Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1.

PURPOSE: To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). DESIGN: Multicenter cohort study. METHODS: A discovery cohort of 27 individuals with LECD from 17 families, including 7 affected members from the original LECD family, 6 patients from 2 new families and 14 simplex cases, was recruited. A cohort of 6 individuals carrying a pathogenic MCOLN1 (mucolipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequencing were used in all patients to identify pathogenic or likely pathogenic variants and penetrance of variants. RESULTS: Nine rare heterozygous MCOLN1 variants were identified in 23 of 27 affected individuals from 13 families. The truncating nature of 7 variants and functional testing of 1 missense variant indicated that they result in MCOLN1 haploinsufficiency. Importantly, in the homozygous and compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysosomal storage disorder mucolipidosis IV (MLIV). Autosomal recessive MLIV is a systemic disease and comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. However, the 6 parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype, suggesting MCOLN1 haploinsufficiency may be associated with reduced penetrance and variable expressivity. CONCLUSIONS: MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlapping clinical features of corneal epithelial cells with autofluorescent inclusions reported in both LECD and MLIV, it is concluded that some carriers of MCOLN1 haploinsufficiency-causing variants present with LECD.

The Hematologic Definition of Monoclonal Gammopathy of Undetermined Significance in Relation to Paraproteinemic Keratopathy (An American Ophthalmological Society Thesis).

PURPOSE: To determine if paraproteinemic keratopathy (PPK) in the setting of monoclonal gammopathy of undetermined significance (MGUS) causes distinct patterns of corneal opacification that can be distinguished from hereditary, immunologic, or inflammatory causes. METHODS: A retrospective, interventional study of patients showed distinct bilateral opacity patterns of the cornea at the eye clinics of Hanau, Mainz, Helsinki, Marburg, and Berlin between 1993 and 2015. Data on patient characteristics and clinical features on ophthalmic examination were collected, and serum protein profiles were evaluated. A literature review and analysis of all published studies of MGUS with PPK is also presented. RESULTS: The largest group of patients diagnosed with MGUS-induced PPK is analyzed in this study. We studied 22 eyes of 11 patients (6 male, aged 43 to 65, mean age 54; 5 female, aged 49 to 76, mean age 61) with distinct corneal opacities and visual impairment who were first suspected of having hereditary, inflammatory, or immunologic corneal entities. Subsequently, serum protein electrophoresis revealed MGUS to be the cause of the PPK. Literature review revealed 72 patients with bilateral PPK (34 male, mean age 57; 38 female, mean age 58) in 51 studies of MGUS published from 1934 to 2015 and disclosed six additional corneal opacity patterns. CONCLUSIONS: This thesis shows that MGUS is not always an asymptomatic disorder, in contrast to the hematologic definition, which has no hint of PPK. The MGUS-induced PPK can mimic many other diseases of the anterior layer of the eye. A new clinical classification for PPK in MGUS is proposed.

Erratum: The Hematologic Definition of Monoclonal Gammopathy of Undetermined Significance in Relation to Paraproteinemic Keratopathy (An American Ophthalmological Society Thesis).

[This corrects the article on p. T7 in vol. 114, PMID: 28050052.].

Intraocular lens calcification after keratoplasty.

PURPOSE: To report calcification of intraocular lenses (IOLs) after various keratoplasty procedures. METHODS: Clinical data of all cases with calcified IOLs after keratoplasty procedures were analyzed. A total of 6 explanted IOLs were analyzed with light microscopy before and after staining with 1% alizarin red and the von Kossa method. RESULTS: A total of 7 cases occurred after Descemet stripping automated endothelial keratoplasty, 1 case after deep anterior lamellar keratoplasty, and 2 cases after penetrating keratoplasty. Median time interval from keratoplasty to first notice of IOL opacification was 6.5 months (minimum 3 months, maximum 51 months). A total of 3 IOLs had been placed at the time of keratoplasty and 7 IOLs before keratoplasty. All affected IOLs were hydrophilic acrylic and comprised IOLs from at least 3 different polymer sources. Common clinical aspects were some amount of inflammation in the anterior chamber during the postoperative period and use of air at the end of surgery in 8 of the 10 cases. Histochemical analysis demonstrated the presence of fine granular deposits located within the very superficial optic material in all cases. The deposits stained positive for calcium with alizarin red and the von Kossa method. CONCLUSIONS: IOL calcification associated with keratoplasty in our series does not seem to be a problem related to a specific IOL model or polymer. The process of calcification may be mediated by inflammation, which also may be related to multiple injections of air into the anterior chamber.

Amniotic bands as a cause of congenital anterior staphyloma.

BACKGROUND: Congenital anterior staphyloma is a rare, complex malformation syndrome of the anterior segment. Only a few reports on associated systemic malformations have been published. We herein present a rare manifestation of congenital anterior staphyloma (CAS) combined with amniotic band disruption syndrome (ABS). PATIENT AND METHODS: Shortly after birth, a massive enlargement of the left eye was observed in a female child. Furthermore, an extensive bilateral congenital cleft lip and cleft alveolar ridge with oblique facial cleft extending into the left medial canthal region, coloboma(s) of the left eyelids, extensive adhesions between lids and eye bulb, as well as circumferential grooves, clubfeet, and terminal transverse defects in both hands and feet were present. Due to severe progression of eye bulb protrusion with thinning of the sclera, enucleation of the left eye was performed at the age of 3 years in order to prevent complications including perforation of the globe and with the aim of improving cosmetic aspects. RESULTS: Histopathological examination of the enucleated eye disclosed findings typical of congenital anterior staphyloma, including massive corneal staphylomatic deformation with superficial vascularization and elapsed corneoscleral margin, destruction of Bowman's layer, absence of Descemet's layer, corneal endothelium, and angle structures. The lens was only partially formed, and had mainly dissolved. The neural retina appeared normal. The optic nerve disc revealed a pronounced excavation. Facial clefts, lid colobomas, congenital constriction bands, and amputation of distal limbs match ABS. This malformation complex develops in early pregnancy, probably prior to 35 days post conception. CONCLUSION: This is the first report on an association of these two rare complex congenital malformations, congenital anterior staphyloma and amniotic band syndrome. The anterior staphyloma was unilateral, and related to facial clefts and lid coloboma in the area adjacent to the anterior staphyloma. Furthermore, the systemic deformities are clearly due to the amniotic bands, and the timing of the development of both complex malformations seems to be similar. All findings suggest that the presence of amniotic bands is a causative factor for all observed abnormalities including anterior staphyloma.

Chameleon-like appearance of immunotactoid keratopathy.

PURPOSE: To demonstrate 5 different patterns of immunotactoid keratopathy (ITK) in monoclonal gammopathy of undetermined significance (MGUS) that can mimic hereditary and degenerative disorders. First follow-up of 1 female patient was performed. METHODS: Colored slit-lamp photodocumentation of 6 MGUS light kappa patients with different types of ITK, one patient with a follow-up of 7 years. Systemic and serological examinations of all 6 patients were performed. RESULTS: The systemic and serological examinations disclosed an MGUS light kappa in all 6 patients. The 7-year follow-up of case 2 showed a reduction of lattice-like opacity to moderate diffuse corneal opacity. Corneal opacity patterns of the 6 patients were as follows: pattern 1, crystalline-like; pattern 2, lattice-like; pattern 3, peripheral granular-like; pattern 4, peripheral band-like; and patterns 5 and 6, peripheral patch-like. CONCLUSIONS: ITK of MGUS can mimic cystinosis, Schnyder corneal dystrophy (CD), pre-Descemet CD, lattice CD, granular CD, arcus lipoides, lecithin-cholesterol acyltransferase deficiency, gelatinous drop-like CD, and Salzmann nodular degeneration. ITK can be the first symptom of MGUS. An annual internal check of MGUS is recommended because of occurrence of a systemic monoclonal gammopathy in 20% of cases.

Expression of c-Kit and its ligand SCF in primary uveal melanoma.

PURPOSE: To evaluate the concurrent rate of expression of c-Kit and its ligand stem cell factor (SCF) in uveal melanoma in respect to the further clinical course and the correlation of these markers. METHODS: Paraffin sections from 35 primary uveal melanomas were evaluated immunohistochemically for the expression of c-Kit and SCF. Sixteen cases developed systemic metastasis during the follow-up (median: 5 years after diagnosis). The patients who did not develop metastasis (n = 19) had a mean follow-up of 10.6 (9-13) years. Radiation was performed in 6 patients. RESULTS: c-Kit and SCF were expressed in all patients who did or did not develop metastasis in the further clinical course. A mean SCF expression of 77.2% (range 52.7%-97.5%) of tumors that did not develop systemic metastasis and 30.1% (range 2.9%-61.5%) of tumors with systemic metastasis were evident. Uveal melanomas revealing an increased SCF expression were found to develop no metastasis more frequently (p<0.0001; hazard ratio (HR) = 0.963, 95% confidence interval (CI) 0.945-0.981). A mean c-Kit expression of 58.01% (range 5.9%-97.9%) in the group who did not develop metastasis and 48.9% (range 5.0%-95.9%) in the group with systemic metastasis were observed. c-Kit expression was not associated with increased rates of metastasis formation (p = 0.7329; HR = 0.997, 95% CI 0.982-1.013). The correlation between SCF and c-Kit is weak (0.39; 95% CI 0.06-0.63). CONCLUSIONS: c-Kit expression was not found to be associated with metastasis formation. A high SCF expression of primary choroidal melanomas was significantly associated with a lower incidence of systemic metastasis, which indicated SCF as a benign prognostic factor in the further clinical course.

Cyclo-oxygenase-2 expression in photon-radiated and non-radiated uveal melanomas.

PURPOSE: To determine and compare cyclo-oxygenase-2 (COX-2) expression in photon-radiated and non-radiated malignant uveal melanomas and to analyse the correlation between COX-2 expression and prognosis. METHODS: Immunohistochemical staining for COX-2 was performed on 21 uveal melanomas that were endoresected after prior stereotactic radiotherapy with photons and on 22 tumours that were treated by endoresection without prior radiotherapy. COX-2 staining was further analysed in respect to cell type, maximal prominence, time interval between radiotherapy and surgery, apoptotic index (AI), proliferative index (PI) and the development of metastatic disease. RESULTS: There was no difference in COX-2 expression between radiated and non-radiated melanomas (P>0.15). COX-2 staining correlated with neither the tumour prominence (P>0.40) nor the AI or the PI (both P>0.35). Tumours with high COX-2 expression were significantly more likely to develop metastasis (P=0.022). CONCLUSION: Radiotherapy with photons does not induce COX-2 expression in malignant melanomas of the uvea. But high COX-2 expression may be a marker for poor prognosis.

Primary silicone oil tamponade in the management of severe intraocular foreign body injuries: an 8-year follow-up.

PURPOSE: To evaluate the long-term outcome of pars plana vitrectomy and primary silicone oil tamponade in patients with severe intraocular foreign body (IOFB) injuries and high risk of proliferative vitreoretinopathy (PVR). METHODS: This retrospective consecutive study included 23 patients with severe IOFB injuries who had extensive lacerations including sclera, choroid, and retina, and were complicated by predictive factors for elevated proliferative activity and an unfavorable outcome. All patients underwent pars plana vitrectomy, removal of the IOFB, and primary silicone oil tamponade and were followed up for a mean 8.9 years. Main functional outcome was assessed as final best-corrected visual acuity. Anatomic success was defined as permanent retinal attachment. RESULTS: PVR occurred in 70% of all eyes and required 16 revisions. Silicone oil was removed in 78% of the eyes after a mean tamponade duration of 9.1 months. Complete retinal attachment was achieved in 83% of the eyes. Three eyes developed a persisting hypotony that was stabilized under permanent silicone oil. Functional stabilization was observed in the third year resulting in a final visual acuity of 20/630. Useful vision of better than 20/400 could be preserved in 55% of the patients. Only one eye underwent a late enucleation after 6.8 years. CONCLUSIONS: Primary silicone oil stabilizes the retina during the critical period of active PVR and may limit the visual loss in selected high-risk eyes in the long term.

Sutureless amniotic membrane fixation using fibrin glue for ocular surface reconstruction in a rabbit model.

PURPOSE: Amniotic membrane transplantation has become an important treatment option for corneal surface reconstruction. However, suture fixation of the transplant has various disadvantages like corneal irritation, scarring, graft loss due to membrane shrinkage, and the need for subsequent suture removal. Replacement of sutures by bioadhesives might be an advantageous alternative. This controlled study was designed to evaluate a new sutureless technique for amniotic membrane fixation onto the corneal surface by using fibrin glue. METHODS: Standardized disks of cryopreserved amniotic membranes were transplanted onto the deepithelialized cornea of 12 rabbits using either conventional suture fixation or a new fibrin glue technique. The rabbits were followed-up with slit-lamp examination and fluorescein staining until epithelialization was completed. Consecutively, the rabbits were killed and the eyes processed for histology and immunohistochemistry for cytokeratin-3. RESULTS: All membranes of both groups stayed in place throughout the follow-up time and showed a progressive graft epithelialization that was completed after 12 days. Whereas suture-fixated membranes showed progressive tissue shrinkage, fibrin-glued sheets remained unaltered. In the bioadhesive group, histology revealed a smooth fibrin layer in the graft-host interface and a continuous, stratified layer of cytokeratin-3 expressing corneal epithelial cells on the membrane surface. In contrast, suture-fixated membranes showed contracted and prominent membrane edges with epithelial ingrowth into the submembrane interface. CONCLUSION: Our results demonstrate the general feasibility of reproducible and reliable sutureless amniotic membrane fixation onto the corneal surface in rabbits. Stable adherence is maintained until epithelialization is completed. The sutureless technique gives sufficient manipulation time for the sheet before the final cross-linking process is completed. Furthermore, several advantageous characteristics could be demonstrated as increased biocompatibility, better epithelialization pattern and the lack of membrane shrinkage.

Experimental implantation and long-term testing of an intraocular vision aid in rabbits.

OBJECTIVE: To develop an intraocular vision aid to provide artificial vision in severely traumatized eyes, where neuroretinal function could be preserved but irreversible anterior segment opacification resulted in blindness. METHODS: The basis of an intraocular vision aid is in principle a telemetric circuit to bridge the opaque cornea and to allow for artificial light stimulation of the retina. The visual prosthesis comprises an external high-dynamic range complementary metal oxide semiconductor camera and digital signal processing unit and an intraocular miniaturized light-emitting diode array to project the image onto the retina. For in vivo testing of long-term function and biocompatibility, silicone-encapsulated active photodiodes were implanted in 13 pigmented rabbits and were followed up for up to 21 months. RESULTS: Lens extraction and stable fixation of the device in the ciliary sulcus were successful in all cases. For up to 21 months inductive energy transmission and wireless stimulation of the implants could be maintained. Electrophysiologic data and histology demonstrated a good tissue biocompatibility in the long-term follow-up. CONCLUSION: The results demonstrate the general feasibility and biocompatibility to implant and fixate an intraocular light-emitting diode prosthesis. Inductive energy transmission to the intraocular device and wireless light stimulation are assured in the long term but depend on meticulous water-impermeable encapsulation of the delicate microelectronic components. Clinical Relevance An intraocular vision aid compound system with a high-resolution light-emitting diode matrix might be a future treatment option to restore vision in blind eyes with severe anterior segment disorders.