In the past few years we have seen a great acceleration of discoveries in the field of keratoconus including new treatments, diagnostic tools, genomic and molecular determinants of disease risk. ...Recent genome-wide association studies (GWAS) of keratoconus cases and population wide studies of variation in central corneal thickness and in corneal biomechanical properties confirmed already identified genes and found many new susceptibility variants and biological pathways. Recent findings in genetic determinants of familial keratoconus revealed functionally important variants and established first mouse model of keratoconus. Latest transcriptomic and expression studies started assessing novel non-coding RNA targets in addition to identifying tissue specific effects of coding genes. First genomic insights into better prediction of treatment outcomes are bringing the advent of genomic medicine into keratoconus clinical practice.
Both genetic and environmental factors have been considered to play a role in the etiology keratoconus. Eye rubbing, and more recently eye compression due to sleeping position, have been identified ...to be highly related to the condition, and are present in a high percentage of patients. Today, the predominant model is that these factors can provide the “second hit” necessary to generate the condition in a genetically susceptible individual. In addition, the extremely high prevalence in Arab populations, where endogamy could play a role, the high concordance rate in monozygotic twins, and the presence of family history of the condition between 5 and 23% of cases, support a genetic influence. Segregation analysis studies suggest that keratoconus is a complex non-Mendelian disease. Results from linkage analysis, next generation sequencing studies and genome-wide association studies also have suggested that genetic factors are involved in the condition. Recently, it has been proposed that mechanical trauma (i.e. eye rubbing or eye compression at night), is a sine quanon condition for the onset of keratoconus, and quite possibly its only cause. There are various arguments for and against this hypothesis. Indeed, it is possible, as initially suggested around 55 years ago, that the term “keratoconus” include diverse phenotypically similar conditions, which are actually of different etiology.
•Eye rubbing, and eye compression at night, are risk factors for keratoconus.•They seem to trigger the condition in a genetically susceptible cornea.•High prevalence where endogamy is customary, support a genetic influence.•High concordance rate in twins, and family history, also suggest genetic factors.•Uncommonly secondary keratoconus can be due only to tenacious eye rubbing.
To comprehensively review the available published literature for cross-linking in the pediatric population.
Review of the literature published in English in PubMed.
Two hundred ten publications were ...considered. One hundred fifteen were considered relevant to this review.
Studies of cross-linking in pediatric patients are sparse, with relatively short follow-up times, and mostly on small groups of patients. Treatment with cross-linking halts progression of keratoconus in the pediatric population, and early treatment seems to be cost-effective compared with later penetrating keratoplasty. Long-term effects and regression rates remain unclear, and further studies are needed in this population.
Genetics in Keratoconus: where are we? Bykhovskaya, Yelena; Margines, Benjamin; Rabinowitz, Yaron S
Eye and vision (Novato, Calif.),
06/2016, Letnik:
3, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Keratoconus (KC) is a non-inflammatory thinning and protrusion of the cornea in which the cornea assumes a conical shape. Complex etiology of this condition at present remains an enigma. Although ...environmental factors have been involved in KC pathogenesis, strong underlining genetic susceptibility has been proven. The lack of consistent findings among early genetic studies suggested a heterogeneity and complex nature of the genetic contribution to the development of KC. Recently, genome-wide linkage studies (GWLS) and genome-wide association studies (GWAS) were undertaken. Next-generation sequencing (NGS)-based genomic screens are also currently being carried out. Application of these recently developed comprehensive genetic tools led to a much greater success and increased reproducibility of genetic findings in KC. Involvement of the LOX gene identified through GWLS has been confirmed in multiple cohorts of KC patients around the world. KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated. Rare variants in the ZNF469 gene (mutated in corneal dystrophy Brittle Cornea Syndrome) and in the TGFBI gene (mutated in multiple corneal epithelial-stromal TGFBI dystrophies) have been repeatedly identified in familial and sporadic KC patients of different ethnicities. Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC. Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness. These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.
Keratoconus (KC) is the most common corneal ectasia. We aimed to determine the differential expression of coding and long noncoding RNAs (lncRNAs) in human corneas affected with KC.
From the corneas ...of 10 KC patients and 8 non-KC healthy controls, 200 ng total RNA was used to prepare sequencing libraries with the SMARTer Stranded RNA-Seq kit after ribosomal RNA depletion, followed by paired-end 50-bp sequencing with Illumina Sequencer. Differential analysis was done using TopHat/Cufflinks with a gene file from Ensembl and a lncRNA file from NONCODE. Pathway analysis was performed using WebGestalt. Using the expression level of differentially expressed coding and noncoding RNAs in each sample, we correlated their expression levels in KC and controls separately and identified significantly different correlations in KC against controls followed by visualization using Cytoscape.
Using |fold change| ≥ 2 and a false discovery rate ≤ 0.05, we identified 436 coding RNAs and 584 lncRNAs with differential expression in the KC-affected corneas. Pathway analysis indicated the enrichment of genes involved in extracellular matrix, protein binding, glycosaminoglycan binding, and cell migration. Our correlation analysis identified 296 pairs of significant KC-specific correlations containing 117 coding genes enriched in functions related to cell migration/motility, extracellular space, cytokine response, and cell adhesion. Our study highlighted the potential roles of several genes (CTGF, SFRP1, AQP5, lnc-WNT4-2:1, and lnc-ALDH3A2-2:1) and pathways (TGF-β, WNT signaling, and PI3K/AKT pathways) in KC pathogenesis.
Our RNA-Seq-based differential expression and correlation analyses have identified many potential KC contributing coding and noncoding RNAs.
To determine in a longitudinal study whether there is correlation between videokeratography and clinical signs of keratoconus that might be useful to practicing clinicians.
Cornea-Genetic Eye ...Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Eyes grouped as keratoconus, early keratoconus, keratoconus suspect, or normal based on clinical signs and videokeratography were examined at baseline and followed for 1 to 8 years. Differences in quantitative videokeratography indices and the progression rate were evaluated. The quantitative indices were central keratometry (K), the inferior-superior (I-S) value, and the keratoconus percentage index (KISA). Discriminant analysis was used to estimate the classification rate using the indices.
There were significant differences at baseline between the normal, keratoconus-suspect, and early keratoconus groups in all indices; the respective means were central K: 44.17 D, 45.13 D, and 45.97 D; I-S: 0.57, 1.20, and 4.44; log(KISA): 2.49, 2.94, and 5.71 (all P<.001 after adjusting for covariates). Over a median follow-up of 4.1 years, approximately 28% in the keratoconus-suspect group progressed to early keratoconus or keratoconus and 75% in the early keratoconus group progressed to keratoconus. Using all 3 indices and age, 86.9% in the normal group, 75.3% in the early keratoconus group, and 44.6% in the keratoconus-suspect group could be classified, yielding a total classification rate of 68.9%.
Cross-sectional and longitudinal data showed significant differences between groups in the 3 indices. Use of this classification scheme might form a basis for detecting subclinical keratoconus.
•Corneal collagen crosslinking (CXL) is a safe and effective way of stabilizing corneal ectasia induced by LASIK (post-LASIK ectasia, PLE).•These data were previously shown to be true during a ...shorter post-operative period (less than five years) or among fewer patients.•CXL for PLE is now known to be safe and effective for up to five years after the procedure in a large sample size.•This paper re-affirms that CXL could be considered for patients with progressive refractive changes after LASIK.
To evaluate the safety and efficacy of epithelium-off (epi‑off) corneal cross-linking (CXL) in patients with post-LASIK corneal ectasia (PLE)
Private clinical practice
Prospective clinical trial
82 eyes of adult patients post-LASIK, ages 21–67, with a topography pattern consistent with corneal ectasia, corrected distance visual acuity (CDVA) worse than 20/20, and minimum corneal pachymetry > 400 µm underwent epi‑off CXL. Exclusion criteria were patients with corneas that were thinner than 400 μm or demonstrated central corneal scarring, history of herpetic eye disease, pregnancy or nursing. Follow up examinations of spherical equivalent, uncorrected distance visual acuity (UDVA), CDVA, steep keratometry (KSteep) and minimum pachymetry occurred on different but highly overlapping subsets of the operated eyes yearly until 5 years post-CXL.
Over the 5 years of follow up, spherical equivalent did not significantly change while UCVA and CDVA stabilized or improved to a non-significant degree. KSteep and minimum pachymetry continued to be decreased to a statistically significant degree (p < 0.05 at 5 years).
CXL in PLE patients is safe and efficacious: it halts progression of PLE and may improve visual function. KSteep and minimum pachymetry decrease post-CXL. Patients with PLE should be encouraged to stop progression of the disease by undergoing epi‑off CXL once progression is established.
This paper will compare the visual outcomes of two different penetrating keratoplasty (PKP) techniques in patients with keratoconus. It is a retrospective comparative surgical case series of 116 ...keratoconus patients (137 eyes) who had PKP at the Cornea Eye Institute, Beverly Hills, California, USA.
56 keratoconus patients (66 eyes) underwent femtosecond laser-enabled keratoplasty (FLEK) with a zig-zag incision configuration. Their visual parameters were compared with those of 60 patients (71 eyes) who had traditional blade mechanical trephination PKP. The range of follow-up was between 3 and 6 months. The main outcome measures included uncorrected visual acuity and best spectacle-corrected visual acuity (BSCVA), manifest refractive spherical equivalent and topographically determined astigmatism.
BSCVA was significantly better as early as 3 months postoperatively (p=0.001) in the FLEK group. Visual recovery to 20/40 after 3 months was significantly better in the FLEK group (p<0.001). Topographic astigmatism was lower in the FLEK group, but the difference between the two groups reached significance only at 3 months of follow-up (p=0.001). Postoperative complications noted were not different between the two groups.
Faster visual recovery and better long-term outcomes were observed in keratoconus patients who had FLEK compared with those who had the mechanical PKP procedure with 6 months of postoperative follow-up.
To determine if differences in topographic progression between unaffected keratoconus relatives and normal controls can predict factors associated with the development of keratoconus in a ...longitudinal study. We recruited 369 unaffected keratoconus relatives and 119 normal controls in Los Angeles. Both eyes of subjects were examined at baseline clinically and by quantitative videokeratography and at a period ranging from 1
year to 8
years. Progression to keratoconus was evaluated by quantitative videokeratography variables. Unaffected relatives had higher Central K (CK), I-S and KISA values and were younger than normal controls (CK: 44.70 vs 44.01,
P
<
0.01; I-S: 0.76 vs 0.58,
P
<
0.01, KISA: 29.97 vs 23.89,
P
=
0.02; age: 34.8 vs 41.0,
P
<
0.01) at baseline. All three indices significantly increased with age, and CK and KISA values were associated with a positive family history for keratoconus (
P
<
0.001 for CK and
P
=
0.05 for KISA), however, the two groups were not statistically different in progression of keratoconus. After grouping unaffected relatives as high risk (age
≤
30 or Central K
≥
47.2 and I-S
≥
1.2 or KISA
≥
60) and low risk (age
>
30 and Central K
<
47.2 and I-S
<
1.2 and KISA
<
60), relatives in the high risk group had a greater increase in CK and I-S values than those in the low risk group (CK:
P
=
0.009; I-S:
P
<
0.001), which indicated that there were significantly different rates of progression between two groups. Unaffected relatives had higher videokeratography indices than normal controls, but overall they did not progress to keratoconus quicker than normal controls. However, relatives in the high risk group may have a greater risk of progression to keratoconus.
Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in ...keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.
Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.
Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.
Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.
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