nemoci-sympt/OCNI/astigmatismus-keratokonus/rizikove-zhorsujici
Asociace
Keratokonus se většinou nevyskytuje samostatně, tj. je-li pacient postižen tímto onemocněním, trpí často i řadou jiných nemocí. (O’Brart – Petrarca, 2006a; Kuchynka, 2007)
- Vernální konjunktivitidy
- Zánět pigmentového epitelu sítnice
- Modrá skléra
- Aniridie
- Dislokace čočky
- Lebrova kongenitální amauróza
- Atopický ekzém
- terapie - příčina nebo následek ?
- Senná rýma
- Alergie
- Nedostatek hořčíku
- Supplementovat hořčík !!!
- Molecular and cellular alterations specific to the keratoconic cornea, including: thinning and fragmentation of membranes, degenerated cells and collagen fibres, swelling of the mitochondria, and biochemical abnormalities in protein synthesis. Similar alterations have reportedly been induced by magnesium deficiency.
- Turnerův syndrom
- Ehlersův–Danlosův syndrom
- Marfanův syndromv
- Prolaps mitrální chlopně
- Laurence-Moon-Biedlův syndrom
- Riegerův syndrom
- Neurofibromatóza
- Downův syndrom
- Asi 7 % lidí s keratokonem je postiženo Downovým syndromem. (Waheeda, 2006)
- Downův syndrom je má souč. 0,5–15 % keratokonus (10–300 krát více než je výskyt v běžné populaci - 0,5 % případů).
- Asi 10 % případů výskytu má hereditární původ
- Většina případů však vznikne spontánně
Literatura:
1) is.muni.cz/th/214888/lf_b/Keratokonus_-_moznosti_korekce_a_lecby_-_FINAL.pdf
Keratokonus
Etiologie
- Hromadění destruktivních aldehydů uvnitř keratokonické rohovky
- omezit alkohol ?
- Abnormální produkce volných radikálů a peroxidů
- prostředí, záněty, antioxidanty v kapičkách ?
- Proces apoptózy objevující se u nevratně poškozených buněk
- antioxidanty ?
- Hojení ran
- brýle, ochrana před prachem ?
- Reparace buněk u reversibilně poškozených buněk
- chránit oko, antiox., sluneční brýle ?
- Ložiskové tenčení rohovky a vazivovatění v oblastech, kde se hojí rána
- Rychlou progresi zapříčiní dlouhodobé přenášení kontaktních čoček či mnutí oka. (Epstein, 2000)
- bez čoček, nemout oči - léčit hned vše, co provokuje mnutí - korekce dioptrií, záněty, alergie, suché oko ?
- Hormonální změny
- Abnormální úroveň aktivity degenerativních proteinů může způsobit pomalý rozpad Bowmanovy membrány a bazální membrány epitelu. Epitel se pak dostane do kontaktu se stromatem rohovky, uvolní se růstové faktory a následkem toho se objevuje jizvení tkáně. (Epstein, 2000)
- CD45 je označení pro běžný antigen leukocytu (nebo také T200)
- Transmembránová fosfotyrosinová fosfatáza (transmembrane phosphotyrosine phosphatase)
- Ve více keratocytech v rohovce postižené keratokonem než u keratocytů nacházejících se ve zdravé rohovce
- Mohou představovat zdroj některých proteolytických enzymů, o kterých se míní, že jsou spojeny s keratokonem
- Hlavním důvodem protenčování rohovky se uvádí změna aktivity keratocytů a snížená biosyntéza kolagenních vláken ve stromatu. 1)
- Vitamín C, vit. A, k. hyaluronová v gtt ?
- Immunoglobulin kappa chain, zinc-?2-glycoprotein , and lactoferrin are under-expressed in the tears of patients diagnosed with bilateral KC compared with healthy subjects. www.ncbi.nlm.nih.gov/pubmed/21042560
- Increased expression of matrix metalloproteinase-1 (MMP-1) was found in keratoconus subjects with and without gas permeable contact lenses (p=0.02). Unique proteins more associated with keratoconus included several keratins, immunoglobulins alpha and kappa, precursors to prolactin, lysozyme C, and lipocalin. www.ncbi.nlm.nih.gov/pubmed/21031023
- Long-term damage to and stimulation of the corneal epithelium play a key role in the pathogenesis of keratoconus.
- When the corneal epithelium is damaged, surrounding stromal keratocytes disappear due to apoptosis, and that an imbalance between cell death and proliferation is involved in the pathological mechanism of keratoconus. The apoptosis of keratocytes plays an important role in the corneal thinning in keratoconus www.ncbi.nlm.nih.gov/pmc/articles/PMC2786887/
Literatura:
1) is.muni.cz/th/214888/lf_b/Keratokonus_-_moznosti_korekce_a_lecby_-_FINAL.pdf
Genetika
- Genetický faktor u keratokonu je již znám, stejně tak i jeho výskyt u monozygotních dvojčat. (Waheeda, 2006; O’Brart – Petrarca, 2006)
- 21. chromozom - gen pro autozomální dominantní formu keratokonu (Waheeda, 2006)
- Genový produkt označovaný jako glukózou regulovaný protein GRP78 (glucose regulated protein) se vyskytuje více ve tkáních zdravých rohovek.
- Je to protein, který reguluje a usměrňuje syntézu a sekreci dalších proteinů v buňkách.
- Snížení GRP78 může ovlivnit sekreci a syntézu hlavních strukturálních proteinů rohovky, které jsou již tak redukovány v keratokonické rohovce 1)
- The role of VSX1 in the pathogenesis of keratoconus is still controversial. VSX1 mutations are responsible for a very small fraction of all observed keratoconus cases. The absence of pathogenic mutations in VSX1 in our patients indicates that other genetic loci like 13q32 as suggested by a recent study may be involved in the pathogenesis of this disorder. www.ncbi.nlm.nih.gov/pubmed/21139977
- COL4A3 and COL4A4 genes in KC patients to establish the status of these genes and compare them to a control population. Analysis of COL4A3 and COL4A4 revealed no mutations related to KC patients, but specific genotypes of seven previously described polymorphisms are significantly associated with KC under dominant, recessive, or additive models. Differences in the expression of type IV collagen in previously published data about chromosomal instabilities in the regions in which the analyzed genes were mapped and our data indicate a probability that some of the polymorphisms we detected could be related to KC. We detected eight polymorphisms in the COL4A3 gene and six in the COL4A4 gene. Allele differences in D326Y in COL4A3 and M1237V and F1644F in COL4A4 are significantly distinctive of KC patients (Fisher's exact test, p<0.05). When analyzing different genotypes under three models (dominant, recessive, and additive), we established that P141L, D326Y, and G895G in COL4A3 and P482S, M1327V, V1516V, and F1644F in COL4A4 have significant differences in genotype distribution between KC patients and the control group. www.ncbi.nlm.nih.gov/pubmed/20029656
- Overexpression of bone morphogenetic protein 4 (BMP4)
- BMP4 is known to mediate apoptosis or alternative developmental fates of neural crest and other types of cells during development [15-17]. BMP4 and its receptor are found in all cell types (epithelial cells, keratocytes, and endothelial cells) of the human cornea [18,19]. Because keratocytes are derived from neural crest, BMP4 stimulates apoptosis in corneal fibroblasts and has a role in mediating keratocyte proliferation and apoptosis in the cornea [15-20]. From the higher expression of BMP4 in keratoconus in this study, it was suggested that BMP4 might play an important role in mediating the apoptosis of keratocytes in keratoconus.
- Cofilin 1 (CFL1)
- CFL1 is well characterized as an actin depolymerization factor and crucial for many cellular processes, such as cell motility, cell division, and membrane organization. Binding of CFL1 to actin filaments alters the twist of the filament, thereby promoting filament severing and depolymerization. CFL1 is involved in the organization of the cytoskeleton [21,22]. It also has an important function during the initiation phase of apoptosis, which it induces by being translocated to mitochondria during the initial stage of apoptosis [23]. CFL1 was also a gene whose expression was increased in keratoconus.
- JAW1-related protein (MRVI1)
- MRVI1, although no function of this gene is well known, is involved in the control of growth and/or differentiation of hematopoietic cells, and supposed to be a tumor suppressor gene. MRVI1 functions as cofactor in several signaling-transduction systems that affect cellular growth, differentiation, motility, and adhesion [24]. Although it has not been studied in the tissue of cornea, the upregulation of MRVI1 in keratoconus in this study suggested that MRVI1 might retard the cell cycle of keratocytes and affect the cytoskeleton as well as wound healing. Further studies of MRVI1 involving the cornea should help to define the mechanism of keratoconus related with the MRVI1 gene.
- Underexpression of actin
- Meanwhile, ACTA2, which has been known to be involved in the cytoskeleton [25], showed low expression in keratoconus. ACTA2 is a functional marker for a fibroblast subtype that rapidly remodels the extracellular matrix [26]. Keratocytes can become myofibroblasts during corneal injury and wound healing, and the transformation of keratocytes into myofibroblasts is a key point in the healing process [27]. Myofibroblast cells are characterized by alpha–smooth muscle actin expression and have additional differences relative to keratocytes that include increased production of growth factors, collagen, glycosaminoglycans, collagenases, gelatinases, and metalloproteinases associated with remodeling of the collagen and the stroma. ACTA2 is expressed at the mRNA level within 24 h of injury to the corneal stroma, is expressed at the protein level at day 3, and declines at the mRNA level by day 5. Therefore, ACTA2 is important for the wound healing process and the cytoskeleton [28,29]. Although alpha smooth muscle actin is normally not expressed in significant levels in keratocytes and the expression of the ACTA2 gene in the normal cornea could be affected by culture process, it is possible for normal keratocytes to express this gene in case of the potential corneal injury, and further study of ACTA2 should be undertaken.
- Alpha 2 (ACTA2), gene rich cluster, and C 10 gene (GRCC10), tissue inhibitor of metalloproteinase 3 (TIMP3), tissue inhibitor of metalloproteinase 1 (TIMP1), and somatostatin receptor 1 (SSTR1) were verified, and these results were confirmed by reverse transcriptase PCR and quantitative real-time PCR. Eight genes were identified to be differentially expressed in keratoconus and related with apoptosis, the cytoskeleton, wound healing, and nerve fibers. The genes identified may be involved in the mechanism underlying stromal thinning; thus, they could be important and deserve further investigation.
- GRCC10 is located at the CD4 locus on human chromosome 12p13 and possesses diverse expression patterns and functions, ranging from signal transduction and glycolysis to regulation of cell proliferation and ubiquitin-dependent proteolysis [30,31]. The underexpression of genes such as ACTA2 and GRCC10 in keratoconus was believed to delay the growth of keratocytes that were necessary for the synthesis and maintenance of collagen fibrils and the extracellular matrix.
www.ncbi.nlm.nih.gov/pubmed/19956410
- Microarray analysis revealed up to a 212 fold reduction in the mRNA levels of alcohol dehydrogenase (class 1) beta polypeptide (ADH1B) in KC fibroblasts (p=0.04). Decreased alcohol dehydrogenase in KC fibroblasts was confirmed by western blot analysis of early passage primary keratocyte cell lysates. Immunohistochemistry using a monoclonal mouse immunoglobulin G (IgG) against human liver alcohol dehydrogenase revealed a dramatic difference in protein staining in the keratocytes of the KC group compared to the normal cornea group. Immunohistochemistry also showed decreased immunostaining against alcohol dehydrogenase in the KC stromal sections compared to those obtained from Fuchs' endothelial corneal dystrophy samples.
- CONCLUSIONS: Decreased alcohol dehydrogenase in KC corneal fibroblasts represents a strong marker and possible mediator of keratoconus.
- We analyzed a total of 12 polymorphic sites in the IL1 gene cluster. Among them, the -511 (rs16944) and -31 (rs1143627) positions in the promoter region of IL1B were significantly different between patient and control groups. The C allele of rs16944 (-511C>T, p=0.022, odds ratio of risk [OR]=1.46, 95% confidence intervals [CI] 0.94<2.27) and the T allele of rs1143627 (-31T>C, p=0.025, OR=1.43, 95% CI 0.92<2.22) were associated with a significantly increased risk of keratoconus in Korean patients. Linkage of the two alleles, -31*C and -511*T, was associated with an increased risk for keratoconus with OR=2.38 (p=0.012, 95% CI=1.116-5.046). The *C/*A genotype of rs2071376 in IL1A intron 6 was significantly different between the keratoconus patients and control subjects (p=0.034, OR=0.59, 95% CI 0.32<1.11). Other polymorphisms did not show an association with keratoconus risk.
- CONCLUSIONS: This is the first report of IL1 gene cluster mutation screening in Korean keratoconus patients. Significant differences in allelic frequency of IL1B between keratoconus patients and the control group suggest that IL1B polymorphisms may play a role in the susceptibility of unrelated Koreans to develop keratoconus. www.ncbi.nlm.nih.gov/pubmed/19043479
- All previously reported KTCN loci were excluded. VSX1 and SOD1 were sequenced, and no potentially functional variants were found. One KTCN family yielded a maximum multipoint parametric LOD score of 4.1 and multipoint nonparametric linkage (NPL) LOD score of 3.2. Multipoint linkage and haplotype analysis narrowed the locus to a 5.6-Mb region between the SNPs rs9516572 and rs3825523 on 13q32.
- RESULTS: The chromosomal regions 5q32-q33, 5q21.2, 14q11.2, 15q2.32 exhibited the strongest evidence of linkage by nonparametric analysis (NPL = 3.22, 2.73, 2.62, and 2.32, respectively). The regions 5q32-q33 and 14q11.2 were also supported by multipoint parametric analysis, for which heterogeneity LOD (HLOD) scores of 2.45 (alpha = 0.54) and 2.09 (alpha = 0.46), respectively, were obtained under an affected-only dominant model.
Literatura:
1) is.muni.cz/th/214888/lf_b/Keratokonus_-_moznosti_korekce_a_lecby_-_FINAL.pdf
