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Fuchs endothelial corneal dystrophy: for professionals

Clinical phenotype

Incidence
  • >1% (FECD type 3 secondary to TCF4 mutations)
Corneal Features
  • Central corneal guttata (posterior focal thickening of the Descemet membrane) is the earliest manifestation
  • Areas with corneal guttata progressively enlarge over time
  • Associated with endothelial cell loss, corneal oedema, epithelial bullae and subepithelial fibrosis (advanced stage)
  • 2 forms: early-onset (uncommon) and late-onset (prevalent)
  • Early-onset FECD is usually clinically evident in 1st decade of life (1:1 gender ratio)
  • Clinical features in late-onset FECD tend to be detected in the 4th or 5th decade of life (female predominance with a ration of 3.5:1)[1]
Symptoms
  • Glare due to light scatter from guttata
  • Progressive visual loss from enlarging guttata and corneal oedema
  • Diurnal variation of visual acuity as oedema tends to be worse in the mornings
  • Painful corneal erosions due to ruptured epithelial bullae in advanced cases
Multiple clear cystic-like lesions on a red background.
Retroillumination image demonstrating multiple punctate guttata

Credit: Mr Stephen Tuft, consultant ophthalmologist, Moorfields Eye Hospital, London

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Genetics

Gene/Locus
(OMIM no.)		Phenotype (OMIM no.)Remarks
COL8A2 (#120252)Corneal dystrophy, Fuchs endothelial, 1 (#136800); Early-onset FECD[2]
13pter-q12.13 (#610158)Corneal dystrophy, Fuchs endothelial, 2 (#610158); Late-onset FECD[3]Exact gene not identified yet but mapped to chromosome 13
TCF4 (#602272)Corneal dystrophy, Fuchs endothelial, 3 (#613267); Late-onset FECD[4]
  • Most common cause of FECD
  • About 75% of Caucasian FECD are due to CTG trinucleotide repeat (CTG18.1 allele) expansion (≥50 copies)[5,6]
  • Disease severity associated with repeat length in Caucasian populations[7]
SLC4A11 (#610206)Corneal dystrophy, Fuchs endothelial, 4 (#613268); Late-onset FECD[8]Biallelic mutations (AR) associated with congenital hereditary endothelial dystrophy
5q33.1-q35.2 (#613269)Corneal dystrophy, Fuchs endothelial, 5 (#613269); Late-onset FECD[9]Exact gene not identified yet but mapped to long arm chromosome 5
ZEB1 (#189909)Corneal dystrophy, Fuchs endothelial, 6 (#613270); Late-onset FECD[10]Null mutations are associated with posterior polymorphous corneal dystrophy
9p24.1-p22.1 (#613271)Corneal dystrophy, Fuchs endothelial, 7 (#613271); Late-onset FECDPresence of both the p.Gln840Pro allele in ZEB1 and the 9p locus can cause a more severe FECD phenotype than their individual phenotypes[10]
AGBL1 (#615496)Corneal dystrophy, Fuchs endothelial, 8 (#615523); Late-onset FECD[11]

Mutations in all the identified genes and chromosomal loci are inherited in an autosomal dominant manner. The genotypes associated with late-onset Fuchs endothelial corneal dystrophy (FECD) have incomplete penetrance with variable expressivity while COL8A2 mutations causing early-onset FECD are more highly penetrant.

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Key investigations

  • Anterior segment OCT or Scheimpflug imaging (Pentacam)— To assess corneal shape and thickness
  • Specular microscopy—To detect guttata and assess overall endothelial cell density, variations in size (polymegathism) and shape (pleomorphism)
  • Confocal microscopy—Guttata appear as round hyporeflective areas with occasional central highlight in the endothelial level; It is superior to specular microscopy in visualising the endothelium in the presence of corneal oedema[12]

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Diagnosis

FECD can be diagnosed clinically. Genetic testing can be undertaken to confirm the diagnosis, facilitate genetic counselling, provide accurate advice on prognosis and future family planning, and aid in clinical trial participation.

This can be achieved through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (anterior segment dysgenesis)
  • Whole exome sequencing
  • Whole genome sequencing

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Management

  • Visual rehabilitation with glasses or rigid contact lenses if refractive error is present
  • Mild cases are managed with topical hypertonic (5%) sodium chloride drops
  • Corneal transplantations are needed for advanced cases (one of the most common indications for keratoplasties in developed countries)
  • Endothelial keratoplasty (EK) is the preferred surgical option currently due to faster visual recovery, less post-operative astigmatism, lower rejection rates and absence of sutures[13]
  • Descemet stripping endothelial keratoplasty (DSEK)[14]/Descemet stripping automated endothelial keratoplasty (DSAEK)[15] and Descemet membrane endothelial keratoplasty (DMEK)[16] are widely used EK techniques

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Current research

1) Cell-based therapy

The scarcity of appropriate graft tissue has led to the development of cell culture technologies to generate transplant grade corneal endothelial cells.[17] The cultured cells can be transplanted into donor corneas in two ways:

  • As a cultured corneal endothelial sheet similar to DSEK/DSAEK and DMEK (technically more challenging)
  • Injected into the anterior chamber as a cell suspension supplemented with a rho-associated protein kinase (ROCK) inhibitor (a simpler procedure)—shown to be safe in a non-randomised, single group study[18]

Inhibition of the ROCK signalling pathway have been shown to enhance corneal endothelial cell proliferation, promote cell adhesion and suppress cell apoptosis.[19] Pre-clinical and small-scale human pilot studies have shown that administration of topical ROCK inhibitor eye drops cleared corneal oedema secondary to endothelial dysfunction but larger randomised controlled trials are needed to validate this finding.[20]

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2) Neuroprotection

Oxidative stress[21], endoplasmic reticulum stress (from accumulation of misfolded proteins)[22] and apoptosis[23] have been implicated as underlying disease mechanisms of FECD. Several drugs have been identified as potential protective factors against these pathologic responses:

3) Gene/allele-based therapies

Antisense RNA oligonucleotides (AONs)

AONs are small molecules that works in an allele-specific manner. It binds complementarily to their target messenger RNAs (mRNA) to block the transcription of a mutant allele or correcting splicing defects at the pre-mRNA level.

Ex vivo studies of human FECD corneas have demonstrated that AONs targeting the CTG18.1 allele in TCF4 are able to ameliorate disease-associated markers of RNA toxicity as a result of the trinucleotide repeat expansion.[6,24] Pre-clinical study using mouse models have also shown that intravitreal injections are a viable delivery method for the AON to access the corneal endothelium.[6]

Gene editing

Utilisation of the CRIPSR/Cas9 technology to treat FECD due to CTG trinucleotide repeat expansion has amassed interest following the successful treatment of a rodent model of Huntington’s disease, a neurodegenerative disorder associated with trinucleotide repeat expansion.[25]

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Further information and support

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References

  1.  Afshari NA, Pittard AB, Siddiqui A, Klintworth GK. Clinical study of Fuchs corneal endothelial dystrophy leading to penetrating keratoplasty: a 30-year experience. Arch Ophthalmol. Jun 2006;124(6):777-80. doi:10.1001/archopht.124.6.777
  2.  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
  3.  Sundin OH, Jun AS, Broman KW, et al. Linkage of late-onset Fuchs corneal dystrophy to a novel locus at 13pTel-13q12.13. Invest Ophthalmol Vis Sci. Jan 2006;47(1):140-5. doi:10.1167/iovs.05-0578
  4.  Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med. Sep 9 2010;363(11):1016-24. doi:10.1056/NEJMoa1007064
  5.  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. doi:10.1371/journal.pone.0049083
  6.  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. doi:10.1016/j.ajhg.2018.02.010
  7.  Soliman AZ, Xing C, Radwan SH, Gong X, Mootha VV. Correlation of Severity of Fuchs Endothelial Corneal Dystrophy With Triplet Repeat Expansion in TCF4. JAMA Ophthalmol. Dec 2015;133(12):1386-91. doi:10.1001/jamaophthalmol.2015.3430
  8.  Vithana EN, Morgan PE, Ramprasad V, et al. SLC4A11 mutations in Fuchs endothelial corneal dystrophy. Hum Mol Genet. Mar 1 2008;17(5):656-66. doi:10.1093/hmg/ddm337
  9.  Riazuddin SA, Eghrari AO, Al-Saif A, et al. Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1-q35.2. Invest Ophthalmol Vis Sci. Dec 2009;50(12):5667-71. doi:10.1167/iovs.09-3764
  10.  Riazuddin SA, Zaghloul NA, Al-Saif A, et al. Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Genet. Jan 2010;86(1):45-53. doi:10.1016/j.ajhg.2009.12.001
  11.  Riazuddin SA, Vasanth S, Katsanis N, Gottsch JD. Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. Am J Hum Genet. Oct 3 2013;93(4):758-64. doi:10.1016/j.ajhg.2013.08.010
  12.  Chiou AG, Kaufman SC, Beuerman RW, Ohta T, Soliman H, Kaufman HE. Confocal microscopy in cornea guttata and Fuchs’ endothelial dystrophy. Br J Ophthalmol. Feb 1999;83(2):185-9. doi:10.1136/bjo.83.2.185
  13.  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
  14.  Price FW, Jr., Price MO. Descemet’s stripping with endothelial keratoplasty in 50 eyes: a refractive neutral corneal transplant. J Refract Surg. Jul-Aug 2005;21(4):339-45
  15.  Gorovoy MS. Descemet-stripping automated endothelial keratoplasty. Cornea. Sep 2006;25(8):886-9. doi:10.1097/01.ico.0000214224.90743.01
  16.  Melles GR, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea. Sep 2006;25(8):987-90. doi:10.1097/01.ico.0000248385.16896.34
  17.  Okumura N, Kinoshita S, Koizumi N. Cell-Based Approach for Treatment of Corneal Endothelial Dysfunction. Cornea. 2014;33:S37-S41. doi:10.1097/ico.0000000000000229
  18.  Kinoshita S, Koizumi N, Ueno M, et al. Injection of Cultured Cells with a ROCK Inhibitor for Bullous Keratopathy. N Engl J Med. Mar 15 2018;378(11):995-1003. doi:10.1056/NEJMoa1712770
  19.  Okumura N, Ueno M, Koizumi N, et al. Enhancement on Primate Corneal Endothelial Cell Survival In Vitro by a ROCK Inhibitor. Investigative Ophthalmology & Visual Science. 2009;50(8):3680-3687. doi:10.1167/iovs.08-2634
  20.  Okumura N, Kinoshita S, Koizumi N. Application of Rho Kinase Inhibitors for the Treatment of Corneal Endothelial Diseases. Journal of Ophthalmology. 2017/07/02 2017;2017:2646904. doi:10.1155/2017/2646904
  21.  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. doi:10.2353/ajpath.2010.100279
  22.  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. doi:10.1016/j.ajo.2009.09.009
  23.  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
  24.  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. doi:10.1093/hmg/ddy018
  25.  Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. Oct 2017;16(10):837-847. doi:10.1016/s1474-4422(17)30280-6

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Updated on November 30, 2020
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