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Meesmann epithelial corneal dystrophy: for professionals

Clinical phenotype

Incidence
  • Unknown
Corneal Features
  • Tiny round to oval punctate opacities predominantly in the central interpalpebral zone (direct illumination)
  • May extend to the limbus
  • Best visualised with retroillumination—multiple clear intra-epithelial microcysts
  • Cysts do not stain with fluorescein except when it has broken through to the surface
Symptoms
  • Childhood onset
  • Most are relatively asymptomatic throughout childhood
  • Some can experience foreign body sensation, glare, photophobia and painful epithelial erosions during adult life due to ruptured cysts
  • Symptoms may worsen with age due to increasing number of cysts
  • Severe visual loss may rarely occur due to secondary Salzmann degeneration, corneal vascularisation and amblyopia[1]
Close up image of multiple small clear cysts on the cornea
Retro-illumination image showing multiple intraepithelial cysts

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

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Genetics

Gene (OMIM no.) and associated function
  • KRT3 (#148043) and KRT12 (#601687)
  • Encodes cornea-specific cytokeratins (K3 and K12)
  • K3 and K12 form intermediate filaments that are integral to the mechanical strength and support of the epithelial cells[2]
Genotype-phenotype correlation
  • Meesmann epithelial corneal dystrophy (MECD) is mainly caused by missense mutations in the terminal regions flanking the central rod domain of KRT3 (exon 7) and KRT12 (exons 1 and 6)[3]
  • The terminal regions are crucial for correct protein folding and the assembly of intermediate filaments
  • KRT12: p.Arg135Thr mutation is common in Europe[4]; p.Leu132Pro mutation is associated with a severe disease phenotype[1]
Inheritance pattern

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Key investigations

  • Anterior segment OCT (AS-OCT): Hyper-reflective vacuoles measuring about 50𝜇m diameter

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Diagnosis

MECD can be diagnosed through slit lamp examination. AS-OCT supports the diagnosis by identifying the hyper-reflective vacuoles in the epithelial layer. Genetic testing can be undertaken to confirm the diagnosis of TGFBI-associated corneal dystrophies, 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

  • Topical lubricants and/or extended wear therapeutic contact lenses are primary therapeutic options for patients experiencing painful recurrent erosions; topical antibiotics can be added during acute flare-ups to prevent secondary infections
  • Excimer laser superficial phototherapeutic keratectomy (PTK) may help with more severe recurrent erosions but rapid recurrence is common
  • Corneal thickness must be measured prior to PTK as it may thin the cornea[5]
  • The number of PTK attempts are limited due to progressive corneal thinning with repeated procedures
  • Corneal transplantations (lamellar or penetrating keratoplasty) may be required for more severe phenotypes but recurrence can occur within the graft; Most likely due to the repopulation of the host’s dysfunctional epithelial cells differentiated from the limbal stem cells

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Current research in MECD

The pathogenic mutations in KRT3 and KRT12 causing MECD act in a dominant negative manner. This means that therapies that suppress the transcription of the mutant allele may reverse the disease phenotype as normal allele expression is not disrupted.

Two therapeutic approaches for MECD have been investigated so far in vitro, which are:

  • gene silencing with allele-specific short-interfering RNA (siRNA) molecules and
  • (gene editing using the CRISPR/Cas9 technology.[6,7]

Gene silencing or RNA interference is a naturally occurring process used by cells to regulate gene expression. It is mediated by three types of small RNA molecules, siRNAs, micro RNAs and piwi-interacting RNAs.[8] Allele-specific siRNAs can be designed for the treatment of various conditions, including the severe MECD phenotype associated with the p.Leu132Pro mutation.[9-11] CRISPR/Cas9 gene editing can identify the  mutated DNA sequence using a guide RNA, then correct this by cutting out the mutation and using a template to repair the DNA sequence. Although these are promising therapies for the future, delivery to the cornea remains a significant challenge that needs to be overcome.[12]

Related links

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Further information and support

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References

  1.  Hassan H, Thaung C, Ebenezer ND, Larkin G, Hardcastle AJ, Tuft SJ. Severe Meesmann’s epithelial corneal dystrophy phenotype due to a missense mutation in the helix-initiation motif of keratin 12. Eye (Lond). Mar 2013;27(3):367-73. doi:10.1038/eye.2012.261
  2.  Herrmann H, Aebi U. Intermediate Filaments: Structure and Assembly. Cold Spring Harb Perspect Biol. Nov 1 2016;8(11)doi:10.1101/cshperspect.a018242
  3.  Omary MB, Coulombe PA, McLean WH. Intermediate filament proteins and their associated diseases. N Engl J Med. Nov 11 2004;351(20):2087-100. doi:10.1056/NEJMra040319
  4.  Corden LD, Swensson O, Swensson B, et al. Molecular genetics of Meesmann’s corneal dystrophy: ancestral and novel mutations in keratin 12 (K12) and complete sequence of the human KRT12 gene. Exp Eye Res. Jan 2000;70(1):41-9. doi:10.1006/exer.1999.0769
  5.  Hieda O, Kawasaki S, Yamamura K, Nakatsukasa M, Kinoshita S, Sotozono C. Clinical outcomes and time to recurrence of phototherapeutic keratectomy in Japan. Medicine. 2019;98(27):e16216-e16216. doi:10.1097/MD.0000000000016216
  6.  Courtney DG, Atkinson SD, Allen EH, et al. siRNA silencing of the mutant keratin 12 allele in corneal limbal epithelial cells grown from patients with Meesmann’s epithelial corneal dystrophy. Invest Ophthalmol Vis Sci. May 6 2014;55(5):3352-60. doi:10.1167/iovs.13-12957
  7.  Courtney DG, Moore JE, Atkinson SD, et al. CRISPR/Cas9 DNA cleavage at SNP-derived PAM enables both in vitro and in vivo KRT12 mutation-specific targeting. Gene Ther. Jan 2016;23(1):108-12. doi:10.1038/gt.2015.82
  8.  Chery J. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc J. Jul 2016;4(7):35-50. doi:10.14304/surya.jpr.v4n7.5
  9.  Liao H, Irvine AD, Macewen CJ, et al. Development of allele-specific therapeutic siRNA in Meesmann epithelial corneal dystrophy. PLoS One. 2011;6(12):e28582. doi:10.1371/journal.pone.0028582
  10.  Davis ME, Zuckerman JE, Choi CH, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. Apr 15 2010;464(7291):1067-70. doi:10.1038/nature08956
  11.  Leachman SA, Hickerson RP, Schwartz ME, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther. Feb 2010;18(2):442-6. doi:10.1038/mt.2009.273
  12.  Schiroli D, Gomara MJ, Maurizi E, et al. Effective In Vivo Topical Delivery of siRNA and Gene Silencing in Intact Corneal Epithelium Using a Modified Cell-Penetrating Peptide. Mol Ther Nucleic Acids. Sep 6 2019;17:891-906. doi:10.1016/j.omtn.2019.07.017

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Updated on November 30, 2020
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