) 15(12): e50017. DOI 10.7759/cureus.50017.
[8]
Luo H, Xie S, Ma C, Zhang W, Tschöpe C, Fa X, Cheng J, Cao J. Correlation Between Thymus Radiology and Myasthenia Gravis in Clinical Practice. Front Neurol. 2019 Jan 15;9:1173. doi: 10.3389/fneur.2018.01173. PMID: 30697185; PMCID: PMC6340958.
[9]
Chen J, Tian D-C, Zhang C, et al. Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study. The Lancet Regional Health - Western Pacific. 2020;5(100063). https://doi.org/10.1016/j.lanwpc.2020.100063.
[10]
Lazaridis K, et al. Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics. Front Immunol. 2020 Feb 14;11:212. doi: 10.3389/fimmu.2020; 00212. Last accessed: June 2024.
[11]
Myasthenia Gravis Foundation of America (MGFA). Seronegative MG Resource Center. Available at: https://myasthenia.org/Newly-Diagnosed/Seronegative-MG-Resource-Center Last accessed: June 2024.
[12]
Jackson et al. Understanding the symptom burden and impact of myasthenia gravis from the patient’s perspective: A qualitative study. Neurology and Therapy. 2022;12:1; 107–128. Available at: https://doi.org/10.1007/s40120-022-00408-x.
[13]
Myasthenia Gravis Foundation of America (MGFA). Myasthenia Gravis Clinical Overview. Available at: https://myasthenia.org/Professionals/Clinical-Overview-of-MG#DIAGNOSTIC. Last accessed: June 2024
[14]
NHS. Myasthenia Gravis. Available at: https://www.nhs.uk/conditions/myasthenia-gravis/ Last accessed: June 2024.
[15]
NHS. Diagnosis Myasthenia Gravis. Available at: https://www.nhs.uk/conditions/myasthenia-gravis/diagnosis/ Last accessed: June 2024.