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Fuchs endothelial corneal dystrophy: for patients


Overview

Fuchs endothelial corneal dystrophy is the most common form of corneal dystrophy. It is an inherited condition caused by changes in various genes, which lead to the abnormal function of the innermost layer of the cornea, the endothelium. The endothelium is made up of a single layer of cells (endothelial cells) which rest on a thin membrane (Descemet’s membrane). Endothelial cells normally function to keep the cornea clear and transparent by pumping fluid out of the stroma (the thick middle layer of the cornea).

The three main layers of the cornea. The thick stromal layer is sandwiched in between the superficial epithelium and the deep endothelial layer.
Different layers of the cornea

A small number of endothelial cells are normally lost when we get older but in Fuchs dystrophy this process is accelerated, causing the cornea to swell and become cloudy (corneal oedema), which in turn makes vision blurry. The blurriness is usually worse in the mornings and gets better as the day goes on. However, corneal oedema becomes more permanent over time as more endothelial cells are lost, and eventually cause permanent haziness of vision and blisters to form on the surface of the cornea, which can then burst and cause pain.

Fuchs dystrophy usually develops around middle age (40s or 50s) and tends to affect women more than men. Patients may not experience any symptoms initially but some do go on to develop problems with their vision over time that requires a corneal transplant surgery to restore vision. Rarely, Fuchs dystrophy can also occur in young children.

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The condition

Symptoms

Most patients do not experience any symptoms when the first sign of Fuchs dystrophy is detected (known as corneal guttata), often by an optician during a routine eye check. As the condition progresses slowly over time, a variety of symptoms can occur:

  • Glare due to scattering of light by the corneal guttata
  • Blurry vision which tends to be worse in the morning and improves throughout the day (due to fluid accumulation in the stroma overnight which dries up from the corneal surface once the eyes are open)
  • Progressive worsening of vision as corneal oedema becomes more permanent due to further loss of endothelial cells
  • Grittiness and discomfort once oedema start affecting the superficial layer of the cornea (epithelium) and form blisters
  • The blisters may break in advanced stages, causing a red and painful eye

It is important to note that the severity of symptoms and the rate of disease progression are highly variable among patients, even from within the same family.

Cause

So far changes in 5 genes have been identified to cause Fuchs dystrophy, and the most common gene responsible for Fuchs dystrophy is the TCF4 gene. About 75% of cases in the Caucasian population are caused by a specific mutation (CTG18.1 expansion) in the TCF4 gene.[1,2] Mutations in the COL8A2 gene is specifically associated with a rare type of Fuchs dystrophy that occur in children.[3]

How is it diagnosed?

Fuchs dystrophy is usually diagnosed with an eye examination by an ophthalmologist. There are usually tiny lumps inside the cornea called guttata which is characteristic of this condition. During the eye clinic appointment, you may undergo further tests using specialised cameras and microscopes to assess the shape of the cornea and the health of the endothelial cells. You may also encounter other healthcare professionals such as an optometrist (previously known as opticians) that will perform tests to see if glasses/contact lenses are needed to help you see better.

Genetic testing can be undertaken to help identify the gene responsible so that families can have a more informed genetic counselling session.

Multiple clear cystic-like lesions on a red background.
Corneal guttata which is typical of Fuchs endothelial dystrophy

How is it inherited?

Corneal dystrophies are inherited in various ways depending on the condition and the responsible gene.

1) Autosomal dominant (AD) inheritance

Only one copy of the faulty gene (inherited from either parent) is required to cause Fuchs dystrophy. This means that each newborn of someone affected by Fuchs dystrophy has a 50% chance of inheriting the condition, regardless of gender. Not everyone who inherits a faulty gene causing Fuchs dystrophy will develop the condition in the same way or at all.

The faulty gene copy is present in the father while the mother is not affected. Each newborn of this couple has a 50% chance to be affected by the condition.
Autosomal dominant inheritance

As Fuchs dystrophy is an inherited condition, families may choose to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

Though the underlying genetic cause of Fuchs dystrophy cannot yet be treated, several treatment options are available to improve symptoms. These include:

  • Glasses or rigid contact lenses to sharpen the vision
  • Saline eye drops can help to reduce corneal swelling that leads to blurry vision in the mornings
  • A specialised contact lens (bandage contact lens) can be used to ease the pain caused by broken blisters on the corneal surface while waiting for corneal transplant
  • Corneal transplant surgery is required if there is significant pain associated with the blisters or if the vision is severely affected and not amenable to eye drops

Corneal transplant is a major eye surgery that involves replacing the affected cornea with a healthy cornea from a deceased donor. The donor cornea (graft) can be transplanted in two different ways with comparable visual outcomes:

  • Partial thickness (lamellar keratoplasty)—only the affected layer(s) are replaced
  • Full thickness (penetrating keratoplasty)—all layers of the cornea are replaced

Fuchs dystrophy is now commonly treated with a type of partial thickness graft known as endothelial keratoplasty (EK). The most common EK transplants are Descemet stripping endothelial keratoplasty (DSEK), Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). In DSEK/DSAEK, you receive a new endothelium, Descemet’s membrane and some stroma from the donor tissue. On the other hand, DMEK only involves transplanting the endothelium and Descemet’s membrane. Compared to full thickness penetrating keratoplasty (PK) grafts, EK grafts offer quicker visual recovery time (as not stitches are used) and less risk of rejection.[4]

A graft rejection occurs when the immune system in your body recognises the transplanted cornea as foreign and try to mount an inflammatory response to fight it, which could result in failure of the graft. The inflammatory response can normally be controlled with steroid eye drops but sometimes transplant surgery may need to be repeated with a new graft if there are repeated rejection issues with the current graft.

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Current research in Fuchs dystrophy

1) Gene-based therapy

A specific mutation (CTG18.1 expansion) in the TCF4 gene (most common gene associated with Fuchs dystrophy) contributes to approximately 75% of Fuchs dystrophy cases in Caucasian populations. Consequently, research into therapies that can potentially correct this particular mutation has amassed much interests.

One such therapy is called antisense RNA oligonucleotides (AONs). These are small molecules that are genetically engineered and subsequently injected into the eye to correct a disease-causing genetic mutation. AON treatment targeting the CTG18.1 expansion in cell and animal models have shown some promising results but more work needs to be done before human trials can begin.[2,5] Gene editing using CRISPR/Cas9 technology is also another promising approach that can correct the CTG18.1 mutation.[6]

2) Stem cells

The lack of suitable donor corneal grafts with healthy endothelium has made tissue-engineered endothelial grafts an attractive solution. The grafts can be cultured from stem cells, or reprogrammed from fully developed corneal cells. However, the development of a reliable protocol to culture such grafts that are suitable for human transplantation and the search for an optimum technique to deliver the cultured grafts into the human eye remain challenges that need to be overcome before tissue engineering therapy can be implemented.[7,8]

3) Neuroprotection

Neuroprotective agents encompass a broad range of therapies that aim to promote cell survival and preserve function. Toxic free radicals generated from oxygen consumption by corneal cells have been implicated as the underlying disease mechanisms of Fuchs endothelial corneal dystrophy.[9-11]  A few medications have been identified as potential treatments for Fuchs endothelial corneal dystrophy but further studies are required to confirm these findings. The potential medications are:

Related links

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Practical advice

Living with Fuchs dystrophy

The visual function of patients affected by Fuchs dystrophy is highly variable and most achieve good vision with a combination of supportive measures and/or surgery; some may only have very mild symptoms for majority of their lives. For patients with permanent reduced vision, they are still able to lead a relatively independent life through maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
  • Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

More information can be found in our “How do I see a genetic eye specialist?” page.

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Further information and support

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A patient’s perspective

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References

  1.  Wieben ED, Aleff RA, Tosakulwong N, et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS One. 2012;7(11):e49083
  2.  Zarouchlioti C, Sanchez-Pintado B, Hafford Tear NJ, et al. Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity. Am J Hum Genet. Apr 5 2018;102(4):528-539
  3.  Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. Oct 1 2001;10(21):2415-23
  4.  Baydoun L, Dapena I, Melles G. Evolution of Posterior Lamellar Keratoplasty: PK–DLEK–DSEK/DSAEK–DMEK–DMET. Current Treatment Options for Fuchs Endothelial Dystrophy. Springer; 2017:73-85
  5.  Hu J, Rong Z, Gong X, et al. Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs’ dystrophy. Hum Mol Genet. Mar 15 2018;27(6):1015-1026
  6.  Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. Oct 2017;16(10):837-847
  7.  Okumura N, Kinoshita S, Koizumi N. Cell-Based Approach for Treatment of Corneal Endothelial Dysfunction. Cornea. 2014;33:S37-S41
  8.  Chen S, Zhu Q, Sun H, et al. Advances in culture, expansion and mechanistic studies of corneal endothelial cells: a systematic review. Journal of Biomedical Science. 2019/01/04 2019;26(1):2
  9.  Jurkunas UV, Bitar MS, Funaki T, Azizi B. Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy. Am J Pathol. Nov 2010;177(5):2278-89
  10.  Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS. Unfolded protein response in fuchs endothelial corneal dystrophy: a unifying pathogenic pathway? Am J Ophthalmol. Feb 2010;149(2):194-202.e2
  11.  Borderie VM, Baudrimont M, Vallée A, Ereau TL, Gray F, Laroche L. Corneal endothelial cell apoptosis in patients with Fuchs’ dystrophy. Invest Ophthalmol Vis Sci. Aug 2000;41(9):2501-5

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Updated on November 30, 2020
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