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Biomedical subjects

R G Weleber

Publications and source records attributed to R G Weleber.

At least 55 records · Page 3Linked to original sources
PubMed1997

Discrete expression and distribution pattern of TIMP-3 in the human retina and choroid.

PURPOSE: Extracellular matrix homeostasis is dependent in part upon a family of matrix metalloproteinases and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recently, gene defects in TIMP-3 have been identified in the affected individuals of several families with Sorsby's fundus dystrophy (SFD). Very little information is available regarding TIMP-3 function or even its existence in the retina or choroid. METHODS: We used reverse transcription-polymerase chain reaction and Northern analysis to evaluate the expression of TIMP mRNA and Western immunoblots to evaluate TIMP protein produced by select cells of the human retina and choroid. We also used these methods and immunohistochemistry to localize the TIMPs in the retina and choroid. RESULTS: TIMP-3 transcripts are found in cultured human retinal pigment epithelium (RPE), choroidal microcapillary endothelium and pericytes. RPE cells also express and secrete TIMP-3 protein, which is localized to the extracellular matrix and is not found in culture medium; TIMP-1 and -2 are found almost exclusively in the medium. Immunohistochemistry of human retina/choroid sections shows pronounced TIMP-3 immunostaining in Bruch's membrane, particularly near the surface of the RPE and endothelial cells, presumably in their basement membranes, with minimal staining in other portions of the retina. Immunostaining for TIMP-1 is absent and for TIMP-2 is much less prevalent, but detectable in Bruch's membrane. CONCLUSIONS: TIMP-1, -2 and -3 exhibit distinctive expression patterns in the retina and choroid. This distribution and expression pattern partially explains why TIMP-3 mutations result in SFD, rather than other retinal pathologies, such as those associated with proliferative diabetic retinopathy.

Cells, Cultured↗
PubMed1997

Gyrate atrophy-like phenotype with normal plasma ornithine.

PURPOSE: To describe the clinical characteristics of a chorioretinal disease with a gyrate atrophy-like phenotype and normal plasma ornithine. METHODS: One family with three men who had progressive chorioretinal disease and three additional patients with simplex cases were examined clinically and with standard electroretinography, electrooculography, and dark adaptometry. RESULTS: In the family, a 70-year-old man and his two sons (39 and 41 years of age) were affected. On ophthalmoscopy, sharply demarcated peripheral patches of retinal pigment epithelium and choroidal atrophy were seen to progress to the posterior pole in the father's eye. In three unrelated men (62, 70, and 80 years of age), chorioretinal atrophy was present in the mid- and far periphery. Visual acuity was normal in the two youngest of all six patients; however, electroretinogram and electrooculogram waves were reduced. Advanced visual field defects and visual acuity loss occurred in the four older patients. Electroretinogram and electrooculogram were reduced, and the dark adaptation thresholds were elevated. In all patients, serum ornithine levels were normal. Ornithine-delta-aminotransferase activity in cultured skin fibroblasts and the apparent Michaelis constant (Km) for ornithine and alpha-ketoglutarate were within the normal range in all patients. CONCLUSIONS: A gyrate atrophy-like phenotype can result from causes other than deficient ornithine-delta-aminotransferase. Its occurrence in three male members in two generations in one family suggests an autosomal dominant inheritance in at least some such patients.

Adult↗
PubMed1997

Sperm abnormalities in retinitis pigmentosa.

PURPOSE: To determine the fatty acid composition of erythrocytes and sperm, along with the functional characteristics of sperm, in patients with retinitis pigmentosa. Sperm and retinal cells share important homologies. Both are rich in the highly polyunsaturated fatty acid, docosahexaenoic acid (DHA, 22:6[n-3]), and both contain a structural component called the axoneme. Low concentrations of DHA in the retina of monkeys are known to cause visual impairment. Because blood levels of DHA in retinitis pigmentosa patients are less than normal, reduced DHA in the retina might contribute to the visual impairment characteristic of this disease. This study was conducted on the hypothesis that the sperm of retinitis pigmentosa patients might be abnormal and that these abnormalities might infer similar lipid and structural abnormalities of the retina. METHODS: The lipid composition of erythrocytes and sperm (fatty acids and sterols) and sperm function were analyzed in 26 patients with retinitis pigmentosa and in 8 healthy men. RESULTS: The sperm of patients with retinitis pigmentosa had a much lower DHA concentration, a lower desmosterol-to-cholesterol ratio, reduced motility, abnormal structure, and lower sperm counts compared with that in normal subjects. Usher's II patients exhibited the most pronounced reductions of DHA in sperm. Sperm DHA concentration was positively correlated to sperm motility, to sperm count, and to the desmosterol-to-cholesterol ratio. Lower erythrocyte DHA was also observed in retinitis pigmentosa patients. CONCLUSIONS: These results indicate that the sperm of patients with retinitis pigmentosa, particularly those with Usher's II, have an abnormal lipid composition that is associated with reduced motility. The possibility exists that these patients might have similar abnormalities in the DHA biochemistry of the retina. Sperm biochemistry and function may be a marker for this disease. A clinical trial of DHA in retinitis pigmentosa is suggested for future study.

Biomarkers↗
PubMed1996

Sorsby fundus dystrophy. A family with the Ser181Cys mutation of the tissue inhibitor of metalloproteinases 3.

Sorbsy fundus dystrophy (SFD) is an autosomal dominant disorder that is characterized by bilateral loss of central vision secondary to choroidal neovascularization and/or pigment epithelial atrophy in the macula, with onset of visual symptoms usually in the fourth or fifth decade. Drusenlike changes may occur, with impaired dark adaptation and abnormal electroretinographic results.

Adult↗
PubMed1995

Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism.

Autosomal recessive ocular albinism (AROA) is a disorder characterized by reduced pigmentation of the retina and iris, hypoplastic fovea, variably reduced visual acuity and nystagmus. Pigmentation of the skin and hair is normal, but is usually slightly lighter than in unaffected sibs. We analysed 12 unrelated patients with AROA, and found that two had abnormalities of the tyrosinase (TYR) gene. These two patients were each a compound heterozygote for a different pathologic mutant allele and an allele containing a 'normal' polymorphism, Arg402Gln, which results in a tyrosinase polypeptide with reduced thermal stability. In these patients, AROA thus appears to represent a clinically mild form of OCA1, with a fixed visual deficit resulting from low tyrosinase activity during fetal development but with normal pigmentation of the skin and hair postnatally.

Albinism, Ocular↗
PubMed1995

mdxCv3 mouse is a model for electroretinography of Duchenne/Becker muscular dystrophy.

PURPOSE: To identify an animal model for the abnormal scotopic electroretinogram found in a majority of Duchenne and Becker muscular dystrophy patients. METHODS: Ganzfeld electroretinograms were recorded in dark-adapted normal C57BL/6 mice, and two strains of mice with different X-linked muscular dystrophy mutations (mdx and mdxCv3). Responses for the right eye were averaged and the amplitudes and implicit times of the a-wave and b-wave were measured. The electroretinogram was digitally filtered to extract the oscillatory potentials. Statistical analyses included one-way analysis of variance and the Scheffé S test. RESULTS: While the electroretinogram in mdx was normal, in mdxCv3 the scotopic b-wave was markedly reduced and the oscillatory potentials were delayed, similar to changes observed in Duchenne and Becker muscular dystrophy patients. Some of the mdxCv3 animals demonstrated negative configuration electroretinograms, with the b-wave amplitude reduced compared to that of the a-wave. CONCLUSIONS: Abnormalities found in the electroretinograms of Duchenne and Becker muscular dystrophy patients led to the identification of dystrophin in human retina and the discovery that dystrophin is required for normal retinal electrophysiology. These results indicate that mdxCv3 is a model for elucidating the role of dystrophin in retina and suggest that dystrophin isoforms, consisting of only the C-terminal domains of the full-length protein, may be important to the development of normal retinal electrical potentials.

Animals↗
PubMed1994

Characterization of the ocular phenotype of Duchenne and Becker muscular dystrophy.

PURPOSE: Dystrophin, the Duchenne muscular dystrophy gene product, has been localized to the outer plexiform layer of normal human retina. The purpose of this study is to define completely the ocular phenotype associated with mutations at Xp21, the Duchenne muscular dystrophy gene locus. METHODS: Twenty-one patients with a diagnosis of Duchenne muscular dystrophy and five patients with Becker muscular dystrophy had ophthalmologic examinations, including electroretinograms (ERGs). Electroretinogram results were correlated with respect to patient DNA analysis. RESULTS: Twenty-three (88%) patients had reduced scotopic b-wave amplitudes to bright-white flash stimulus, including nine with negative-shaped ERGs. Rod-isolated responses were reduced or not recordable above noise in 14 (67%) patients. Most isolated cone responses (92%) were normal. Flicker amplitudes were reduced in seven patients. Two of these patients with proximal (5' end) deletions had normal scotopic b-waves to dim blue and bright-white flash stimulus. Patients with deletions toward the middle of the gene had greater reductions in their scotopic b-wave amplitudes than patients with deletions located toward the 5' end. Most patients had normal color vision, extraocular muscle function, and Snellen visual acuity. Increased macular pigmentation was seen in 16 patients with Duchenne muscular dystrophy. CONCLUSION: Most patients with Duchenne or Becker muscular dystrophy have evidence of abnormal scotopic ERGs. Patients with deletions in the central region of the gene had the most severe ERG changes. This study supports previous suggestions that dystrophin may play a role in retinal neurotransmission. The presence of increased macular pigmentation and normal photopic ERGs distinguishes patients with Duchenne muscular dystrophy mutations from other X-linked retinal disorders with negative-shaped ERGs.

Adolescent↗
PubMed1994

Effect of methazolamide on chronic macular edema in patients with retinitis pigmentosa.

PURPOSE: To determine the effectiveness of methazolamide for improving visual acuity and macular edema in patients with retinitis pigmentosa. METHODS: Seventeen subjects with retinitis pigmentosa and chronic macular edema participated in a prospective, placebo-controlled, double-masked, crossover design study in which either methazolamide or a placebo was taken for 3 weeks. Visual acuity, fluorescein angiograms, and subjective impressions were obtained at baseline and after 3 weeks of treatment with each substance. A subgroup of subjects were enrolled in a more extended period of methazolamide treatment for an additional 3 months. RESULTS: Methazolamide resulted in the improvement of angiographic macular edema in 9 of 17 subjects. As a group, visual acuity statistically improved with methazolamide. However, improvement in at least one eye, of between two and four lines more than while taking placebo, occurred in only three (undilated pupils) or four (dilated pupils) subjects. Subjective improvement during treatment with methazolamide but not placebo occurred in only one subject. An extended period of methazolamide treatment for an additional 3 months in a subgroup of patients did not result in additional beneficial effects on visual acuity. In fact, a partial rebound in the extent of macular edema was found. CONCLUSIONS: Although angiographic improvement of macular edema can occur in patients with retinitis pigmentosa treated with methazolamide, notable (between 3 and 4 lines) or even moderate (between 2 and 3 lines) visual acuity improvement was seen in relatively few patients. When methazolamide was administered in a placebo-controlled fashion, subjective improvement in visual function also was not readily apparent. A more substantial subjective improvement in visual function had occurred with the use of acetazolamide in five of six subjects who also had participated in a previous treatment trial with the use of acetazolamide.

Adolescent↗
PubMed1994

Phenotypic variability in X-linked ocular albinism: relationship to linkage genotypes.

One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. We suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes.

Albinism, Ocular↗
PubMed1993

Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene.

BACKGROUND AND OBJECTIVES: Mutations of the peripherin/RDS gene have been reported in autosomal dominant retinitis pigmentosa, pattern macular dystrophy, and retinitis punctata albescens. We report herein the occurrence of three separate phenotypes within a single family with a novel 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene. DESIGN: Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics. SETTING: University medical centers. PATIENTS: A 75-year-old woman, her two daughters (aged 44 and 50 years), and her 49-year-old son were screened for peripherin/RDS mutations because of the presence of multiple phenotypes within the same family. RESULTS: The mother presented at age 63 years with a profoundly abnormal electroretinogram (ERG) and adult-onset retinitis pigmentosa that progressed dramatically over 12 years, with marked loss of peripheral visual field. One daughter developed pattern macular dystrophy at age 31 years. At age 44 years, her ERG was moderately abnormal but her clinical disease was limited to the macula. Another daughter presented at age 42 years with macular degeneration and over 10 years developed the clinical picture of fundus flavimaculatus. Her peripheral visual field was preserved but her ERG was moderately abnormal. The son had onset of macular degeneration at age 44 years. Pericentral scotomas were present and the ERG was markedly abnormal. Fluorescein angiography revealed punctate pigment epithelial transmission defects. CONCLUSIONS: A 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene can produce clinically disparate phenotypes even within the same family.

Adult↗
PubMed1993

Negative-configuration electroretinogram in Oregon eye disease. Consistent phenotype in Xp21 deletion syndrome.

OBJECTIVE: To determine whether abnormal configurations on electroretinogram were a consistent finding in patients with Xp21 deletion and to characterize the associated ophthalmologic phenotype. DESIGN: Case series. SETTING: University hospitals and eye institutes. PATIENTS: Five patients with complex glycerol kinase deficiency (Duchenne-type or Becker's muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia) and demonstrated chromosomal deletions at Xp21. Control patients were matched by age. MAIN OUTCOME MEASURES: Clinical information was obtained from medical records. Complete ophthalmologic examinations were performed. Electroretinography was performed using a Ganzfeld technique and chloral hydrate sedation. RESULTS: We report the clinical features and abnormal configurations on electroretinograms of five patients with complex glycerol kinase deficiency, including follow-up studies on a previously described patient. The original patient had ocular hypopigmentation; four, strabismus; two, myopia; three, astigmatism; and one, symptomatic night blindness. All had negative configurations on scotopic electroretinograms showing a reduced-amplitude B wave in the dark-adapted state. CONCLUSIONS: Our original report suggested a diagnosis of Aland Island eye disease, which appears to be an incomplete form of congenital stationary night blindness. Linkage data place Aland Island eye disease and congenital stationary night blindness at Xp11, whereas our patients had deletions at Xp21. The phenotype reported here may represent the effects of a single gene defect or the compound effects of the Xp21 contiguous gene syndrome (complex glycerol kinase deficiency). The phenotype is referred to as Oregon eye disease.

Adolescent↗
PubMed1993

Dystrophin expression in the human retina is required for normal function as defined by electroretinography.

We have studied retinal function by electroretinography in five Becker and six Duchenne muscular dystrophy patients. All had abnormal electroretinograms with a markedly reduced amplitude for the b-wave in the dark-adapted state. Using three antisera raised to different domains of dystrophin, we identified dystrophin in the outer plexiform layer of human retina. The retinal dystrophin is present in multiple isoforms as the result of alternative splicing. The localization of dystrophin to the outer plexiform layer coincident with the abnormal b-wave suggests that dystrophin is required for normal retinal electrophysiology.

Adolescent↗