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Biomedical subjects

R G Weleber

Publications and source records attributed to R G Weleber.

At least 91 records · Page 5Linked to original sources
PubMed1989

Gyrate atrophy of the choroid and retina: characterization of mutant ornithine aminotransferase and mechanism of response to vitamin B6.

The purpose of this study was to characterize the mutant enzyme in nine patients with gyrate atrophy of the choroid and retina associated with ornithine aminotransferase (OAT) deficiency, to elucidate the mechanism of response to pyridoxine in four pyridoxine-responsive patients, and to determine the extent of genetic heterogeneity in both groups of patients. We have measured the apparent Km for pyridoxal phosphate (PLP) in fibroblast mitochondria and the heat stability of OAT at 45 degrees C in the presence and absence of PLP, using a sensitive radiochemical assay. The apparent Km for PLP was higher in pyridoxine-responsive patients than in nonresponsive patients whose apparent Km for PLP was normal. In contrast, the apparent Km for ornithine was normal in the seven patients studied. Surprisingly, the responsive patient with mildest clinical disease had the highest Km for PLP. However, she had the most stable enzyme, which presumably contributed to her milder phenotype. Western blot analyses of mitochondrial proteins, using antibody to human OAT, indicated clearly detectable OAT protein in pyridoxine-responsive patients and in two of five nonresponders, but low or undetectable levels in the other three patients. These data clarify the mechanism of pyridoxine response and indicate heterogeneity within as well as between the pyridoxine-responsive and the nonresponsive patients with gyrate atrophy.

Atrophy↗
PubMed1989

Inheritance of ornithine aminotransferase gene, mRNA, and enzyme defect in a family with gyrate atrophy of the choroid and retina.

We studied the human ornithine aminotransferase (OAT) gene, mRNA, and enzyme activity in fibroblasts from a family with gyrate atrophy (G.A.) of the choroid and retina, using a normal human OAT cDNA as a probe. The family consists of an affected patient, who is heterozygous for a partial deletion of the functional OAT gene and whose cells produce no mRNA, and of his father, mother, two sons, and a daughter. Southern blot analysis of the OAT gene showed the partial deletion in the patient and in his father and daughter and in one son. Northern blot analysis revealed no OAT mRNA in the patient and approximately 50% of the normal level of OAT mRNA in the father, mother, two sons, and daughter. Assay showed that the OAT activity in these individuals mirrored the OAT mRNA levels. The results indicate that an active allele of the OAT gene expresses 50% of the total normal OAT mRNA and activity and that both alleles of the gene are inactive in the patient in this pedigree, a situation resulting in a complete absence of the OAT mRNA, in accordance with the autosomal recessive mechanism of this disease; they also indicate a 50% decrease of OAT mRNA and enzyme activity in obligate heterozygous carriers carrying one defective allele and that these defects are stably inherited.

Alleles↗
PubMed1988

Normal alpha-L-fucosidase and other lysosomal enzyme activities in progressive cone dystrophy.

We conducted a cross-sectional study of 24 patients with cone dystrophy to investigate a possible link between this disease and deficient activity of alpha-L-fucosidase. We studied patients with several forms of cone dystrophy, including six with similar clinical characteristics to two patients previously reported to be alpha-L-fucosidase deficient. Activities for alpha-L-fucosidase and several other lysosomal enzymes (beta-D-glucuronidase, beta-D-hexosaminidase (A + B), and alpha-D-mannosidase) were determined in serum and leukocytes. None of our patients with cone dystrophy were deficient in alpha-L-fucosidase or any other lysosomal enzyme investigated. No relationship was found between alpha-L-fucosidase deficiency and any type of cone dystrophy studied.

Adolescent↗
PubMed1988

Dose-response relationship between light irradiance and the suppression of plasma melatonin in human volunteers.

This study tested the capacity of different irradiances of monochromatic light to reduce plasma melatonin in normal humans. Six healthy male volunteers, 24-34 years old, were exposed to 0.01, 0.3, 1.6, 5, or 13 microW/cm2 of 509 nm monochromatic light for 1 h during the night on separate occasions. Light irradiance depressed plasma melatonin in a dose-response pattern. The data indicate that the mean threshold irradiance for suppressing melatonin is between 1.6 and 5 microW/cm2. Individual variations in threshold responses to monochromatic light were observed among the volunteers.

Adult↗
PubMed1988

Ruvalcaba-Myhre-Smith syndrome.

In 1980 a syndrome was first described in two adult males, consisting of macrocephaly, pigmented macules on the glans and shaft of the penis, and hamartomatous intestinal polyps. Since then, 10 additional cases have been identified. Herein, we present two new cases and review the cutaneous manifestations as well as additional features in patients with the Ruvalcaba-Myhre-Smith syndrome.

Child, Preschool↗
PubMed1988

Expression defect of ornithine aminotransferase gene in gyrate atrophy.

A generalized deficiency in the mitochondrial enzyme, ornithine aminotransferase (OAT: EC 2.6.1.13), is the hallmark of gyrate atrophy (GA), a hereditary degenerative disease of the choroid and retina of the eye that leads to blindness. A human OAT cDNA, previously constructed and characterized in our laboratory, and anti-human OAT antibody were used as probes to examine the OAT gene, mRNA and protein of GA patients. A blot analysis of the genomic DNAs, RNAs and proteins of 14 GA patients identified a case with a partial heterozygous deletion of the functional OAT gene located on chromosome 10, no detectable OAT mRNA, and a barely detectable level of OAT antibody-reactive protein. The rest of the cases showed grossly normal OAT gene, mRNA, and variably reduced levels of OAT protein. A restriction fragment length polymorphism (RFLP) was identified in the functional OAT gene sequence with EcoRI which may be useful for prenatal diagnosis of GA. RFLPs were also identified in the OAT-related gene sequences located on the X chromosome with Hind III and Pst I which may potentially show linkage to X-linked retinitis pigmentosa locus. The finding of an OAT gene, mRNA, and protein defect in a GA case constitutes the first real demonstration of the molecular genetic defect of OAT in GA.

Choroid↗
PubMed1987

Congenital stationary night blindness presenting as Leber's congenital amaurosis.

Two siblings with autosomal-recessive congenital stationary night blindness were clinically blind in infancy. Both had markedly abnormal electroretinograms that, in the first child, led consultants at two university centers to make the diagnosis of Leber's congenital amaurosis. The patients had intermittent nystagmus and esotropia, but good photopic vision developed eventually. Scotopic vision was clearly defective in each child. Refractive error in both patients was close to emetropic in early infancy but became myopic by 1 year of age. Congenital stationary night blindness must be considered in the differential diagnosis of the blind infant.

Blindness↗
PubMed1987

Retinal dystrophy in Jeune's syndrome.

Jeune's syndrome is an autosomal-recessive condition characterized by multiple organ abnormalities, the most severe of which affect the skeleton, kidneys, and eyes. Severe respiratory insufficiency frequently results in death in infancy, but several patients have been reported to survive to adulthood. For this reason the prognosis for patients with ocular abnormalities is of interest in counseling families. We report a sibship of two patients who showed evidence for progression by visual field and electroretinogram testing when followed up over 3.7 years. Progressive electroretinographic abnormalities consisted of the following: progressive decrease in responses mediated by dark-adapted rods and both dark- and light-adapted cones in the first patient and progressive increase in b-wave implicit time elicited by 30-Hz flicker stimulation in the second patient.

Abnormalities, Multiple↗
PubMed1987

Non-Hodgkin's lymphoma causing fundus picture simulating fundus flavimaculatus.

Two apparently healthy patients experienced visual loss and had a peculiar flecked retina simulating fundus flavimaculatus in one eye some months before developing signs and symptoms of the systemic form of non-Hodgkin's large-cell lymphoma. Both experienced spontaneous improvement in visual symptoms and partial resolution of the fundus changes.

Aged↗
PubMed1986

Ophthalmologic and systemic manifestations of Alström's disease.

Alström's syndrome consists of pigmentary retinopathy, diabetes, obesity, normal mental capacity, and sensorineural deafness. The early retinal findings are optic atrophy, salt-and-pepper pigment epithelial abnormalities, and marked vascular attenuation. Later in the disease process, diffuse areas of chorioretinal atrophy and large clumps of pigment develop. Severe visual loss in the first decade is characteristic and is an important point in the differential diagnosis. Clinically evident renal disease is a variable age-related phenomenon, and is probably the most frequent cause of death.

Adult↗
PubMed1986

Computerized quantitative analysis of kinetic visual fields.

Kinetic perimetry is still a widely accepted and used means of assessing the visual field. Attempts at quantifying the area of vision for given isopters have been limited to area measurements on visual field charts, which are azimuthal equidistant polar map projections of the inside surface of the perimetry bowl. Such measurements distort the true size of scotomas (or seeing areas) when the boundaries measured are farther from the center of the field on the chart because of cartographic distortion inherent with this projection. We believe that the solid angle in steradians subtended by the scotoma or the seeing area is a more appropriate measure of the visual field than area on a flat representation. We used a simple computer program to determine the solid computer program to determine the solid angle for given isopters of graphed perimetric visual field data.

Computers↗
PubMed1986

Abnormal retinal function associated with isotretinoin therapy for acne.

Three of 50 patients treated with isotretinoin (1 mg/kg/day) for cystic acne complained of poor night vision and/or excessive glare sensitivity. While still receiving the drug or shortly thereafter, two patients were found to have abnormal dark-adaptation curves, with elevations of either cone or rod thresholds, or both. Two patients had abnormal electroretinograms (ERGs). One had a mildly abnormal electro-oculogram. The dark-adaptation curves were normal for one patient several months after isotretinoin therapy was discontinued. Two patients had elevated cone thresholds at least one year later. Six months following cessation of therapy, the ERG was still abnormal for one patient, but continued improvement was evident at 25 months; for the second patient, the ERG was normal at one year. Analysis of Naka-Rushton parameters for the ERG scotopic b-wave stimulus-response curves indicated response compression for two patients, as evidenced by a reduction in the maximum response. For one patient, the half-saturation constant was elevated 0.7 log units, suggesting reduction of retinal sensitivity, perhaps from decrease in retinal photopigment concentration. We suspect that isotretinoin may complete for normal retinol binding sites on cell surfaces or transport molecules. A prospective study is currently underway to determine if a clinically measurable adverse effect on retinal function is seen with greater frequency.

Acne Vulgaris↗
PubMed1986

X-linked recessive cone dystrophy with tapetal-like sheen. A newly recognized entity with Mizuo-Nakamura phenomenon.

We encountered a new X-linked recessive cone dystrophy in which patients have a greenish-golden tapetal-like sheen of the retina; while the retinal sheen and electroretinographic abnormalities are present from childhood, patients are not symptomatic until adult years. All of the male patients tested showed evidence of cone dysfunction on color vision testing, dark adaptometry, and electroretinography. After three hours of dark adaptation, the tapetal-like sheen disappeared, with most areas changing from greenish-golden shades to orange-red hues (Mizuo-Nakamura phenomenon). One male patient had a retinal detachment from atrophic round holes in the equatorial retina.

Adolescent↗
PubMed1986

Dysmorphic syndrome with phytanic acid oxidase deficiency, abnormal very long chain fatty acids, and pipecolic acidemia: studies in four children.

We describe a relatively new syndrome in four children with characteristic facial dysmorphism, sensorineural hearing loss, severe visual impairment with retinitis pigmentosa, hypotonia, hepatomegaly, and severe developmental delay. Two patients had intracranial hemorrhage secondary to a vitamin K-responsive clotting defect; both had steatorrhea. Liver biopsy specimens in two children showed an accentuated lobular architecture with prominent fibrous bands in the portal area. In one, the ultrastructure showed accumulation of abnormal substances and occasional trilaminar structures in hepatocytes and other cells. All four patients had elevated serum phytanic acid concentrations (0.3 to 2.7 mg/dl, normal less than 0.2 mg/dl) and deficient fibroblast phytanic acid oxidase activity (0.1 to 6.7 pmol/mg protein/hr, normal 23 to 87 pmol/mg protein/hr). Serum pipecolic acid was 7 to 55 times normal, and the ratio of C26/C22 very long chain fatty acids was increased (0.10 to 0.22; normal less than 0.03). This characteristic syndrome has been described in several children and called infantile Refsum disease or phytanic acid storage disease. Its relationship to neonatal adrenoleukodystrophy, hyperpipecolic acidemia, and Zellweger syndrome is discussed.

Child↗
PubMed1985

Tandem duplication of proximal 22q: a cause of cat-eye syndrome.

A boy with bilateral colobomas, preauricular pits, and developmental delay had a 46,XY,22q+ karyotype. His parents had normal chromosomes. The abnormality of 22q was interpreted as a de novo tandem duplication of 22q11.1----q11.2. Although no anal abnormality was identified, his manifestations are otherwise consistent with those of the cat-eye syndrome. Blood marker results and the levels of galactosidase-2, galactosidase-B and arylsulfatase-A, which are known to be coded on 22q, are normal.

Abnormalities, Multiple↗
PubMed1985

Heterogeneity and complementation analysis of fibroblasts from vitamin B6 responsive and non-responsive patients with gyrate atrophy of the choroid and retina.

Fibroblasts from four pyridoxine responsive and three non-responsive patients with gyrate atrophy of the choroid and retina have been examined. Responsive patients had higher activity of ornithine ketoacid transaminase (OKT) in cell homogenates and greater incorporation of radioactivity from 14C-ornithine into protein in cultured cells in situ compared to non-responsive patients. Complementation analysis of the cells from these seven patients was performed, based on the ratio of incorporation of 14C/3H into protein in fused cells incubated in 14C-ornithine and 3H-leucine. Lack of positive complementation in these crosses suggests that pyridoxine responsive and non-responsive patients with gyrate atrophy represent different allelic mutations of the same genetic locus coding for OKT.

Atrophy↗
PubMed1984

Ophthalmic manifestations of infantile phytanic acid storage disease.

Two patients had infantile phytanic acid storage disease. Patient 1 had nystagmus from early infancy, epicanthal folds, esotropia, and a pigmentary retinopathy. The second case had similar manifestations; however, no nystagmus was present. Both patients were hypotonic as infants, had a severe hearing impairment, and were moderately severely developmentally delayed. Serum phytanic acid levels in both cases were clearly elevated. The fundus and fluorescein angiogram showed macular and diffuse retinal pigment epithelial defects, vascular attenuation, and pigmentary dispersion. The electroretinogram demonstrated severely subnormal rod- and cone-mediated responses, with greater involvement evident for responses generated by middle and inner retinal neurons compared with responses mediated by photoreceptors. The ophthalmologist may be the first to recognize the characteristic features of this disorder. Early diagnosis may be important because this disorder may be ameliorated by dietary restriction of phytanic acid.

Child, Preschool↗