Phenotype of autosomal recessive congenital microphthalmia mapping to chromosome 14q32.
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BACKGROUND: Congenital microphthalmia (OMIM: 309700) may occur in isolation or in association with a variety of systemic malformations. Isolated microphthalmia may be inherited as an autosomal dominant, an autosomal recessive, or an X linked trait. METHODS: Based on a whole genome linkage analysis, in a six generation consanguineous family with autosomal recessive inheritance, the first locus for isolated microphthalmia was mapped to chromosome 14q32. Eight members of this family underwent clinical examination to determine the nature of the microphthalmia phenotype associated with this locus. RESULTS: All affected individuals in this family suffered from bilateral microphthalmia in association with anterior segment abnormalities, and the best visual acuity achieved was "perception of light". Corneal changes included partial or complete congenital sclerocornea, and the later development of corneal vascularisation and anterior staphyloma. Intraocular pressure, as measured by Schiotz tonometry, was greatly elevated in many cases. CONCLUSIONS: This combination of ocular defects suggests an embryological disorder involving tissues derived from both the neuroectoderm and neural crest. Other families with defects in the microphthalmia gene located on 14q32 may have a similar ocular phenotype aiding their identification. (+info)
A first British case of fish-eye disease presenting at age 75 years: a double heterozygote for defined and new mutations affecting LCAT structure and expression.
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Fish-eye disease is a familial syndrome with corneal opacification, major high density lipoprotein (HDL) deficiency in plasma, significant cholesterol esterification in plasma on non-HDL lipoproteins, generally without premature coronary disease. This first British male case from unrelated British parents had infarcts when aged 49 and 73 years but was asymptomatic at age 81 years, with plasma cholesterol 4.3-7.1 mmol/litre, triglycerides 1.8-2.2 mmol/litre, HDL cholesterol < 0.1 mmol/litre, apolipoprotein A-I < 0.16 g/litre, lipoprotein(a) 0.61 g/litre. Cholesterol esterification was impaired using HDL-3 and A-I proteoliposomes but not using VLDL/IDL/LDL. The findings are those of LCAT deficiency with the classic fish-eye disease defect. Most of the 22 reported cases were homozygous or heterozygous for a Thr-Ile mutation at codon 123 of the lecithin:cholesterol acyltransferase (LCAT) gene. This patient was a double heterozygote for this mutation and a second new incompletely defined mutation affecting LCAT expression as defined by reduced mass and activity in plasma. (+info)
Functional human corneal equivalents constructed from cell lines.
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Human corneal equivalents comprising the three main layers of the cornea (epithelium, stroma, and endothelium) were constructed. Each cellular layer was fabricated from immortalized human corneal cells that were screened for use on the basis of morphological, biochemical, and electrophysiological similarity to their natural counterparts. The resulting corneal equivalents mimicked human corneas in key physical and physiological functions, including morphology, biochemical marker expression, transparency, ion and fluid transport, and gene expression. Morphological and functional equivalents to human corneas that can be produced in vitro have immediate applications in toxicity and drug efficacy testing, and form the basis for future development of implantable tissues. (+info)
Persistent corneal haze after excimer laser photokeratectomy in plasminogen-deficient mice.
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PURPOSE: Excimer laser photorefractive keratectomy creates a nonvascular wound of the cornea. Fibrin deposition and resolution after excimer laser photokeratectomy were investigated in relation to corneal repair and restoration of clarity in mice with a genetic deficiency of plasminogen. METHODS: A Summit Apex Laser (Summit, Waltham, MA) was used to perform 2-mm, 175-pulse, transepithelial photoablations that resulted in deep stromal keratectomies. Photokeratectomy was performed on the corneas of plasminogen-deficient (Plg-/-) mice and littermate control animals. Eyes were examined for re-epithelialization and clarity throughout the 21-day observational period. Histologic sections were taken during the observational period and fibrin(ogen) was detected immunohistochemically. RESULTS: Re-epithelialization was rapid and complete within 3 days in both control and Plg-/- animals. Exuberant corneal fibrin(ogen) deposition was noted in Plg-/- mice and sparse fibrin(ogen) deposition in control mice on days 1 and 3 after injury. Fibrin(ogen) deposits resolved in control mice but persisted in Plg-/- mice (74% of eyes at 21 days; P < 0.004). Corneal opacification, scarring, and the presence of anterior chamber fibrin(ogen) occurred in plasminogen-deficient mice but not in control mice. CONCLUSIONS: Fibrin(ogen) deposition occurs during corneal wound repair after photokeratectomy. Impaired fibrinolysis in Plg-/- mice caused persistent stromal fibrin deposits that correlated with the development of corneal opacity. (+info)
Relationship between structure and biochemical phenotype of lecithin:cholesterol acyltransferase (LCAT) mutants causing fish-eye disease.
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In order to test the hypothesis that fish-eye disease (FED) is due to a deficient activation of lecithin:cholesterol acyltransferase (LCAT) by its co-factor apolipoprotein (apo) A-I, we overexpressed the natural mutants T123I, N131D, N391S, and other engineered mutants in Cos-1 cells. Esterase activity was measured on a monomeric phospholipid enelogue, phospholipase A(2) activity was measured on reconstituted high density lipoprotein (HDL), and acyltransferase activity was measured both on rHDL and on low density lipoprotein (LDL). The natural FED mutants have decreased phospholipase A(2) activity on rHDL, which accounts for the decreased acyltransferase activity previously reported. All mutants engineered at positions 131 and 391 had decreased esterase activity on a monomeric substrate and decreased acyltransferase activity on LDL. In contrast, mutations at position 123 preserved these activities and specifically decreased phospholipase A(2) and acyltransferase activites on rHDL. Mutations of hydrophilic residues in amphipathic helices alpha 3;-4 and alpha His to an alanine did not affect the mutants' activity on rHDL. Based upon the 3D model built for human LCAT, we designed a new mutant F382A, which had a biochemical phenotype similar to the natural T123I FED mutant. These data suggest that residues T123 and F382, located N-terminal of helices alpha 3-4 and alpha His, contribute specifically to the interaction of LCAT with HDL and possibly with its co-factor apoA-I. Residues N131 and N391 seem critical for the optimal orientation of the two amphipathic helices necessary for the recognition of a lipoprotein substrate by the enzyme. (+info)
Ocular changes in beagle dogs following oral administration of CGS 24565, a potential hypolipidemic agent.
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(11R)-N,15-dideoxo-1-deoxy-1,15-epoxy-11-hydroxy-4-0methy l-8-0-(2, 2-dimethyl-1-oxopropyl)-3-[4- inverted question mark(2,4, 6-trimethylphenyl)methyl inverted question mark-1-piperazinyl]rifamycin has been evaluated as a potential hypolipidemic agent. As part of a safety evaluation program, a 3-month oral toxicity study was performed in which CGS 24565 was administered to beagle dogs via gelatin capsules at 10, 50, or 300 mg/kg/day. Ophthalmoscopic examinations (using focal illumination and indirect opthalmoscopy) on day 83 (week 12) revealed bilateral adnexal and corneal changes affecting 5 dogs (3 males, 2 females, 300 mg/kg/day). Ophthalmoscopically, dogs from the 300 mg/kg dose level exhibited the adnexal changes characterized as ptosis, conjunctivitis, episcleritis, and relaxed membrane nictitans, while the corneal changes were characterized as posterior stromal edema (cloudy, diffuse opacity usually accompanied by deep neovascularization; the diffuse edema masked the complete evaluation of other ocular structures) and stromal infiltrates in the area of Decement's membrane (appeared to be multifocal, polymorphic changes/alterations in Decement's membrane, or endothelial swelling). No changes from normal were seen clinically in the eyes of other dogs on this experiment. In those dogs affected by the ocular changes caused by CGS 24565, a visual deficit in acuity was suspected. The corneal changes, as manifested, were suggestive of permanent, irreversible corneal damage. Subsequent ophthalmoscopic examinations performed at established intervals during weeks 15 through 26, revealed abatement of the adnexal changes, while the corneal changes, as described above, remained generally unchanged, confirming irreversibility of the corneal changes within the recovery period of 13 weeks. Light microscopy confirmed irreversible corneal neovascularization, vacuolar degeneration of the keratocytes at 300 mg/kg, and polymorphic infiltrates in the region of Decement's membrane. The results demonstrate that the cornea was the target tissue of toxicity for CGS 24565, and indicated that the findings represent a significant toxic effect. The correlation of histopathological findings support the hypothesis of the diagnosis of interstitial stromal degeneration/atrophy. The potential for a similar result to the cornea of humans does exist. Due to these changes and other toxic effects associated with this class of compound, further development was terminated. (+info)
A simple method to evaluate the massive dose vitamin A prophylaxis program in preschool children.
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A massive dose vitamin A prophylaxis program is currently in operation in several States of India. Evaluation of this program on a large scale has so far been difficult due to lack of baseline data on the prevalence of vitamin A deficiency in children. In this study, a simple evaluation method which makes use of the linear relationship that exists between age on one hand and prevalence of ocular signs of vitamin A deficiency (Bitot's spots) on the other is described. Regression coefficients between age and prevalence of vitamin A deficiency of areas not covered by the program (control areas) were found to be significantly different both from zero and from regression coefficients of regularly covered areas (experimental areas). Also, all regression lines of control areas were found to be above the regression zone of experimental areas. These differences between the experimental and control areas which were significant, indicate the impact of the program in areas where the program is in operation. The regression coefficient calculated for one area where the program was discontinued after some time was found to be significantly different from zero, also it was different from the regression zone of the experimental areas. However, the regression coefficient of the discontinued area was found to be significantly different from the experimental areas only at 10% level, indicating a lesser degree of efficiency of the program in this area as compared to regularly fed areas. It is, therefore, suggested that evaluation of the massive dose prophylaxis program be done against the null hypothesis beta = 0.0065--the regression coefficient achievable under field conditions. (+info)
Excimer laser phototherapeutic keratectomy: indications, results and its role in the Indian scenario.
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PURPOSE: To report indications, technique, and results of excimer phototherapeutic keratectomy (PTK), and describe possible reasons for the small numbers of such procedures performed in a referral institute in India. METHODS: Retrospective review of case records of 10 patients (11 eyes) who underwent excimer PTK at our institute between February 1994 and September 1997. RESULTS: Corneal scars were the most common indication for treatment. Best-corrected visual acuity (BCVA) improved in 6 eyes (mean: 2 lines of Snellen acuity). All eyes had BCVA > or = 6/12 after treatment. None of the patients experienced loss of BCVA after treatment. Unaided visual acuity improved in 3 eyes and decreased in 2 eyes. Change in spherical equivalent refraction > or = 1 diopter occurred in 77.8% of eyes after treatment. Treating central corneal scars resulted in a significant hyperopic shift in refraction. CONCLUSIONS: Excimer PTK is a safe and effective procedure for the treatment of superficial corneal opacities. Post-treatment ametropia may require further correction with optical aids. Inappropriate referrals, deep corneal scars, and cost of the procedure could have contributed to the small numbers of PTK performed at our institute. Improved understanding of procedural strengths and limitations could lead to increased use of this procedure, with satisfying results in selected patients. (+info)