[TGC Repeats in Intron 2 of the TCF4 Gene have a Good Predictive Power Regarding to Fuchs Endothelial Corneal Dystrophy]. / TGC-Repeats im Intron 2 des TCF4-Gens haben eine große Vorhersagekraft bezüglich Fuchs-Hornhautendotheldystrophie.

BACKGROUND: Fuchs endothelial corneal dystrophy (FECD) is one of the most common indications for corneal transplants. FECD is associated with various genes, e.g., COL8A2 or SLC4A11. Among other things a TGC trinucleotide repeat expansion in intron 2 of the TCF4 gene has been characterised in FECD patients and the allele G of the polymorphism rs613872 in intron 3 of the same gene has been associated with this disease. Our intention was to investigate sources in molecular genetics in the German population and to calculate the odds ratio as indicator for the chance to suffer from FECD. PATIENTS AND METHOD: 42 unrelated FECD patients, 93 unrelated controls and 17 members of a family with four FECD affected patients have been examined for the described changes in the TCF4 gene. After amplification of the TGC repeats with specific PCR the obtained products were electrophoretically divided according to their length and investigated with a triplet-primed PCR. Polymorphism rs613872 was analysed by Sanger sequencing. All coding exons of the adjacent genes TCF4 and LOXHD1 were sequenced in six patients in order to exclude potential disease associated mutations. RESULTS: 33 out of 42 unrelated analysed patients (79 %) had a TGC repeat expansion (> 50 TGC repeats) in intron 2 of the TCF4 gene. Out of 93 controls only 10 (10.8 %) showed an expanded allele. In the family the four diseased and four healthy subjects of the 17 examined family members had an expanded allele. Analysis of the polymorphism rs613872 in intron 3 of the TCF4 gene exhibited 33 of 42 unrelated patients (78.6 %) heterozygous TG and four homozygous GG (9.5 %). 65 of 93 controls were homozygous TT (69.9 %) and only 21 heterozygous TG (22.6 %). Of the 17 family members nine had the genotype TG, including the four FECD patients. Sequencing of the coding exons of TCF4 and LOXHD1 in six patients showed no variant described with FECD. The odds ratio as indicator for being affected by FECD in our data for the expanded TGC allele is 30. The chance of being affected is thus 30 times higher when someone exhibits the expanded allele. For a carrier of the risk allele G the chance is 16.5 times higher. DISCUSSION: An expanded TGC allele with more than 50 TGC repeats in intron 2 and the described risk allele G of the polymorphism rs613872 in intron 3 of the TCF4 gene appear as an association to FECD. The chance to be affected by FECD is up to 30 times higher. With molecular genetics also donors with clinically unknown FECD may be detected.

[Mutational analysis of VSX-1 in one patient with posterior polymorphous corneal dystrophy and in three families with hereditary Fuchs endothelial dystrophy]. / Mutationsanalyse im VSX1-Gen bei einem Patienten mit posteriorer polymorpher Hornhautdystrophie und drei Familien mit autosomal-dominant vererbter Fuchs'scher Hornhautendotheldystrophie.

BACKGROUND: Fuchs endothelial corneal dystrophy is the most common disease of the corneal endothelium. Besides some sporadic cases, an autosomal dominant inheritance is frequently described. Mutations in the VSX-1 gene are identified as the underlying gene defect for a rarer kind of endothelial dystrophy, posterior polymorphous endothelial dystrophy. We report on mutational analysis of the VSX-1 gene in affected and non-affected family members of three families with autosomal dominant inherited Fuchs endothelial corneal dystrophy and one male patient showing posterior polymorphous endothelial dystrophy. PATIENTS/MATERIALS AND METHODS: From one patient with posterior polymorphous endothelial dystrophy and 10 affected and 15 non-affected family members of three families with autosomal dominant inherited Fuchs endothelial corneal dystrophy DNA was extracted from leukocytes of the peripheral blood and mutational analysis was performed by direct sequencing of the VSX-1 gene. RESULTS: Screening of the VSX-1 gene did not reveal sequence variants in any affected or non-affected individuals from the three families with Fuchs endothelial corneal dystrophy or the patient with posterior polymorphous endothelial dystrophy. CONCLUSIONS: The absence of pathogenic mutations in the VSX-1 gene in affected family members of 3 pedigrees indicates that other genetic factors are involved in the development of familial Fuchs endothelial corneal dystrophy. In addition, VSX-1 seems unlikely to be the crucial gene in our patient with posterior polymorphous endothelial dystrophy.

[Results of low-vision rehabilitation in vision impaired patients]. / Ergebnisse der optischen Rehabilitation mit vergrössernden Sehhilfen bei Patienten mit irreversibel visuslimitierenden Erkrankungen.

PURPOSE: Diseases of the retina, the optic nerve and the cornea may lead to a non-treatable loss of central vision. We report on low vision rehabilitation in 100 vision impaired patients. METHODS: Low vision rehabilitation was performed in 100 consecutive patients (61 % AMD, 23 % diabetic retinopathy, 16 % other diseases). Most of the patients were between 70 and 90 years old (78 %). In 62 cases we fitted optic systems for visual rehabilitation of the far distance (Galilei systems 54; Kepler systems 8), in additional 54 of them we fitted optic systems for the reading distance (additional lens 40; others 14; e. g. magnifier, television reader) and in 38 patients we fitted optic systems for visual rehabilitation only of the reading distance (magnifier 21, reading glasses with higher refraction and additional prism system 17). RESULTS: In 62 patients with low vision fitted with a system for the far distance we reached an increase of the visual acuity of more than one line in 95 %. In all 92 patients fitted with a system for the reading distance the reading of newspaper letters was possible. In 8 patients we could not fit a low vision systems due to handling difficulties. CONCLUSIONS: We could reach a satisfactory improvement of visual acuity in more than 90 % of the patients fitted for the far and the reading distance. Especially in elderly, vision impaired patients significant improvements in overall quality of life and specific areas of daily living are possible.

[Molecular genetic and histopathological examinations for genotype-phenotype analysis in patients with TGFBI-linked corneal dystrophy]. / Molekulargenetische und histopathologische Untersuchungen zur Genotyp-Phänotyp-Analyse bei Patienten mit TGFBI-gekoppelten Hornhautdystrophien.

PURPOSE: Different missense mutations in the TGFBI gene cause granular (Groenouw CDGG1, Avellino CDA, Reis-Bücklers CDB1) and lattice (Type I; Biber-Haab-Dimmer; CDL1) corneal dystrophies and, in some reports, corneal dystrophy Thiel-Behnke (CDB2). We report on the mutation spectrum and the genotype-phenotype correlations on the basis of clinical and histopathological examinations of 13 German families with TGFBI-linked corneal dystrophies. METHODS: In 31 patients with different corneal dystrophies, DNA was extracted from leukocytes of the peripheral blood and mutation analysis was performed by direct sequencing of the TGFBI gene. Clinical and histopathological findings were compared with the molecular genetic findings for genotype-phenotype correlations. RESULTS: In 6 patients (2 families/one single person) with clinical and histopathological CDL1 we found a Missense mutation Arg124Cys and in 7 patients (3 families/one single person) with clinical and histopathological CDA we found a Missense mutation Arg124His in the exon 4 of the TGFBI gene. In 12 patients (4 families/2 single persons) with clinical and histopathological CDGG1 we found a Missense mutation Arg555Trypt in the codon 12 of the TGFBI gene. In all five patients (1 family/4 single persons) with clinical and histopathological CDB2 we could not find any mutation in the TGFBI gene. In one patient with exceptional clinical and histopathological findings we found a Missense mutation Ala546Asp, which was reported before only twice in connection with polymorphous corneal amyloidosis. CONCLUSIONS: In comparison of our clinical and histopathological findings and the molecular genetic results we found a strong genotype-phenotype correlation in patients with TGFBI-linked corneal dystrophies. Rare mutations can lead to exceptional clinical and histopathological findings which cannot be classified into the different groups of corneal dystrophies. In our patients with CDB2 we could not find any molecular genetic correlation to the TGFBI gene.

[Keratoconus: epidemiology, risk factors and diagnosis]. / Keratokonus: Epidemiologie, Risikofaktoren und Diagnostik.

Keratoconus is a bilateral, non-inflammatory and progredient corneal ectasia with an incidence of approximately 1 per 2,000 in the general population. Within the second decade of life the cornea develops a conical shape, due to thinning of the corneal stroma with subsequent irregular astigmatism and myopia leading to marked impairment of vision. The most common presentation of the keratoconus is as a sporadic disorder, but it has long been recognized that a significant minority of patients exhibit a family history as an autosomal dominant mode of inheritance. Most investigators suggest complete penetrance of predisposing factors with variable phenotypic expression. In some patients heterozygous mutations in the VSX1 gene are described as the underlying gene defect. An association with Down syndrome, monosomia X (Turner syndrome), Leber's congenital amaurosis, mitral valve prolaps, collagenosis, retinitis pigmentosa and Marfan syndrome is described. The role of corneal cells in the pathogenesis of keratoconus is supported by the published reports of recurrence of keratoconus in eyes after penetrating keratoplasty due to graft repopulation by the recipient cells. Placido-based computeed videokeratographic corneal curvature mapping systems, linked with pachymetry, are useful for identifying overt and subclinical cases of keratoconus. Different indices may quantify the clinical features of keratoconus and may improve the classification. We compared videokeratometric data (Fourier series harmonic analysis and wavefront analysis) in eyes with keratoconus to answer the question of which parameters are useful for early diagnosis of keratoconus.

[Idiopathic orbital inflammatory syndrome (orbital pseudotumors): diagnosis and therapy]. / Idiopathische entzündliche intraorbitale Fibrosklerose: Diagnostik und therapeutische Möglichkeiten.

BACKGROUND: Pseudotumors of the orbit comprise a group of idiopathic inflammatory processes and are, except for endocrine orbitopathy, the most common reason for exophthalmos in adults. Orbital pseudotumors, also called idiopathic orbital inflammatory syndrome (IOIS), can be determined from orbital involvement in systemic fibrosing diseases. Finding the correct diagnosis can be challenging. Due to the topographic relations of the orbit to neighbouring structures, a multidisciplinary cooperation is highly recommended. CASE REPORT: We report a case of a 42-year-old woman with unilateral exophthalmos. Additionally we found impaired motility of the affected bulbus, ptosis and reduction of visual acuity. Orbital MR imaging demonstrated dense fibrotic masses filling the whole orbita including the extraocular muscles as well as the optic nerve. Tissue specimens were extracted while performing orbital decompression via a lateral orbitotomy. Histological examination revealed a lymphatic infiltration and fibrotically destroyed tissue containing the lacrimal gland. After surgical decompression, oral steroid therapy and immunotherapy, a recovery of the visual loss could be seen. CONCLUSIONS: Intraorbital fibrosclerosing pseudotumors often require a difficult long-term treatment. Therapeutic options are steroid therapy, immunotherapy, radiotherapy and surgery. The diagnostic steps include blood tests, ultrasound, CT and/or MRI as well as histological differentiation. Solid tumors and orbital involvement in diseases of the hematopoetic system have to be excluded. Since intraorbital fibrosis can be accompanied by manifestations in various other organs, a complete investigation of the body and thorough follow up are crucial.

[Molecular genetic analysis of the BIGH3 gene in lattice type I (Biber-Haab-Dimmer) and granular type II (Avellino) corneal dystrophy: is indirect mutation analysis for hot spots recommended?]. / Molekulargenetische Analyse des BIGH3-Gens bei gittriger Hornhautdystrophie Typ I (Biber-Haab-Dimmer) und bei bröckliger Hornhautdystrophie Typ II (Avellino): Erlauben Hot Spots einen indirekten Mutationsnachweis?

BACKGROUND: Mutations of the BIGH3 gene were delineated as the underlying gene defect for corneal dystrophy Lattice Type I (CDL1) and corneal dystrophy Avellino type (CDA) in families with different regional provenance. Missense mutations in exon 4 with single base pair substitution which result in amino acid alterations Arg124Cys (CDL1) and ARG124His are described as hot spots. We report on histopathological and molecular genetic investigations in 2 German families and a single patient with CDL1 and CDA. METHOD: In 3 affected family members and 1 unaffected family member and in one single patient with CDL1 and in 3 affected family members and 1 unaffected family member of a family with CDA mutation analysis in exon 4 of BIGH3 gene by direct sequencing of genomic DNA from peripheral blood was performed. Histopathological examination of corneal tissue of both index patients was performed after penetrating keratoplasty. RESULTS: We revealed a heterozygous single base pair substitution 417C-->T in family A and patient B (CDL1) and a heterozygous single base pair substitution 418G-->A in family C (CDA). In all index patient's diagnosis was confirmed by histopathological examination of corneal tissue. The sequencing results were confirmed by restriction digestion with HpyCH4V (NEB; CDL1) restriction endonuclease site and AvaII (NEB; CDA) restriction endonuclease site. The heterozygous 417C-->T transition in family A and patient B alters the amino acid sequence from Arg124Cys while the heterozygous 418G-->A transition in family C alters the amino acid sequence from Arg124His in the keratoepithelin. COMMENT: Codon 124 of the BIGH3 gene appears as a mutation hot spot also in German families with CDL1 and CDA. Indirect mutation analysis with restriction digestion is suggested as first step investigation in families with relevant corneal dystrophies. Direct sequencing of all exons is recommended as a second step if there are no results in restriction digestion.

[Quantitative assessment of topographical parameters to differentiate keratoconus from pellucid marginal corneal degeneration and ]. / Quantitative Evaluierung topographischer Parameter zur Differenzierung von Keratokonus und pelluzidaler marginaler Hornhautdegeneration.

INTRODUCTION: The purpose is to compare videokeratometric data (Fourier series harmonic analysis and wave-front analysis) in eyes with ectatic corneal disease (keratoconus; pellucid marginal corneal degeneration [PMCD]) and to determine parameters for early diagnosis and distinction of keratoconus and PMCD. PATIENTS AND METHODS: 13 eyes with PMCD, 32 eyes with keratoconus and 18 healthy eyes were included. Computerized videokeratographic methods were assessed, using Fourier series harmonic analysis, Zernike coefficients and eccentricity. RESULTS: Irregular astigmatism (Fourier series harmonic analysis: decentration and/or irregularity) and the aberration coefficient were out of the normal range in all pathologic eyes. Both the nasal and the temporal eccentricities were greater than 0.63 in all PMCD patients, whereas either the superior or the inferior eccentricity was negative in all patients. In keraotoconic eyes, all quadrant eccentricities were positive and greater than 0.4. CONCLUSIONS: Irregular astigmatism and the aberration coefficient are useful parameters in detecting ectatic corneal disease using a computerized videokeratoscope. The calculation of the spherical equivalent (Fourier series harmonic analysis: no decrease of spherical equivalent in PMCD subjects) and of quadrant eccentricities are useful tools in distinguishing PMCD and keratoconus.

[The autologous ipsilateral rotating penetrating keratoplasty: an early surgical procedure to prevent deep irreversible amblyopia in Peters anomaly]. / Die ipsilaterale autologe Rotationskeratoplastik: Eine Möglichkeit der frühen Amblyopieprophylaxe bei Peters'scher Anomalie.

PURPOSE: It is a challenge to prevent irreversible amblyopia in infants suffering from Peters anomaly. In some cases of centrally located corneal opacifications an optical sector iridectomy can not lead to a clear optical axis. The homologous penetrating keratoplasty as early surgical procedure has shown an extremely poor outcome with a high risk of irreversible graft failure. We report on the autologous ipsilateral rotating penetrating keratoplasty in an eight-week-old infant suffering from Peters anomaly. PATIENTS: An autologous ipsilateral rotating penetrating keratoplasty was performed in an eight-week-old infant suffering from Peters anomaly to prevent irreversible amblyopia. RESULTS: After a follow-up time of 8 months we saw a clear graft within the optical axis without any complications in wound healing. We removed the single sutures two months after keratoplasty. Postoperative astigmatism could be corrected first by fitting a special nursery contact lens and after reduction of astigmatism because of suture removal we fitted special nursery glasses. The intraocular pressure remained within the normal range during the follow-up period. CONCLUSION: The autologous ipsilateral rotating penetrating keratoplasty should be considered superior to homologous keratoplasty in infants with Peters anomaly if sector iridectomy is not advisable because of a central corneal opacification. Resulting high refractive errors can be successfully corrected by special contact lens fitting or by nursery glasses.

[Contact lens fitting as a possibility for visual rehabilitation in patients after open globe injuries]. / Kontaktlinsenversorgung als Möglichkeit der visuellen Rehabilitation bei Patienten nach offenen Augenverletzungen.

INTRODUCTION: Visual rehabilitation after open globe injury may be a challenging process because of ametropia following aphakia, corneal scarring with high or irregular corneal astigmatism or loss of contrast sensitivity due to traumatic aniridia. We report on contact lens fitting for visual rehabilitation in patients after open globe injury. PATIENTS: From 2000 to 2003, contact lenses were fitted unilaterally for the visual rehabilitation in 13 patients after open globe injury. In three patients we found unilateral aphakia, in 8 patients a high or irregular astigmatism after penetrating or autorotation keratoplasty and in two patients a traumatic aniridia, in one case combined with aphakia. RESULTS: 11 rigid contact lenses were fitted with different designs of the front and back surface as well as two iris-print lenses. In 11 patients (86 %) a good visual rehabilitation was achieved with an increase of visual acuity up to 9 lines while obtaining a good contact lens tolerance. One patient wearing an iris-print contact lens was unable to tolerate the contact lens due to its thickness and its weight. In another patient fitting of a contact lens was not possible because of the complicated corneal condition. We did not observed severe contact lens complications at any time. CONCLUSIONS: In addition to operative procedures for visual rehabilitation after open globe injuries, the use of contact lenses is another possible procedure for refractive correction. Different problems such as ametropia following aphakia, irregular or high astigmatism or aniridia can be solved with good visual results, good tolerance and less complications.