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Purpose: 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. Methods: 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. Results: 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 Parkinsonʼs disease like findings in Drosophila. Conclusions: 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.

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.

BACKGROUND: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE: The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS: This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a welldefined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d . KEY WORDS: corneal dystrophy, inherited corneal disease, genetic corneal disease, corneal histopathology, gene, mutation, key reference, eponym, epithelial basement membrane dystrophy, epithelial recurrent erosion dystrophy, subepithelial mucinous corneal dystrophy, Meesmann corneal dystrophy, Lisch epithelial corneal dystrophy, gelatinous drop-like corneal dystrophy, Grayson-Wilbrandt corneal dystrophy, lattice corneal dystrophy, lattice gelsolin type dystrophy, granular corneal dystrophy 1, granular corneal dystrophy 2, Avellino corneal dystrophy, Reis-Bucklers corneal dystrophy, Thiel-Behnke corneal dystrophy, macular corneal dystrophy, Schnyder corneal dystrophy, Schnyder crystalline corneal dystrophy, congenital stromal corneal dystrophy, fleck corneal dystrophy, posterior amorphous corneal dystrophy, central cloudy dystrophy of Francxois, pre-Descemet corneal dystrophy, Fuchs endothelial corneal dystrophy, posterior polymorphous corneal dystrophy, congenital hereditary endothelial dystrophy 1, congenital hereditary endothelial dystrophy 2, X-linked endothelial corneal dystrophy

Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E.

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. © Springer-Verlag 2004., National Eye Institute: EY12972, Acknowledgements We thank SCCD family members for their participation and Dr. Howard Kruth for his insightful suggestions concerning the study. This work was supported in part by the National Eye Institute (grant EY12972 to J.S.W.).

Objective To analyze corneal morphology in Schnyder crystalline corneal dystrophy (SCCD) in vivo. Design Observational case series. Participants Five eyes of four patients of various belonging to the same family were examined. Methods The eyes were examined using in vivo confocal microscopy (CM). Main outcome measures The corneal morphology including keratocytes and stromal extracellular matrix, as well as basal epithelial/subepithelial nerves is, described. Results The right eye of a 48-year-old male patient had been treated with anterior keratectomy and the left eye with phototherapeutic keratectomy (PTK). The right eye presented with increased stromal reflectivity owing to accumulation of extracellular matrix and large subepithelial crystalline deposits. Far fewer crystals could be observed in the left eye. The haze, however, was increased, either because of the dystrophy or the excimer laser treatment. The anterior keratocytes appeared irregular, and the subepithelial nerves were undetectable in both eyes. His 78-year-old mother showed more advanced changes with dense crystals, highly fibrotic stroma, and severely damaged corneal innervation. The partly irregular anterior keratocytes of the 9- and 7-year-old children contained intracellular deposits, although the corneas were clinically clear with only subtle subepithelial crystalline formation. Accumulation of similar reflective material was also observed in association with the prominent subepithelial nerves. Conclusions In the early stages of SCCD, highly reflective deposits accumulate intracellularly and around anterior keratocytes and along subepithelial nerves. With time, the normal corneal architecture becomes disturbed by large extracellular crystalline deposits and accumulation of highly reflective extracellular matrix resulting in central opacity and disruption of the subepithelial nerve plexus. Furthermore, neural regeneration after keratectomy appears delayed in SCCD.

Purpose: To determine the percentage of patients with Schnyder crystalline dystrophy who had corneal crystal deposition. Methods: Thirty-three patients with Schnyder crystalline dystrophy were identified by the author since 1987. Each patient had a complete ophthalmic evaluation, including slit-lamp examination by the author. Results: Only 51% (17 of 33) of patients with Schnyder crystalline corneal dystrophy actually had clinical evidence of corneal crystalline deposits. Conclusions: Because of the confusing nomenclature, many ophthalmologists presume that the presence of corneal crystals is an integral part of the diagnosis of Schnyder crystalline dystrophy. The clinician should be aware that despite the fact that the noncrystalline form of the dystrophy has been poorly recognized, it is equally common.

Schnyder corneal dystrophy (SCD) is a rare corneal dystrophy characterized by abnormally increased deposition of cholesterol and phospholipids in the cornea leading to progressive vision loss. SCD is inherited as an autosomal dominant trait with high penetrance and has been mapped to the UBIAD1 gene on chromosome 1p36.3. Although 2/3 of SCD patients also have systemic hypercholesterolemia, the incidence of hypercholesterolemia is also increased in unaffected members of SCD pedigrees. Consequently, SCD is thought to result from a local metabolic defect in the cornea. The corneal findings in SCD are very predictable depending on the age of the individual, with initial central corneal haze and/or crystals, subsequent appearance of arcus lipoides in the third decade and formation of midperipheral haze in the late fourth decade. Because only 50% of affected patients have corneal crystals, the International Committee for Classification of Corneal Dystrophies recently changed the original name of this dystrophy from Schnyder crystalline corneal dystrophy to Schnyder corneal dystrophy. Diagnosis of affected individuals without crystalline deposits is often delayed and these individuals are frequently misdiagnosed. The differential diagnosis of the SCD patient includes other diseases with crystalline deposits such as cystinosis, tyrosinemia, Bietti crystalline dystrophy, hyperuricemia/gout, multiple myeloma, monoclonal gammopathy, infectious crystalline keratopathy, and Dieffenbachia keratitis. Depositions from drugs such as gold in chrysiasis, chlorpromazine, chloroquine, and clofazamine can also result in corneal deposits and are different from SCD. Diseases of systemic lipid metabolism that cause corneal opacification, such as lecithin-cholesterol acyltransferase deficiency, fish eye disease and Tangier disease, should also be considered although these are autosomal recessive disorders.

TERE1/UBIAD1 is involved in SCCD (Schnyder crystalline corneal dystrophy) and multiple human cancers. So far, the molecular mechanism of TERE1/UBIAD1 in tumourigenesis is unclear. Here, the expression levels of hTERT and TERE1/UBIAD1 in pathologically proven Chinese TCC (transitional cell carcinoma) samples were measured. It was found that decreased TERE1/UBIAD1 expression is closely related to both an increased hTERT expression and activation of Ras–MAPK signalling. Chemically modified TERE1 siRNA oligos were used to knock down TERE1 expression in human L02 cells. Cells transfected with TERE1 siRNA oligos underwent significant cell proliferation. When the levels of hTERT expression and ERK phosphorylation were measured, it was found that both of them increased in the above transfected cells, suggesting the activation of Ras–MAPK signalling. Addition of the MEK inhibitor U0126 into the transfected L02 cells described above inhibited ERK phosphorylation and hTERT expression. Our result is the initial demonstration that down-regulation of TERE1 activates Ras–MAPK signalling and induces subsequent cell proliferation. TERE1 might be a new negative regulator of Ras–MAPK signalling, which plays a pivotal role in the cell proliferation of multiple human cancers.

Background: A large cohort comprising four kindreds of patients with Schnyder's dystrophy has been identified in central Massachusetts. All patients were Swede-Finn with ancestry from the southwest Finnish coast on the Bay of Bothnia. Methods: Of 60 members of this cohort examined by one of the authors (JSW), 18 had evidence of Schnyder's dystrophy. One female with Schnyder's dystrophy from each of three kindreds underwent penetrating keratoplasty for decreased visual acuity. We examined 4 corneal buttons from these unrelated women, aged 47, 63, and 72 years. Results: The fluorescent probe filipin revealed that the majority of the lipid deposits were rich in unesterified cholesterol. Electron microscopy demonstrated abnormal accumulation of lipid and dissolved cholesterol in the epithelium, Bowman's layer, and throughout the stroma. Examination of the kindreds reflected the variable expression of crystals, which were present only in two patients, the 47-year-old and 63-year-old women. Conclusion: Ultrastructural and histochemical studies showed the panstromal localization of lipid in Schnyder's corneal dystrophy in three patients with Schnyder's dystrophy who underwent penetrating keratoplasty.

Schnyder's crystalline dystrophy is an uncommon hereditary disease in which there is abnormal deposition of cholesterol and/or lipid usually in the anterior stroma of the central and peripheral cornea. Four families with Schnyder's dystrophy have been identified in central Massachusetts. Of the 173 living members of these pedigrees, 60 patients were examined by the author. Eighteen patients had Schnyder's dystrophy. Affected individuals less than 23 years of age had bilateral, central disc-like corneal opacification. Those greater than 23 years of age also demonstrated prominent arcus lipoides. By age 40, all affected individuals developed a diffuse stromal haze. Only 50% of affected individuals had corneal crystalline deposits. Abnormal cholesterol deposition affected the entire stromal thickness in the majority of patients. Although the four families said that they were not related to each other, all had ancestry from towns within a 100-k area on the southwest coast of Finland. Patients in this area of Finland were examined by the author and demonstrated signs of Schnyder's dystrophy. This may represent the largest cohort of Schynder's dystrophy described to date.

PURPOSE. Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed. METHODS. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5 untranslated region (UTR) exons. RESULTS. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes). CONCLUSIONS. Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains. (Invest Ophthalmol Vis Sci. 2007;48: 5007‐5012) DOI:10.1167/iovs.07-0845

Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.

Objective To emphasize the effectiveness of phototherapeutic keratectomy (PTK) in a patient with Schnyder crystalline corneal dystrophy (SCCD). Methods Case report. Results Two eyes of a patient with SCCD underwent PTK. Best corrected visual acuity (BCVA) increased from 2/10 to 8/10 (plano/-1.50 x 10) in the right eye in a lit room. BCVA of the left eye was 4/10 (-8.00/-1.50 x 170) and did not change after treatment because of anisometropic amblyopia. No recurrence was detected after 68 months of follow-up. Conclusion PTK may be effective in the treatment of SCCD, especially if the crystals are the cause of visual disturbance.

A crystal structure of a member of the UbiA family of membrane-embedded prenyltransferases reveals the architecture of the active site and suggests a possible mechanism for catalysis., Membrane-embedded prenyltransferases from the UbiA family catalyze the Mg2+-dependent transfer of a hydrophobic polyprenyl chain onto a variety of acceptor molecules and are involved in the synthesis of molecules that mediate electron transport, including Vitamin K and Coenzyme Q. In humans, missense mutations to the protein UbiA prenyltransferase domain-containing 1 (UBIAD1) are responsible for Schnyder crystalline corneal dystrophy, which is a genetic disease that causes blindness. Mechanistic understanding of this family of enzymes has been hampered by a lack of three-dimensional structures. We have solved structures of a UBIAD1 homolog from Archaeoglobus fulgidus, AfUbiA, in an unliganded form and bound to Mg2+ and two different isoprenyl diphosphates. Functional assays on MenA, a UbiA family member from E. coli, verified the importance of residues involved in Mg2+ and substrate binding. The structural and functional studies led us to propose a mechanism for the prenyl transfer reaction. Disease-causing mutations in UBIAD1 are clustered around the active site in AfUbiA, suggesting the mechanism of catalysis is conserved between the two homologs., Author Summary The biosynthesis of Vitamin K and Coenzyme Q requires the transfer of a long, hydrophobic moiety known as an isoprenyl onto an aromatic acceptor compound. This process is catalyzed by a family of proteins known as the UbiA proteins, which are embedded in the hydrophobic environment of cell membranes. To understand how the prenyltransfer reaction is carried out, we solved the three-dimensional structure of a member of the UbiA family by X-ray crystallography. This structure reveals how magnesium ions and the prenyl substrate are bound within a sealed amphipathic chamber inside the protein and suggests how the reaction intermediate may be stabilized by the protein and protected from the solvent. Functional studies carried out on another member of the UbiA family, as well as comparison to known disease-causing mutations in the human homolog UBIAD1, demonstrate that the residues involved in this process are conserved across the UbiA family.

We previously reported a novel human cDNA, designated B120, containing a CAG repeat length polymorphism and many repeat units, loosely identified as YXQQP which is found in several human RNA binding proteins. In the present study, the B120 gene was mapped to human chromosome 1p35-36.1 by fluorescence in situ hybridization (FISH). Several human disorders, including that of Schnyder crystalline corneal dystrophy, have been mapped to this region by genetic linkage. Schnyder crystalline corneal dystrophy is thought to be a primary abnormality of corneal lipid metabolism, resulting in opacification secondary to lipid accumulation. In order to examine the function of B120, we introduced B120 cDNA with an expression vector into various cell lines including Cos1, C3H/10T1/2 and NIH/3T3 cells. These transfected cells exhibited small cytoplasmic spherical bodies. The cytoplasmic bodies appeared to be fat droplets on electron microscopy and histochemical staining. These findings suggested that B120 gene expression is associated with lipid metabolism, and that overexpression of B120 may result in lipid deposition in various cells, including those of fibroblastic cell lines. Since the cornea is composed of fibroblastic cells, overfunction of B120 could be related to the pathogenesis of Schnyder crystalline corneal dystrophy.

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.

Purpose: Schnyder crystalline corneal dystrophy (SCCD) is an autosomal dominant disease characterized by progressive central corneal opacification and premature development of peripheral arcus in the cornea. This disease results from a point mutation of UBIAD1 in chromosome 1p34-36. Until now, 15 different mutations of UBIAD1 gene on chromosome 1p34-36 have been reported for Schnyder crystalline corneal dystrophy. More point mutations are expected to be added to the list in the future. Schnyder crystalline corneal dystrophy is a rare disease, with only three reported cases in Korea, although there has been no report of a genetically confirmed case of the disease. Case summary: We encountered six patients with an N102S mutation of UBIAD1, who are from a family of two generation with 12 family members. Genetic confirmation for Schnyder crystalline corneal dystrophy was performed on these patients. This was the first report of a genetic confirmation of Schnyder crystalline corneal dystrophy in Korea. We will discuss our cases along with a review of the related literature.

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.