This study describes the clinical and genetic features of Meesmann epithelial corneal dystrophy (MECD) in two unrelated families and reports new genotype-phenotype associations. Ten patients from a Lebanese family (n = 4) (Family 1) and a Spanish family (n = 6) (Family 2) underwent ophthalmologic evaluation, in vivo confocal microscopy (IVCM), anterior segment optical coherence tomography (AS-OCT) with epithelial thickness mapping (ET-map), and targeted next-generation sequencing (NGS) using a custom-designed 133-gene panel associated with anterior segment dystrophies. In Family 1, a novel homozygous KRT12 c.1181T>C (p.Leu394Pro) variant was identified in the symptomatic proband and his clinically asymptomatic brother, while both parents, who were first cousins, were heterozygous for this nucleotide variant. The proband also carried the heterozygous KRT3 c.250C>T (p.Arg84Trp) variant, which has been previously reported but, to our knowledge, has not been described in co-occurrence until now. In addition, the proband showed a complex phenotype with signs of MECD and epithelial basal membrane alterations consistent with epithelial basement membrane dystrophy (EBMD). In Family 2, four affected members carried the KRT3 c.1492G>A (p.Glu498Lys) variant in heterozygosity, which has been previously described. The elderly members affected showed typical signs of MECD and EBMD. To our knowledge, these concomitant alterations have not been previously described with genetical confirmation. In conclusion, this study provides the first evidence that the co-occurrence of variants in two Meesmann corneal dystrophy-associated genes (KRT3 and KRT12) can jointly account for the disease phenotype. We also highlight the association of MECD with EBMD in both families. Characterization using IVCM and AS-OCT ET-Map provides a deeper understanding of the morphological changes and phenotypic variability in MECD, confirming the utility of this multimodal imaging approach for diagnosis and management.

Proven in vivo efficacy is a key requirement for novel gene therapies proceeding to clinical trial. No gene therapies for corneal dystrophies have been able to progress into patient-led studies due to a lack of suitable animal models expressing a disease phenotype comparable to that which develops in humans. Herein, we show an allele-specific siRNA targeting the L132P KRT12 mutation, causative of a severe form of Meesmann Epithelial Corneal Dystrophy (MECD), when complexed with silicon-stabilized hybrid lipid nanoparticles (sshLNP), and applied topically twice daily for seven days, results in restoration of corneal thickness in a humanized mouse model (Krt12+/hL132P) for MECD. Furthermore, expression of disease biomarkers elevated in the MECD mouse model and verified in corneal epithelial cells of MECD family members, was reduced to that observed in unaffected wild-type (Krt12+/+) mice. This represents the first successful use of topical mutant allele-specific siRNA in the treatment of an autosomal genetic corneal dystrophy. The successful silencing of disease biomarkers after topical siRNA treatment indicates expected clinical benefit. Furthermore, we demonstrated that siRNA-sshLNPs can be successfully formulated in sodium hyaluronate-containing eye-drops without impairing efficacy of the siRNA.

Background/Objectives: to report a novel KRT3 Meesmann corneal dystrophy (MECD) mutation and its clinical findings in a Spanish family, thus completing the international database. Case series study. Methods: Two generations of three family members were studied. The clinical ophthalmologic evaluation was made including best-corrected visual acuity (BCVA), biomicroscopy with and without fluorescein, fundoscopy, Schirmer test I, non-invasive break-up time (NiBUT), and esthesiometry. In vivo confocal microscopy (IVCM), anterior segment optical coherence tomography (AS-OCT) with an epithelial map, and genetic analysis were also performed. Results: A novel heterozygous mutation in the KRT3 gene c.1527G>T (p. Glu509Asp) was identified. Biomicroscopy revealed bilateral multiple corneal intraepithelial cysts. IVCM showed numerous and relatively small microcysts (12-32 µm), hyperreflective materials, subepithelial nerve and Bowman's layer alterations. AS-OCT scan revealed diffuse hyperreflectivity and the epithelial map displayed thickening of the corneal epithelium in the interpalpebral zone (proband: 52-68 µm and father's proband: 55-71 µm) with a slightly thinned cornea. Conclusions: We identified a new mutation in the KRT3 gene-c.1527G>T (p. Glu509Asp) in a Spanish family with MECD. A comprehensive characterization of the clinical signs, using different techniques, especially an epithelial map, could be useful to diagnose and monitor epithelial changes by quantitative measures. Epithelial map changes provide better understanding of MECD differential epithelial behavior and its progression changes. Larger studies will be necessary to better understand these specific patterns and clinically evaluate new therapies. Corneal dystrophy (CD) is most recently defined as a collection of rare hereditary non-inflammatory disorders of abnormal deposition of substances in the cornea. CD was coined in 1890 by Arthur Groenouw and Hugo Biber, and the efforts of Ernst Fuchs, Wilhelm Uhthoff, and Yoshiharu Yoshida solidified the foundation of the understanding of these diseases. As proposed in 2015 by the International Classification of Corneal Dystrophies (IC3D), CD is sub-classified by the anatomic location affected: epithelial/subepithelial, epithelial-stromal, stromal, and endothelial dystrophies. Discoveries and unique case studies continue to broaden our understanding and classification of these diseases; therefore, it is difficult to categorize every single dystrophy solely into these four major labels.   The objective of this article is to present an overview of the evaluation and management for the most prominent and understood variants of CD. Highlights of these dystrophies will be discussed. However, further in-depth discussion on these dystrophies will be in separate StatPearls articles.  Patients with CD can be asymptomatic, but if symptoms occur, they typically experience bilateral visual acuity loss, typically in the form of irregular astigmatism. Depending on the corneal layer affected, patients may also manifest with photophobia, dry eyes, corneal edema, and recurrent corneal erosions, especially with epithelial-based CD, which causes considerable pain. Symptoms can begin at any age, depending on the diagnosis. Treatment can range from conservative measures to corneal transplantation.   CD is a significant but rare ocular disease. The genetic component of this disease is important for patients to understand, especially for affected patients involved with family planning. As we begin to understand genetics in greater detail, better evaluation and treatments for CD will come to fruition.  The objective of this article is to present an overview of the general evaluation and management for the most prominent and understood variants of CD. Highlights of these dystrophies will be covered, but the author intends to elaborate on these dystrophies separately in other StatPearls articles. The variants of CD based on their new anatomic classifications in IC3D are:  Epithelial and subepithelial dystrophies  : Epithelial basement membrane corneal dystrophy (EBMCD), also previously known as map-finger-dot dystrophy, Cogan microcystic dystrophy, and anterior basement membrane dystrophy. . Epithelial recurrent erosion dystrophies (EREDs) which includes Franceschetti corneal dystrophy, dystrophia smolandiensis, and dystrophia helsinglandica . Subepithelial mucinous corneal dystrophy (SMCD) . Meesmann corneal dystrophy (MECD) also known as juvenile epithelial corneal dystrophy . Lisch epithelial corneal dystrophy (LECD) . Gelatinous drop-like corneal dystrophy (GDLD) . Epithelial-Stromal Dystrophies (still included under epithelial and subepithelial dystrophies) : Lattice corneal dystrophy (LCD), with its subtypes: type I (TGFBI mutation) and type II (familial amyloidosis Finnish type), including LCD variants . Granular corneal dystrophy (GCD), types I and II (Avellino-type)  . Reis-Bückler’s corneal dystrophy (RBCD) . Thiel-Behnke corneal dystrophy (honeycomb dystrophy) (TBCD) . Stromal dystrophies: Macular corneal dystrophy (MCD)  . Schnyder corneal dystrophy (SCD)  . Congenital stromal corneal dystrophy (CSCD)  . Fleck corneal dystrophy (FCD)  . Posterior amorphous corneal dystrophy (PACD)  . Pre-Descemet corneal dystrophy (PDCD)  . Central cloudy dystrophy of francois (CCDF) . Endothelial Corneal Dystrophies: Fuchs endothelial corneal dystrophy (FECD)  . Posterior polymorphous corneal dystrophy (PPCD)  . Congenital hereditary endothelial dystrophy (CHED)  . X-linked endothelial corneal dystrophy (XECD) .

The patient was a 26-year-old woman who had manifest refraction and uncorrected and corrected distance visual acuities of -7.00 × -4.50 at 175°, 20/400, and 20/25, respectively, in the right eye, and -3.25 × -5.25 at 179°, 20/200, and 20/25, respectively, in the left eye. In the right and left eyes, the mean corneal thicknesses were 733 and 749 µm, and the maximum epithelial thicknesses were 70 and 68 µm, respectively. Myriads of intraepithelial cysts were observed in the slit-lamp examination. At 30 months after femtosecond laser-assisted laser in situ keratomileusis (femto-LASIK), the manifest refraction and uncorrected and corrected distance visual acuities were respectively 0.00 × -1.25 at 55°, 20/25, and 20/20 in right eye, and 0.00 × -0.50 at 135°, 20/20, and 20/20 in the left eye. In this case of Meesmann dystrophy, myopia was successfully treated with thick flap femto-LASIK without complications or ectasia. A paciente era uma mulher de 26 anos com refração manifesta, acuidade visual para longe não corrigida e corrigida de -7,00 × -4,50 a175°, 20/400 e 20/25 no olho direito e -3,25 × -5,25 a 179°, 20/200 e 20/25 no olho esquerdo. A espessura média da córnea foi de 733 e 749 µm, e a espessura epitelial máxima foi de 70 e 68 µm, respectivamente no olho direito e no esquerdo. Inúmeros cistos intraepiteliais foram observados no exame com lâmpada de fenda. Trinta meses após o femto-LASIK, a refração manifesta, a acuidade visual para longe não corrigida e corrigida eram respectivamente de 0,00 × -1,25 a 55°, 20/25 e 20/20 no olho direito e 0,00 × -0,50 a 135°, 20/20 e 20/20 no olho esquerdo. Neste caso de distrofia de Meesmann, a miopia foi tratada com sucesso com femto-LASIK de retalho espesso sem complicações ou ectasia.