Schnyder Crystalline Corneal Research Articles

Functional study of SCCD pathogenic gene UBIAD1 (Review).

Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant genetic disorder that is characterized by progressive corneal opacity, owing to aberrant accumulation of cholesterol and phospholipids in the cornea. A number of SCCD affected families have been reported in the world since 1924, when it was first described. In 2007, the molecular basis of SCCD was demonstrated to be associated with a tumor suppressor, UbiA prenyltransferase domain-containing 1 (UBIAD1), which was isolated from the bladder mucosa and demonstrated to be involved in vitamin K2 and CoQ10 biosynthesis. This sterol triggers the binding of UBIAD1 to 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) at endoplasmic reticulum (ER) membranes, which is regulated by an intracellular geranylgeranyl diphosphate (GGpp) molecule. The inability of SCCD-associated UBIAD1 to bind GGpp results in the consistent binding of UBIAD1 to HMGCR at ER membranes. This binding leads to HMGCRs being redundant. Therefore, they cannot be degraded through ER-associated degradation to synthesize abundant cholesterol in tissue cells. Excess corneal cholesterol accumulation thus leads to SCCD disease. After decades, the efforts of numerous ophthalmologists and scientists have helped clarify the molecular basis and pathogenesis of SCCD, which has guided the effective diagnosis and treatment of this genetic disorder. However, more studies need to be conducted to understand the pathogenesis of SCCD disease from a genetic basis by studying the defective gene, UBIAD1. Results would guide effective diagnosis and treatment of the inherited eye disease.

À propos d’un cas évocateur de dystrophie cristalline de Schnyder

Schnyder's crystalline corneal dystrophy is a rare bilateral hereditary disease with various clinical features. It typically presents as a central disc-like opacification with or without crystalline deposits. We report the case of a particular crystalline-free and ring-like pattern dystrophy resembling Schnyder's corneal dystrophy in an 82-year-old woman. In addition, we describe the aspects of this dystrophy with in vivo confocal microscopy using the Heidelberg Retina Tomograph II-Rostock Cornea Module and with anterior segment optical coherence tomography (OCT-Visante((R))). These techniques can be useful in the diagnosis or the therapeutic process, showing crystalline structures that are not clinically distinguishable or validating the histological localization of the corneal disease.

In Vivo Laser Confocal Microscopy Findings and Mutational Analysis for Schnyder's Crystalline Corneal Dystrophy

To identify any mutation of the UbiA prenyltransferase domain-containing protein 1 (UBIAD1) gene in Japanese patients with Schnyder's crystalline corneal dystrophy (SCCD) and to investigate in vivo microstructural phenotype and genotype correlations using laser scanning confocal microscopy (Heidelberg Retina Tomograph 2 Rostock Cornea Module; Heidelberg Engineering GmbH, Dossenheim, Germany). Small, comparative case series. Three patients from 3 pedigrees (3 males) with clinically diagnosed SCCD and their relatives (2 males, 1 female) participated in this study. All participants were examined genetically and by slit-lamp biomicroscopy and in vivo laser confocal microscopy. Genomic DNA from the patients and 100 unrelated healthy volunteers (200 chromosomes) was isolated from blood samples and used for mutation screening of the UBIAD1 gene. Selected confocal images of corneal layers were evaluated qualitatively for shape and degree of light reflection of deposits. Novel mutations in the UBIAD1 gene (Y174C, K181R, and N233H) were identified. Additionally, cosegregation of the mutation (Y174C) and SCCD was confirmed in 1 pedigree, indicating that the mutation of the UBIAD1 gene is causative for SCCD. The 3 mutations were absent in all 200 control chromosomes. In vivo laser confocal microscopy demonstrated subepithelial highly reflective crystals in 4 cases; the shapes of the crystals were needle-shaped (3 cases) or rectangular (1 case). A phenotype and genotype correlation was demonstrated in 1 pedigree, and phenotypic heterogeneity (SCCD with or without crystals caused by a same mutation of Y174C in the UBIAD1 gene) also was demonstrated in 1 pedigree. Nonsynonymous novel mutations in the UBIAD1 gene were detected in 3 unrelated Japanese pedigrees with SCCD, confirming the genetic heterogeneity of this disorder. In vivo laser confocal microscopy is capable of identifying characteristic corneal microstructural changes related to genetically mapped SCCD with high resolution, and phenotypic heterogeneity was presented. Further confocal and mutational analysis using a larger number of patients with SCCD is required to elucidate in vivo microstructural phenotype and genotype correlations. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Morphological evaluation of Schnyder's crystalline corneal dystrophy by laser scanning confocal microscopy and Fourier-domain optical coherence tomography

A 29-year-old Chinese woman with Schnyder's crystalline corneal dystrophy was referred to our clinic. Ocular examination revealed abnormal deposits of cholesterol and lipid within the corneal stroma, appearing as crystalline needle-shaped deposits, in both eyes. In vivo laser scanning confocal microscopy revealed pathological alterations of the normal corneal anatomy in the patient, such as highly reflective crystalline structures in the anterior-and mid-stroma. The images acquired from Fourier-domain optical coherence tomography indicated that the main presence of crystalline deposits was localized within the anterior stroma, extending from the basal epithelium layer to a depth of 80 to 150 microm. To the best of the author's knowledge, it is consistent with the results of the previous histological study.

Fine mapping of the Schnyder's crystalline corneal dystrophy locus.

Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant eye disease with a spectrum of clinical manifestations that may include bilateral corneal clouding, arcus lipoides, and anterior corneal crystalline cholesterol deposition. We have previously performed a genome-wide linkage analysis on two large Swede-Finn families and mapped the SCCD locus to a 16-cM interval between markers D1S2633 and D1S228 on chromosome 1p36. We have collected 11 additional families from Finland, Germany, Turkey, and USA to narrow the critical region for SCCD. Here, we have used haplotype analysis with densely spaced microsatellite markers in a total of 13 families to refine the candidate interval. A common disease haplotype was observed among the four Swede-Finn families indicating the presence of a founder effect. Recombination results from all 13 families refined the SCCD locus to 2.32 Mbp between markers D1S1160 and D1S1635. Within this interval, identity-by-state was present in all 13 families for two markers D1S244 and D1S3153, further refining the candidate region to 1.58 Mbp.

Corneal changes of uncertain etiology in mesoendemic onchocercal communities of Northern Nigeria.

We report an unusual type of corneal change in some communities mesoendemic for onchocerciasis in Kaduna State of Northern Nigeria. Thirty-four villages with an overall average microfilarial skin snip positivity rate of 71% and a total population of about 10,000 were included in a controlled trial of ivermectin for onchocerciasis. Detailed slit lamp examination of 806 persons within this population revealed at least 27 individuals with these lesions. There were 11 women and 16 men, aged between 5 and 70 years with a mean age of 45 years and a SD of 15 years. Drawings and photographs of 22 of these individuals were available for assessment. The lesions were peripheral, silvery white, and of two main types: the first group's lesions were flaky, refractile, and crystalline in appearance; the second group's lesions were more cylindrical in outline and were crisscrossed, giving a lattice-like pattern. There were indeterminate forms in between these polar topographies. Of the 25 subjects who had skin snips performed, 23 were microfilaria-positive. There was no accompanying inflammation and the posterior segments showed no evidence of crystalline deposits or retinitis pigmentosa, as is found in Bietti's dystrophy. The lesions coexisted with typical sclerosing keratitis in six individuals, and changes noted in the posterior pole of ten individuals were typical of onchocercal chorioretinitis. The evidence for consanguinity was not compelling. Differences between and similarities to Bietti's and Schnyder's crystalline corneal dystrophy, which are known to be composed of cholesterol crystals, are discussed. The lesions are also compared with lattice dystrophy known to be composed of amyloid. These lesions may be related to onchocercal infection. We describe some unusual peripheral corneal changes in individuals living within areas of Northern Nigeria mesoendemic for onchocerciasis. These changes take the form of flaky crystals or lattice within the anterior stroma and are common in middle-aged individuals. This may be related to onchocercal infection.

The gene for schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36.

Schnyder's crystalline corneal dystrophy (SCCD) is an autosomal dominant eye disease characterized by a bilateral clouding of the central cornea, arcus lipoides and/or visible crystalline deposits of cholesterol in the stroma. There is accumulation of phospholipid, unesterified cholesterol and cholesterol ester in the corneal stroma; this is believed to be due to an imbalance in the local factors affecting lipid/cholesterol transport or metabolism. The cellular mechanism of abnormal lipid transport and metabolism in SCCD is of interest due to its potential involvement in atherosclerosis, and its implications for the pathogenesis of cerebrovascular, coronary and peripheral vascular disease as well as corneal opacification. To determine the chromosomal location of the SCCD locus, genome-wide linkage analysis has been performed in two large Swede-Finn kindreds recently identified in central Massachusetts. After analysing 300 microsatellite markers > 90% of the genome was excluded from linkage to the SCCD locus. We now report the chromosomal assignment of the gene for SCCD in both families to be 1p34.1-p36; the maximum multipoint lod-score was 8.48 in the interval between D1S214 and D1S503. From haplotype analysis, the SCCD locus lies in the 16 cM interval between markers D1S2663 and D1S228. Several candidate genes for SCCD have been localized to the 1p34.1-p36 interval.

Disappearance of Crystals in Schnyder's Crystalline Corneal Dystrophy After Epithelial Erosion

A 40-year-old woman with Schnyder's crystalline corneal dystrophy had two episodes of epithelial erosion. We reviewed the patient's medical record and photographic file. In the areas underlying the epithelial erosion, the crystalline opacities disappeared. The crystals recurred in the subsequent five years but were not as dense. Crystals in the subepithelial or Bowman's layer may lead to epithelial destabilization and corneal epithelial erosion. Disappearance of the crystalline opacities may occur after disruption of the epithelium.

Linkage analysis in granular corneal dystrophy (Groenouw I), Schnyder's crystalline corneal dystrophy, and Reis-Bücklers' corneal dystrophy.

Tight linkage was excluded for 8 markers in 37 blood relatives from 3 families, 29 of whom had granular corneal dystrophy (Groenouw I). Inconclusive results were obtained for linkage with four marker loci. The highest positive LOD score was 0.57 for linkage between glutamic pyruvic transaminase and granular corneal dystrophy. Tight linkage was excluded for glyoxalase-1 in eight individuals from one family with Schnyder's crystalline corneal dystrophy. Results were inconclusive for another six markers. Positive LOD scores were obtained for linkage with adenylate-kinase 1 and the ABO blood group, with values of 1.16 and 0.67, respectively. Among six blood relatives with Reis-Bücklers' corneal dystrophy, the highest positive LOD score was 1.17 for linkage with mitochondrial malic enzyme. For another six markers informative for linkage analysis, the results were inconsistent.

Corneal Changes in the Dislipoproteinaemias

The corneal changes in the hyper- and hypoproteinaemias may affect vision and/or provide a diagnostic clue to a systemic disorder. This article describes the structure and function of the major lipoprotein classes and the means by which dietary lipid is absorbed and by which exogenous and endogenous lipid is distributed to and cleared from the tissues. In hyper-beta-lipoproteinaemia, lipid arcus formation may be related to the duration and height of the raised cholesterol levels. The peripheral location of the lipid deposit is presumed to be related to peripheral trapping of low-density lipoprotein (LDL) by glycosaminoglycan binding and tight stromal packing with maintained central clearing by high-density lipoprotein (HDL), whose smaller molecular diameter should allow freer stromal diffusion. In the hypolipoproteinaemias, e.g., Tangier disease, generalised (alpha and beta) lecithin cholesterol acyltransferase (LCAT) deficiency, and alpha-LCAT deficiency (fish-eye disease), the absence or abnormality of HDL may impair clearance of endogenous and possibly exogenous stromal lipid. The hyperlipoproteinaemia that sometimes accompanies Schnyder's crystalline corneal dystrophy is thought to modify the effects of a primary failure of corneal stromal lipid metabolism.