Schnyder Corneal Dystrophy Research Articles

Ex vivo 3D human corneal stroma model for Schnyder corneal dystrophy - role of autophagy in its pathogenesis and resolution.

Multilamellar bodies (MLBs) are concentric cytoplasmic membranes which form through an autophagy-dependent mechanism. In the cornea, the presence of MLBs is associated with Schnyder corneal dystrophy (SCD). Ex vivo 3D modelling of the corneal stroma and SCD can help study pathogenesis and resolution of the disorder. Corneal stroma explants were isolated from cadavers and cultivated long-term for more than 3 months to achieve spontaneous 3D outgrowth of corneal stroma-derived mesenchymal stem-like cells (CSMSCs). The 3D tissues were then examined by transmission electron microscopy (TEM) for presence of MLBs, and by immunofluorescent labelling against markers for autophagy (p62, LC3). Autophagy was induced by classical serum starvation or rapamycin (RAP) treatment (50 nM), and inhibited by the autophagy inhibitor 3-methyladenine (3-MA, 10 mM) for 24 hours. CSMSCs can form spontaneously 3D outgrowths over a 3-4 weeks period, depositing their own extracellular matrix containing collagen I. TEM confirmed the presence of MLBs in the long-term (>3 months) 3D cultures, which became more abundant under starvation and RAP treatment, and decreased in number under autophagy inhibition with 3-MA. The presence of autophagy and its disappearance could be confirmed by an inversely related increase and decrease in the expression of LC3 and p62, respectively. MLB formation in long-standing CSMSC cultures could serve as a potential ex vivo model for studying corneal stroma diseases, including SCD. Inhibition of autophagy can decrease the formation of MLBs, which may lead to a novel treatment of the disease in the future.

Geranylgeranyl‐Regulated, ER‐to‐Golgi Transport of UBIAD1: Implications for Cholesterol Homeostasis and Schnyder Corneal Dystrophy

Multiple feedback mechanisms converge on the ER (endoplasmic reticulum)‐localized enzyme HMG CoA reductase, which catalyzes a key step in synthesis of cholesterol and essential nonsterol isoprenoids including Fpp (farnesyl pyrophosphate) and GGpp (geranylgeranyl pyrophosphate), which can become attached to many proteins and are utilized in synthesis of dolichol, ubiquinone, heme, and vitamin K2. One mechanism for feedback control of reductase involves sterol‐induced ubiquitination, which marks the enzyme for ERAD (ER‐associated degradation) that is augmented by GGpp, but not by Fpp. Here, we show that sterols trigger binding of a subset of reductase molecules to UBIAD1 (UbiA prenyltransferase domain‐containing protein‐1), a prenyltransferase that utilizes GGpp to synthesize the vitamin K2 menaquinone‐4. Sterol‐induced binding to UBIAD1 protects reductase from accelerated degradation, permitting continued synthesis of nonsterol isoprenoids in sterol‐replete cells. GGpp triggers release of UBIAD1 from reductase, allowing for maximal ERAD of reductase.Mutations in UBIAD1 cause SCD (Schnyder corneal dystrophy), an autosomal dominant eye disease in humans characterized by corneal accumulation of cholesterol. SCD‐associated mutants of UBIAD1 resist GGpp‐induced displacement from reductase and thereby inhibit its sterol‐accelerated ERAD. In the course of our studies, we discovered that GGpp also stimulates translocation of UBIAD1 from the ER to Golgi. SCD‐associated mutants of UBIAD1 are refractory to GGpp‐induced translocation to the Golgi and remain sequestered in ER membranes where they inhibit reductase ERAD in a dominant‐negative fashion. These results support a model that posits upon sensing GGpp depletion in membranes of the ER, UBIAD1 becomes trapped in the organelle and inhibits reductase ERAD so as to stimulate mevalonate synthesis for replenishment of GGpp. This novel sensing mechanism directly controls ERAD of reductase and becomes disrupted in SCD, which likely contributes to the accumulation of cholesterol that characterizes the eye disease.Support or Funding InformationThis work is supported by NIH grants HL20948, GM112409, and GM119180.

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1. Results of this characterization support a model in which UBIAD1 continuously cycles between the ER and medial-trans Golgi of isoprenoid-replete cells. Upon sensing a decline of GGpp in ER membranes, UBIAD1 becomes trapped in the organelle where it inhibits reductase degradation. Mutant forms of UBIAD1 associated with Schnyder corneal dystrophy (SCD), a human eye disease characterized by corneal accumulation of cholesterol, are sequestered in the ER and block reductase degradation. Collectively, these findings disclose a novel sensing mechanism that allows for stringent metabolic control of intracellular trafficking of UBIAD1, which directly modulates reductase degradation and becomes disrupted in SCD.

The Oskar Fehr Lecture.

The first Oskar Fehr lecture is given in honour of Professor Fehr, a well respected ophthalmologist, who was head physician of the Department of Eye Diseases at the Rudolf Virchow Hospital from 1918. He practiced there until 1938, when he was forbidden to enter the clinic because he was Jewish and subject to the anti-Semitic laws that were instituted after the rise of the Nazi party. Dr. Fehr escaped to Great Britain, where he practiced ophthalmology into his eighties. He was the first to distinguish between granular corneal dystrophy, lattice corneal dystrophy and macular corneal dystrophy. The topic of the first Oskar Fehr lecture is Schnyder corneal dystrophy (SCD), an autosomal dominantly inherited corneal dystrophy associated with abnormal cholesterol deposition in the cornea. The clinical, histopathologic and genetic findings of 115 individuals with SCD followed over 18 years are discussed. The impact of systemic cholesterol metabolism on other diseases is reviewed. Corneal findings in SCD are predictable on the basis of patient age. All patients develop progressive corneal haze because of abnormal deposition of corneal lipid, but only half of patients with SCD have evidence of corneal crystals. The prior name for this disease, Schnyder crystalline corneal dystrophy, led me to create the International Committee for the Classification of Corneal Dystrophies, in order to create a more up-to-date and accurate nomenclature for SCD and other corneal dystrophies. The name was then changed to Schnyder corneal dystrophy. Histopathology of excised SCD corneas demonstrates abnormal deposition of only HDL cholesterol. Mutations in the UBIAD1 gene result in SCD. Three dimensional protein modeling shows that mutations result in impaired vitamin K synthesis, suggesting a common link between vitamin K and cholesterol metabolism. UBIAD1 mutations are associated with other diseases, such as bladder carcinoma and Parkinson's disease like findings in Drosophila. Studies of the cause of SCD have led to the discovery of UBIAD1 gene mutations; further work has demonstrated the systemic importance of this gene. The association of vitamin K metabolism and cholesterol metabolism may give us insight into other diseases, so that SCD research may also have implications beyond ophthalmology.

Identification of two novel mutations in the cornea-specific TGFBI gene causing unique phenotypes in patients with corneal dystrophies.

The purpose of this study was to report on two novel missense mutations of the cornea-specific TGFBI gene in one single patient and in two generations of a family diagnosed with unique corneal dystrophy (CD) phenotypes. Ophthalmologic examination, in several cases ocular coherence tomography of the anterior segment (AS-OCT), was performed in 21 affected patients and in two unaffected members of one affected family. Coding regions of the TGFBI gene were direct sequenced in all 23 individuals. The two novel mutations were verified by RFLP analysis. A novel mutation c.1640T>G (p.Phe574Cys) in exon 12 of the TGFBI gene was detected in one single patient with recurrent granular intrastromal deposits comparable to a type of granular dystrophy. In AS-OCT, the deposit pattern reached up to the Descemet's layer. A further novel mutation c.393G>T(p.Glu131Asp) in exon 4 of the TGFBI gene was detected in all three affected members of one family with superficial cloud- and honeycomb-like opacifications, comparable to a Schnyder corneal dystrophy. Two unaffected members did not carry this alteration. The two identified novel mutations add other two phenotypes in patients suffering from TGFBI-linked CD to those reported so far. In one case, clinical finding indicates a Schnyder corneal dystrophy-like phenotype due to its superficial crystalline shape, and in the second one, granular deposits who reach Descemet's layer indicate a granular CD subtype. Molecular genetic analysis may help to distinguish those subtypes and to decide for specific treatment in time of a wide variation of corneal surgical techniques.

Mutational spectrum of Korean patients with corneal dystrophy.

Corneal dystrophy typically refers to a group of rare hereditary disorders with a heterogeneous genetic background. A comprehensive molecular genetic analysis was performed to characterize the genetic spectrum of corneal dystrophies in Korean patients. Patients with various corneal dystrophies underwent thorough ophthalmic examination, histopathologic examination, and Sanger sequencing. A total of 120 probands were included, with a mean age of 50 years (SD = 18 years) and 70% were female. A total of 26 mutations in five genes (14 clearly pathogenic and 12 likely pathogenic) were identified in 49 probands (41%). Epithelial-stromal TGFBI dystrophies, macular corneal dystrophy and Schnyder corneal dystrophy (SCD) showed 100% mutation detection rates, while endothelial corneal dystrophies showed lower detection rates of 3%. Twenty six non-duplicate mutations including eight novel mutations were identified and mutations associated with SCD were identified genetically for the first time in this population. This study provides a comprehensive characterization of the genetic aberrations in Korean patients and also highlights the diagnostic value of molecular genetic analysis in corneal dystrophies.

Identification of the First De Novo UBIAD1 Gene Mutation Associated with Schnyder Corneal Dystrophy.

Purpose. To report the identification of the first de novo UBIAD1 missense mutation in an individual with Schnyder corneal dystrophy (SCD). Methods. A slit lamp examination was performed on a 47-year-old woman without a family history of corneal disorders. The proband's parents, two sisters, and son were also examined and genomic DNA from all six individuals was collected. The exons and exon-intron boundaries of UBIAD1 were screened using Sanger sequencing. Identified mutations were screened for in 200 control chromosomes. In silico analysis predicted the impact of identified mutations on protein function and structure. Results. Slit lamp examination of the proband revealed findings consistent with SCD. Corneas of the family members appeared unaffected. Screening of UBIAD1 in the proband identified a novel heterozygous c.308C>T mutation, predicted to encode the missense amino acid substitution p.(Thr103Ile). This mutation was not identified in any of the family members or in 200 control chromosomes and was predicted to be damaging to normal protein function and structure. Conclusions. We present a novel heterozygous de novo missense mutation in UBIAD1, p.(Thr103Ile), identified in a patient with classic clinical features of SCD. This highlights the value of genetic testing in clinical diagnostic settings, even in the absence of a positive family history.

Genotype and phenotype correlation of monogenic corneal dystrophies in population of central Poland

PurposeTo assess the genotype‐phenotype correspondence in monogenic corneal dystrophies caused by KRT,TGFBI and UBIAD1 genes mutation.Methods61 patients from 30 Polish families with clinically diagnosed epithelial and stromal corneal dystrophies participated in the study.Corneal phenotypes were assessed by slit lamp, AS‐OCT,and confocal microscopy in vivo. Genomic DNA was obtained from blood samples and respective exons (hot spots) were PCR amplified and sequenced on both strands.ResultsMolecular genetic testing revealed heterozygous missense p.E498V mutation (exon 7) of KRT3 in one family with Meesmann corneal dystrophy phenotype, p.R555W (exon 12) mutation in 19 patients diagnosed with granular type I dystrophy (GCD1). In two patients p.R124H mutation (GCD2, Avellino) was found. In three patients (2 families) heterozygous p.R124L (exon 4) mutation was identified and diagnosed as Reis‐Buecklers dystrophy. In two unrelated patient p.R555Q (exon 12) mutation typical for Thiel‐Behnke dystrophy was found. Heterozygous p.R124C (exon 4), p.T538R (exon 12) and p.H626R (exon 14) mutations were identified, respectively, in 10 patients diagnosed with lattice corneal dystrophy (LCD1). A novel p.L565P mutation was found in one family with late‐onset LCD.Among 18 idividuals (4 families) suffering from stromal Schnyder corneal dystrophy (SCD) molecular genetic testing revealed 3 different UBIAD1 gene mutations: p.N102S, p.D112N, p.T120R.ConclusionsThe genotype typical for monogenic corneal dystrophies caused by KRT and UBIAD1 genes mutation corresponds with its clinical phenotype. TGFBI is associated with phenotype heterogenity and in some cases only genetic tests may confirm the proper diagnosis.This indicates that a relatively straightforward molecular analysis can be a practical use in diagnosis of these conditions and associated genetic counseling.

The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase.

Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

Molecular Pathogenesis of Corneal Dystrophies: Schnyder Dystrophy and Granular Corneal Dystrophy type 2.

The International Committee for Classification of Corneal Dystrophies (IC3D) provides updated data to ophthalmologists by incorporating traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Recent advances in the genetics of corneal dystrophies facilitate more precise classifications and elucidate each classification's molecular mechanisms. Unfortunately, the molecular mechanisms and underlying pathogenic mechanisms have remained obscure, with the exception of Schnyder corneal dystrophy (CD), granular CD type 2 (GCD2), and Fuch's endothelial CD. Here, we review the pathogenesis of Schnyder CD and GCD2.

Stromal corneal dystrophies

AbstractAccording to the IC3D classification the group of the stromal corneal dystrophies include: TGFBI corneal dystrophies, Macular corneal dystrophy (MCD), Schnyder corneal dystrophy (SCD), Congenital stromal corneal dystrophy (CSCD), Fleck corneal dystrophy (FCD), Posterior amorphous corneal dystrophy (PACD), Central cloudy dystrophy of François (CCDF) and Pre‐Descemet corneal dystrophy (PDCD). The lecture summarizes the clinical data of each corneal dystrophy with the referral to the genetic analysis, histological exam and modern non invasive optical imaging techniques as long as presents current treatment options.

Phenotype–Genotype Correlation in Patients With Schnyder Corneal Dystrophy

The aim of this study was to analyze the corneal morphology features and define mutations in the UbiA prenyltransferase domain-containing 1 (UBIAD1) gene in patients with Schnyder corneal dystrophy from a Polish population. Five affected and 15 unaffected members originating from 3 families with Schnyder corneal dystrophy were included in the study. Phenotype analysis consisted of visual acuity, slit-lamp biomicroscopy with photography, time domain optical coherence tomography, spectral domain optical coherence tomography, and confocal microscopy. Three patients underwent a penetrating keratoplasty. Corneal buttons obtained from the penetrating keratoplasty were processed for light microscopy. A novel mutation I245N of the UBIAD1 gene was revealed in 1 proband and associated with the phenotype without central corneal opacities. The analysis of the other patients showed the N102S mutation. In vivo corneal morphology analysis using optical coherence tomography and confocal microscopy confirmed the presence of multiple crystalline corneal deposits in all affected corneas. The histological examination revealed multiple empty widenings of the corneal lamellae that could represent lipids removed from the specimen. N102S may also be a mutation hotspot in the Polish population, as in other previously reported populations. Corneal crystals formed a characteristic pattern on optical coherence tomography scans.

Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression

Heterozygous mutations in the UBIAD1 gene cause Schnyder corneal dystrophy characterized by abnormal cholesterol and phospholipid deposits in the cornea. Ubiad1 protein was recently identified as Golgi prenyltransferase responsible for biosynthesis of vitamin K2 and CoQ10, a key protein in the mitochondrial electron transport chain. Our study shows that silencing UBIAD1 in cultured human hepatocellular carcinoma cells causes dramatic morphological changes and cholesterol storage in the mitochondria, emphasizing an important role of UBIAD1 in mitochondrial function.

A Case of Schnyder Corneal Dystrophy with Crystals

To report a rare corneal dystrophy and its common findings to help aid others in proper and early diagnosis and management. A 56-year-old male patient presented with the concern of blurry vision in both eyes that has progressed over the last 10 years. Anterior segment examination revealed arcus with a central haze in both eyes and crystalline deposition in the right eye. A diagnosis of Schnyder corneal dystrophy was made based on clinical presentation. Schnyder corneal dystrophy is rare but has different presentations and may actually be misdiagnosed. The clinical signs change as the patient ages causing a decrease in vision, which may necessitate referral for phototherapeutic keratectomy, penetrating keratoplasty or deep anterior lamellar keratoplasty. The patient's systemic findings that correlate with the dystrophy need to be assessed and managed appropriately.

A Novel Golgi Retention Signal RPWS for Tumor Suppressor UBIAD1

UBIAD1 plays critical roles in physiology including vitamin K and CoQ10 biosynthesis as well as pathophysiology including dyslipimedia-induced SCD (Schnyder’s corneal dystrophy), Parkinson’s disease, cardiovascular disease and bladder carcinoma. Since the subcellular localization of UBIAD1 varies in different cell types, characterization of the exact subcellular localization of UBIAD1 in specific human disease is vital for understanding its molecular mechanism. As UBIAD1 suppresses bladder carcinoma, we studied its subcellular localization in human bladder carcinoma cell line T24. Since fluorescent images of UBIAD1-EGFP in T24, human prostate cancer cell line PC-3, human embryonic kidney cell line HEK293 and human hepatocyte cell line L02 are similar, these four cell lines were used for present study. Using a combination of fluorescent microscopy and immunohistochemistry, it was found that UBIAD1 localized on the Golgi and endoplasmic reticulum (ER), but not on the plasma membrane, of T24 and HEK293 cells. Using scanning electron microscopy and western blot analysis, we found that UBIAD1 is enriched in the Golgi fraction extracted from the L02 cells, verifying the Golgi localization of UBAID1. Site-directed mutagenesis showed that the RPWS motif, which forms an Arginine finger on the UBIAD1 N terminus, serves as the Golgi retention signal. With both cycloheximide and brefeldin A inhibition assays, it was shown that UBIAD1 may be transported from the endoplasmic reticulum (ER) to the Golgi by a COPII-mediated mechanism. Based upon flow cytometry analysis, it is shown that mutation of the RPWS motif reduced the UBIAD1-induced apoptosis of T24 cells, indicating that the proper Golgi localization of UBIAD1 influences its tumor suppressant activity. This study paves the way for further understanding the molecular mechanism of UBIAD1 in human diseases.

Ocular Phenotypes and In Vivo Laser Confocal Microscopy Findings in a Family with Schnyder Corneal Dystrophy Shared the Same UBIAD1 Mutation Locus (N102S)

Purpose: This study aims to observe the ocular phenotypes of a family with Schnyder corneal dystrophy (SCD) and to assess the image features of SCD by in vivo laser corneal confocal microscopy (IVCM). Methods: A family with SCD was collected, and the corneal lesion of five affected members was observed. Bilateral corneas were examined using IVCM (Heidelberg Retina Tomograph III with Cornea Module) in three adult patients with SCD. Blood samples were collected for genetic analysis in the available family members. Results: Phenotype heterogeneity was found in five affected individuals with a same mutation (N102S). Slit-lamp examination suggested no crystal in the right eye of a 40-year-old male SCD patient, but crystalline materials were found by IVCM. In some images of IVCM, crack-like striaes and crystalline materials with various shapes were observed in the stroma. Conclusions: Extremely varied phenotypes between individual patients are demonstrated in this SCD family with a same mutation locus. Slit-lamp examination cannot find mini crystalline deposits in SCD cornea. Crystalline accumulations can be detected by ICVM at the cellular level prior to slit-lamp examination.

The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to cholesterol metabolic enzymes.

Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone-4 (MK-4, vitamin K(2) ), but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK-4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177-mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two-hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate-binding cleft and substrate-binding overlaps with GGPP binding, an MK-4 substrate, suggesting potential competition between these metabolites. Impaired MK-4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggest a role for endogenous MK-4 in maintaining cornea health and visual acuity.

Diskrete bilaterale korneale Ablagerungen bei einer jungen Frau

A 17-year-old asymptomatic girl presented with discrete bilateral deposits in the superficial corneal stroma. The diagnosis of very early and in this form as yet undescribed manifestation of Schnyder's corneal dystrophy, was only possible based on the family history.

Clinical and pathological features of a non-crystalline form of Schnyder corneal dystrophy

Schnyder corneal dystrophy (SCD) is a rare progressive bilateral disorder of the cornea resulting from an abnormal deposition of (un)esterified cholesterol and phospholipids throughout the cornea. SCD is an entity characterized by a varied spectrum of corneal changes, a fact that may cause difficulties for making the correct diagnosis. In previous publications, the clinical appearance has been described as a deposition of crystals predominantly located in the anterior stroma, accompanied by an arcus lipoides and a stromal haze [1]. However, Weiss et al. demonstrated that corneal crystals are found in only 54% of patients [2, 3], while the other patients presented with a disc-like central corneal opacity without subepithelial cholesterol crystals. Abnormal lipid deposition has been seen throughout the corneal stroma, but also in the basal epithelium, in the Bowman’s layer and occasionally within endothelial cells [2]. We present a patient with a non-crystalline form of SCD. We describe clinical aspects, and demonstrate light and electron microscopic features of this disease.

Chameleon-like Appearance of Immunotactoid Keratopathy

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. 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. 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. 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.