Localization of the gene for autosomal recessive congenital hereditary endothelial dystrophy (CHED2) to chromosome 20 by homozygosity mapping.

Congenital hereditary endothelial dystrophy (CHED) is a corneal disorder that presents with diffuse bilateral corneal clouding. Vision may be severely impaired, and many patients require corneal transplantation. Both autosomal dominant (AD) and autosomal recessive (AR) forms of the disorder have been described. The gene responsible for AD CHED (HGMW-approved symbol CHED1) has been mapped to the pericentromeric region of chromosome 20. Investigating a large, consanguineous Irish pedigree with autosomal recessive CHED, we have previously excluded linkage to this AD CHED locus. We now describe a genome-wide search using homozygosity mapping and DNA pooling. Evidence of linkage to chromosome 20p was demonstrated with a maximum lod score of 9.30 at a recombination fraction of 0.0 using microsatellite marker D20S482. A region of homozygosity in all affected individuals was identified, narrowing the disease gene locus to an 8-cM region flanked by markers D20S113 and D20S882. This AR CHED (HGMW-approved symbol CHED2) disease gene locus is physically and genetically distinct from the AD CHED locus.

Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct.

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region. METHODS: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method. RESULTS: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci. CONCLUSION: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.

Aqueous humor flow in sleeping humans is unaffected by norepinephrine infusion.

PURPOSE: Intravenous administration of the catecholamine epinephrine is known to have a stimulatory effect on aqueous humor flow in sleeping human subjects, an effect that is augmented by plasma corticosteroids. This study was performed to determine whether the closely related catecholamine norepinephrine has a similar effect on aqueous humor flow. METHODS: Twenty normal subjects were studied. Aqueous flow was measured by fluorophotometry. At night during sleep, norepinephrine or placebo was infused intravenously (i.v.) between midnight and 6 AM. The rate of aqueous flow during the norepinephrine infusion was compared with the rate of flow during placebo infusion, with each subject serving as his/her own control. The urinary excretions of epinephrine and norepinephrine were measured at the end of each infusion period. RESULTS: The norepinephrine infusion caused an 8% increase in systolic blood pressure (P < 0.001), a 15% increase in diastolic blood pressure (P < 0.001), and a 9% decrease in heart rate (P=0.003) compared with the placebo. The rate of aqueous humor flow during sleep from 12 AM to 6 AM was unchanged by norepinephrine. The rate was 1.27+/-0.31 microl/min (mean+/-SD) during i.v. infusion of placebo and 1.30+/-0.27 microl/min during infusion of norepinephrine (P=0.63). CONCLUSIONS: An infusion of norepinephrine during sleep that causes measurable changes in cardiovascular parameters has no measurable effects on the rate of aqueous humor flow. The lack of a measurable effect of a norepinephrine infusion contrasts to the stimulatory effect of an epinephrine infusion.

Long-term outcome of patients who undergo tonometry as part of a general physical examination.

OBJECTIVE: To determine the value of including tonometry as part of a general physical examination. MATERIAL AND METHODS: Between Feb. 14, 1977, and Dec. 31, 1980, 849 residents of Rochester, Minnesota, underwent measurement of intraocular pressure by trained ophthalmic technicians at the request of a nonophthalmologist physician as part of a general physical examination. In 1995 and 1996, these cases were reviewed to determine how many patients in this study cohort had subsequently been diagnosed as having glaucoma. The outcome was derived from the examination of medical records and from the responses to mailed questionnaires and telephone interviews with study patients and their physicians. RESULTS: In patients whose intraocular pressures were less than 16 mmHg at baseline, the risk of being diagnosed as having glaucoma within 10 years was 1% (95% confidence interval [CI], 0 to 2%) and within 15 years was 2% (95% CI, 0 to 4%). In patients whose pressure in the higher-pressure eye was 16 to 21 mmHg at baseline, the risk of having glaucoma in 10 years was 3% (95% CI, 2 to 5%) and in 15 years was 5% (95% CI, 3 to 7%). Twenty-four patients were found at baseline to have an intraocular pressure of 22 mmHg or higher in at least one eye or a difference of 5 mmHg or more between the two eyes. In this group, the risk of having glaucoma in 10 years was 17% (95% CI, 0 to 31%) and in 15 years was 26% (95% CI, 6 to 43%). CONCLUSION: When included as part of a general physical examination of older persons, tonometry and a few simple questions provide information that can be used to help the clinician determine the advisability of more detailed ophthalmic examinations.

Response of the pupil to tropicamide is not a reliable test for Alzheimer disease.

OBJECTIVE: To confirm the putative hypersensitivity of the pupil to a weak mydriatic in persons with Alzheimer dementia. DESIGN: Twenty patients with Alzheimer dementia and 20 control subjects were examined. Automated binocular infrared pupillography was performed in the dark after instillation of 0.01% tropicamide or placebo. Ocular penetration of eye drops was assessed simultaneously using 2% fluorescein sodium as a tracer. SETTING: Rochester, Minn. SUBJECTS: Twenty patients and 20 cognitively normal control subjects from the Alzheimer's Disease Patient Registry of the Mayo Clinic, Rochester, Minn. MAIN OUTCOME MEASURE: Percent change in the diameter of the pupil following topical ocular instillation of a diluted concentration of the mydriatic drug tropicamide and penetration of topically applied fluorescein into the aqueous humor. RESULTS: No statistically significant difference was found between patients with Alzheimer disease and control subjects in either the mydriatic response of the pupil or in the rate of penetration of topically applied fluorescein. CONCLUSION: No evidence of pupillary hypersensitivity to an anticholinergic mydriatic drug was found in patients with Alzheimer disease or any evidence that this putative hypersensitivity could be used as an early, simple diagnostic test for Alzheimer disease.

Combined corticosteroid and catecholamine stimulation of aqueous humor flow.

PURPOSE: Epinephrine is known to stimulate aqueous humor flow in humans. Corticosteroids are known to augment the effect of beta-adrenergic agonists on the ciliary body. This experiment was carried out to determine whether a corticosteroid can increase the stimulatory effect of epinephrine on aqueous humor flow. METHODS: Twenty human volunteers were studied for 24 hours. Hydrocortisone was given orally and epinephrine was given intravenously during sleep while aqueous flow was monitored. Flow was compared with a second 24-hour study when oral and intravenous placebos were given. The sequence of administration was randomized. Subjects and investigators were masked. The flows also were compared with a previously published study in which the same dose of epinephrine was administered without steroid. RESULTS: Epinephrine plus hydrocortisone compared with placebos increased aqueous flow 42% in subjects during sleep. The combination of epinephrine and hydrocortisone was a more potent stimulus to aqueous flow than epinephrine alone, which increased aqueous flow by only 27% (P = 0.045). CONCLUSION: The two major hormones of the adrenal gland work in concert to increase the rate of aqueous humor flow in humans.

Association of HLA type with pseudoexfoliation of the lens capsule.

AIMS/BACKGROUND: To identify an HLA association with pseudoexfoliation of the lens capsule to support the hypothesis that there is a genetic predisposition to pseudoexfoliation. A randomised trial would be ideal for establishing a relation but is more costly and time consuming to conduct. Case-control studies provide an alternative method of establishing a relation. METHODS: The study group comprised 128 subjects who presented to a major eye centre with pseudoexfoliation. Data from blood donors representative of the population of Ireland were used to form a control group. RESULTS: An HLA association with pseudoexfoliation is identified for 14 antigens. Eleven antigens (HLA A1, A33, B8, B47, B51, B53, B57, B62, DR3, DR12, and DR13) are significantly more common in the pseudoexfoliation group while three antigens (HLA B12, B17, and DR2) are significantly less common. Four HLA antigens are strongly associated, with odds ratios of over 7.5. CONCLUSION: The strength of this HLA association is supportive evidence for a genetic component to the development of pseudoexfoliation of the lens capsule.

Continuous measurement of intraocular pressure in rabbits by telemetry.

PURPOSE: Intraocular pressure (IOP) is dynamic and can be influenced by the use of tonometers. The authors developed a technique to implant a telemetric pressure transducer to measure IOP continuously in unrestrained rabbits. METHODS: A commercial telemetric pressure transducer was implanted subcutaneously on the dorsal neck, between the scapulae, of pigmented rabbits. A fluid-filled catheter that conducts pressure to the transducer was routed to the orbit subcutaneously and implanted in the anterior chamber through a limbal opening. The transducer measured pressure and broadcast this information by amplitude modulation radio to a receiver in the animal's cage. Data were recorded at a rate of 50 or 100 samples per second for 60 seconds to study transient changes in IOP to tonometry, or for 15 seconds every 2.5 minutes to study circadian behavior of IOP. RESULTS: Intraocular pressure was recorded from seven rabbits for 180 to 370 days. Within 3 to 8 days of implant surgery, IOP began to follow a circadian rhythm: IOP decreased after room lights were turned on at 00:00 CT and increased after they were turned off at 12:00 CT. (The term CT refers to circadian time and begins at 00:00 CT when lights are turned on.) The maximum difference in IOP between light and dark phases ranged from 6.4 mm Hg to 16.6 mm Hg. When the lighting cycle was advanced by 6 hours, the time of nocturnal rise in IOP also advanced, but it did so gradually over 10 to 14 days. CONCLUSIONS: The implanted pressure transducer provides a convenient, preinvasive method to measure and study IOP in unrestrained experimental animals. This technique will be used to study circadian variations in IOP, the effects of environmental stimuli, and the oculohypotensive effects of therapeutic agents.