Showing papers in "Ophthalmic Genetics in 1996"
TL;DR: Significant but correctable ocular problems are present in patients with Down's syndrome and may interfere with the quality of life of the patient and with binocular vision, and surgical intervention may be needed for strabismus and for cataracts.
Abstract: Fifty-five patients with Down's syndrome were examined to evaluate the characteristics and frequency of ocular findings. Of these patients, 29 (52.7%) were hypermetropes, 7 (12.7%) were emmetropes, and 7 (12.7%) were myopes; astigmatism of more than 3.00 diopters was present in 7(12.7%) patients. Strabismus was observed in 12 (21.8%) patients. All but one of these 12 patients also had esotropia. Congenital nasolacrimal duct obstruction was present in 12 subjects (21.8%). Blepharitis was found in 19 (34.5%) cases. Nystagmus occurred in 7 (12.7%) patients. Brushfield spots were detected in only 20 (36.3%) of the patients and were more common in light-colored irides. Lens opacities were diagnosed in 11 (20%) patients, and two underwent successful cataract surgery. On fundus examination, an increased number of retinal vessels crossing the optic nerve head was detected in 21 (38.1%) cases. One of the patients had a retinal detachment. Significant but correctable ocular problems are present in patients with Down's syndrome and may interfere with the quality of life of the patient and with binocular vision. Surgical intervention may be needed for strabismus and for cataracts.
124 citations
TL;DR: This review summarizes the results of laboratory studies indicating that apoptosis is a mechanism of cell death in several important ocular diseases including glaucoma, retinitis pigmentosa, cataract formation,retinoblastoma, retinal ischemia, and diabetic retinopathy and provides a brief description of some of the key molecules involved in the genetic regulation of apoptosis.
Abstract: Apoptosis is a form of genetically programmed cell death that can be induced by a variety of different stimuli. It is often referred to as a form of cellular suicide. Typically, apoptosis is characterized by the condensation and shrinkage of the cellular nucleus and cytoplasm, followed by the complete fragmentation of the cell and subsequent phagocytosis of the debris by surrounding cells. Although important during development, and also for maintaining homeostasis in some adult tissues, apoptosis can also be associated with disease processes. Recent laboratory studies indicate that apoptosis is a mechanism of cell death in several important ocular diseases including glaucoma, retinitis pigmentosa, cataract formation, retinoblastoma, retinal ischemia, and diabetic retinopathy. This review summarizes the results of these studies and provides a brief description of some of the key molecules that are involved in the genetic regulation of apoptosis. It is possible that a complete understanding of how these molecules function may someday lead to new treatment options aimed at blocking the death of cells in a variety of ocular diseases.
116 citations
TL;DR: The size of the family studied allowed definition of the clinical spectrum of this condition and identification of the related genetic defect which allows more precise diagnosis and counseling.
Abstract: The objective of this study was to fully characterize the macular dystrophy phenotype and genotype in a large family of the Zermatt area of Switzerland. Clinical and molecular studies of the family included a comprehensive eye examination and a mutational analysis of the RDS, rhodopsin, and TIMP-3 genes. In selected cases, fluorescein angiography, perimetry, and electroretinography were performed. Forty-two family members at risk of expressing the maculopathy were studied. Of these, 24 were found to be clinically affected. The severity of macular disease in these patients was clearly age-related and different stages of progression were identified. Central pigmentary alterations were seen in adolescent patients, while patients in their late teens and twenties exhibited drusen-like deposits. Later, these defects formed focal areas of atrophy which eventually led to central geographic atrophy with severe visual loss by the fifth decade and cone-rod dysfunction. The transmission of this condition is autosomal dominant with complete penetrance. The underlying genetic defect is a mutation in codon 172 of the RDS/peripherin gene, a gene expressed in both rods and cones, which results in the substitution of tryptophan for an arginine residue at that position. 'Zermatt macular dystrophy' is a dominant, age-related, progressive macular dystrophy which in later stages resembles atrophic age-related macular degeneration. The size of the family studied allowed definition of the clinical spectrum of this condition and identification of the related genetic defect which allows more precise diagnosis and counseling.
60 citations
57 citations
TL;DR: The distribution of pigmented ocular fundus lesions (POFLS) by number and APC mutation in families of the Johns Hopkins Polyposis Registry was studied in this article.
Abstract: Background Familial adenomatous polyposis (FAP) results from a germline mutation in the adenomatous polypsis coli (APC) gene on chromosome 5q21. The extracolonic manifestations of FAP include pigmented ocular fundus lesions (POFLS), cutaneous cysts, osteomas, occult radio-opaque jaw lesions, odontomas, desmoids, and extracolonic cancers. POFLS are present at birth in about 80% of patients with FAP and are excellent clinical congenital markers for the disease. We studied the distribution of POFLS by number and APC mutation in families of the Johns Hopkins Polyposis Registry. Materials and methods Of the 51 families with FAP, 42 (82%) had an identifiable APC mutation. We correlated the presence/absence and distribution by number of POFLS with the type and location of the mutation in the APC gene in 21 families where an ocular examination had been performed in at least one affected member, and where a systematic search for mutations in the APC gene had been undertaken. Families were considered POFL-positive ...
36 citations
TL;DR: The 'GIST' score was developed to facilitate linkage analysis of adult-onset primary open angle glaucoma (POAG) pedigrees in the GIST, and allows the laboratory more flexibility in the use of the members of the pedigree for linkage analysis.
Abstract: The 'GIST' score was developed to facilitate linkage analysis of adult-onset primary open angle glaucoma (POAG) pedigrees in the Glaucoma Inheritance Study of Tasmania (GIST). Previous genetic linkage studies on juvenile open angle glaucoma pedigrees have relied upon an analysis of definitely affected individuals using the 'single best diagnosis' convention. Studies of adult-onset POAG have been complicated by limited numbers of unequivocally affected members identified even in very large pedigrees due to the later onset of the disease. Many members of the pedigree may have equivocal clinical features or are too young to show signs of the disease. The 'GIST score' is a numeric value between zero and one where zero is clinical certainty of absence of the disease and one is the definitive diagnosis of POAG. The score is developed by assigning relative weighting to key clinical features which results in a 'pedigee probability' of the diagnosis being present or absent in a member of a pedigree. Ranking of borderline and unaffected glaucoma subjects allows the laboratory more flexibility in the use of the members of the pedigree for linkage analysis. The score is not intended to have clinical usefulness in management of glaucoma.
34 citations
TL;DR: The electro-oculogram (EOG) was studied in 156 normal patients, 103 patients with Best's disease, and 52 patients with dominant cystoid macular dystrophy to identify the gene defect that interferes with capillary permeability, that becomes susceptible to changes of the female hormones.
Abstract: The electro-oculogram (eog) was studied in 156 normal patients, 103 patients with Best's disease, and 52 patients with dominant cystoid macular dystrophy (dcmd). Statistical analysis was performed by comparing the distribution of Lp/Dt ratios of the groups. Strength of association between Lp/Dt ratio and age was studied with correlation and regression analysis. In normal patients and in those with Best's disease, there was no significant correlation between age and Lp/Dt ratio. Obviously, the gene defect in Best's disease causes an altered light-sensitive slow oscillation that remains stable throughout life. In dcmd patients, there was a significant negative correlation between age and Lp/Dt ratio for the total sample and for the female subgroup. Likely, the gene defect in dcmd interferes with capillary permeability, that becomes susceptible to changes of the female hormones.
34 citations
32 citations
TL;DR: The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australia's island state, Tasmania, and its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucome (POAG) suitable for genetic linkage analysis.
Abstract: The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australia's island state, Tasmania (population 450,000). Its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucoma (POAG) suitable for genetic linkage analysis. POAG is relatively common, affecting around 3% of the Australian population. By finding the large families with POAG and identifying all the descendants in a captive population, it is possible that there may be overlap of different glaucoma pedigrees. Three of the first thirteen families in the study were composed of overlapping pedigrees. In one GIST family, GTas3, there has been intermarriage with other pedigrees with glaucoma on five occasions. The possibility of multiple genotypes was also reinforced by the inability to determine a single glaucoma phenotype in this family. When finding large families of POAG for linkage analysis, researchers must be aware of the risk of affected individuals inheriting their gene from the alternate parent. Thus, the alternate parents or their families must be examined, especially if the phenotype is atypical for the rest of the family.
30 citations
TL;DR: Five hundred and ninety-eight eyes had intraocular disease and 233 had extraocular spread and 58 out of 58 tumors showing systemic involvement had either optic nerve or extrascleral extension at the histopathologic examination of enucleation material.
Abstract: Retinoblastoma (R B) is the most frequent malignant intraocular tumor in childhood. Six hundred and thirty-six cases with 831 RB-affected eyes were diagnosed and treated in our specialist center between 1963-1994. The diagnosis was made by histopathologic examination in 617 cases and clinically in 19 cases. Four hundred and forty-one (69.3%) cases were unilateral and 195 (30.7%) were bilateral. Two hundred and sixty-eight (42.1%) were females and 368 (57.9%) were males. The youngest patient was 20 days old and the oldest was 16 years old at the time of diagnosis (mean: 2.2 years). In thirty-four (5.3%) cases, a family history of RB was present. Ten of these cases were unilateral and 24 were bilateral. The most frequent presenting signs were leukocoria (394 cases, 61.9%), buphthalmos (92 cases, 14.5%), and strabismus (68 cases, 10.7%). The referring initial diagnoses were correct in 519 (81.6%) cases and false-negative in 117 (18.4%) cases. The most frequent initial false-negative diagnoses of the referrin...
26 citations
TL;DR: The characterization of mutations in four Canadian families affected by CHM is reported, finding the mutations will result in accurate predictive testing for carriers, avoid unnecessary repeated examination of at-risk individuals, and add to the understanding of the cause of this disorder.
Abstract: Choroideremia (CHM) is an X-linked heritable progressive dystrophy of the choroid and retina. The condition predominantly affects males beginning in early childhood and eventually results in blindness after a period of 30-40 years. The CHM gene was localized to Xq21 and cloned in the past few years. The gene encodes for Rab escort protein-1, a protein involved in the isoprenylation of intracellular proteins. With the isolation of the gene, a number of mutations have been identified in patients affected by CHM using molecular techniques. Our group reports the characterization of mutations in four Canadian families affected by CHM. In addition, an intragenic polymorphism was identified in exon 5. Finding the mutations in these families will result in accurate predictive testing for carriers, avoid unnecessary repeated examination of at-risk individuals, and add to our understanding of the cause of this disorder.
TL;DR: A large consanguineous Asian family in which the severity of the proband's eye disease suggested homozygosity for a disease allele at this closely linked locus supports autosomal dominant inheritance and demonstrates genetic homogeneity for the ad FEVR disease locus.
Abstract: Familial exudative vitreoretinopathy (FEVR) is a disorder characterised by peripheral retinal vascularisation with subsequent traction of retinal vessels and detachment. Recently, autosomal dominant FEVR (ad FEVR) has been mapped to 11q13 by linkage in four northern European families. We describe a large consanguineous Asian family in which the severity of the proband's eye disease suggested homozygosity for a disease allele. Thirty family members were assessed by ophthalmological examination and fluorescein angiography. Thirteen had unequivocal features of FEVR. A further two were classified as unknown. Two point linkage analysis for DIIS533 and FEVR generated a lod score of 5.55 at a recombination fraction of 0.00. This supports autosomal dominant inheritance and demonstrates genetic homogeneity for the ad FEVR disease locus. The severely affected proband was heterozygous for alleles at this closely linked locus. Other causes, including non-genetic factors, should be considered to explain the extreme variability characteristic of ad FEVR.
TL;DR: The spectrum of abnormalities seen in this family are similar to those described in the branchio-oculo-facial syndrome, a rare dominantly inherited syndrome in which there are a number of developmental abnormalities of the eye, face, and kidney.
Abstract: A young male infant was noted at birth to have bilateral cleft lip and palate, bilateral microphthalmos and ocular colobomata, and a dysplastic left kidney. His mother had similar ophthalmological findings and milder facial anomalies which included abnormality of the philtrum and bilateral congenital nasolacrimal duct obstruction. His maternal grandmother had mild facial anomalies including a short philtrum and bilateral congenital nasolacrimal duct obstruction but had no evidence of any ocular abnormalities. The spectrum of abnormalities seen in this family are similar to those described in the branchio-oculo-facial syndrome, a rare dominantly inherited syndrome in which there are a number of developmental abnormalities of the eye, face, and kidney. Although the precise cause of this syndrome is unknown, it is likely to be caused by mutations in a gene responsible for the ordered closure of the foetal fissure and fusion of facial structures.
TL;DR: It is proposed that the alacrima in this family is inherited in an autosomal recessive fashion.
Abstract: This report describes two phenotypically normal sisters, each married to a phenotypically normal paternal cousin. One couple had one female and one male child with alacrima; the other couple had a similarly affected girl. The keratitis sicca was manifested by punctate staining of the conjunctiva and blotchy staining of the cornea in the interpalpebral zone with fluorescein and Rose Bengal. Apart from an associated atopy in one of the children, pharmacological testing, biochemical analysis, and clinical examination suggested dysfunction of the lacrimal glands. We propose that the alacrima in this family is inherited in an autosomal recessive fashion.
TL;DR: Ocular phenotypes associated with 2 mutations in the Norrie disease gene including a manifesting carrier are described to lead to retinal malformations of variable severity both in hemizygous males and manifesting carriers.
Abstract: Purpose: To describe the ocular phenotypes associated with 2 mutations in the Norrie disease gene including a manifesting carrier. Methods: Ophthalmological examinations were performed in 2 affected males and one manifesting carrier. Genomic DNA was analyzed by direct sequencing of the Norrie disease gene. Results: Family 1: A 29-year-old male had the right eye enucleated at the age of 3 years. His left eye showed severe temporal dragging of the retina and central scars. Visual acuity was 20/300. DNA analysis revealed a C-to-T transition of the first nucleotide in codon 121 predicting the replacement of arginine-121 by tryptophan (R121W). Both the mother and maternal grandmother carry the same mutation in heterozygous form. Family 2: A 3-month-old boy presented with severe temporal dragging of the retina on both eyes and subsequently developed retinal detachment. Visual acuity was limited to light perception. His mother's left eye was amaurotic and phthitic. Her right eye showed severe retinal dragging, v...
TL;DR: The phosducin gene did not show mutations consistent with it being the causative gene for USH2, but its possible pathogenicity in AZOOR or other retinopathies remains an open question which may be answered by further analysis.
Abstract: Phosducin, a retina-expressed gene mapped to chromosome 1q25-32.1, was analyzed as a candidate gene for retinopathies. The phosducin gene was cloned and characterized, and PCR primers were designed. Eighty-three patients with various retinopathies and 45 control subjects (24 American, 21 Japanese) were analyzed for mutations in the phosducin gene by PCR, denaturing gradient gel electrophoresis (DGGE), and sequencing. A heterozygous sequence variant changing a glycine to arginine at codon 178 was found in one Usher syndrome type II (USH2) patient, while the other USH2 patients did not show any coding sequence variant. A heterozygous sequence variant changing an asparagine to lysine at codon 174 was found in a patient with a severe retinal degeneration in the category of diseases known as acute zonal occult outer retinopathy (AZOOR). Three non-coding sequence variants were found. Two of these were always present together and found in 20.8% of American and 2.4% of Japanese control subjects, reflecting a difference in population pools. In conclusion, the phosducin gene did not show mutations consistent with it being the causative gene for USH2, but its possible pathogenicity in AZOOR or other retinopathies remains an open question which may be answered by further analysis.
TL;DR: Two brothers with Hunter syndrome with the previously undocumented ocular finding of bilateral epiretinal membranes are reported, which is an uncommon finding in the paediatric age group.
Abstract: Hunter syndrome or Type II mucopolysaccharidosis is a rare disorder of mucopolysaccharide metabolism. We report the cases of two brothers with Hunter syndrome with the previously undocumented ocular finding of bilateral epiretinal membranes. Epiretinal membranes are an uncommon finding in the paediatric age group.
TL;DR: A large family affected with autosomal dominant retinitis pigmentosa (ADRP) with a sectorial phenotype showed a previously described (G to A) mutation in the rhodopsin gene resulting in the substitution of a glycine residue by an arginine in codon 106 of r Rhodopsin.
Abstract: A large family affected with autosomal dominant retinitis pigmentosa (adrp) with a sectorial phenotype showed a previously described (G to A) mutation in the rhodopsin gene resulting in the substitution of a glycine residue by an arginine in codon 106 of rhodopsin. This mutation shows some unusual characteristics, such as initial pathology of the inferior retina, superior visual field with normal disc and retinal vessels, and erg findings that show a modest reduction in both cone and rod amplitudes with normal implicit times. The Gly 106 Arg mutation has been previously reported in American and British patients. Its presence in a Spanish adrp family confirms that it and its homogeneous associated phenotype are geographically widespread.
TL;DR: A novel rhodopsin missense mutation (M216R) was found in a Danish patient with autosomal dominant retinitis pigmentosa, and clinical examination of the proband disclosed a phenotype of intermediate severity.
Abstract: A novel rhodopsin missense mutation (M216R) was found in a Danish patient with autosomal dominant retinitis pigmentosa. Clinical examination of the proband disclosed a phenotype of intermediate severity. In view of the predicted amino acid substitution in the 5th transmembrane domain of rhodopsin, the clinical picture of the proband is in keeping with the data from the literature on patients carrying similar mutations.
TL;DR: This case represents the rare association of septo-optic dysplasia with complex microphthalmos in an 8-month-old girl and shows no colobomatous lesions and systemic anomalies suggestive of a coloboma syndrome.
Abstract: An 8 -month-old girl was examined because of corneal clouding and microphthalmos. The fundi of both eyes could not be visualized because of corneal clouding. Orbital and cranial computerized tomographic scanning and magnetic resonance imaging demonstrated bilateral microphthalmos and presumed retinal dysplasia, hypoplasia of the optic nerves and chiasm, agenesis of the septum pellucidum, thinning of corpus callosum, and a normal pituitary infundibulum. Cerebral cortex and white matter were unremarkable. Other ocular malformations were anterior segment dysgenesis in the right eye and congenital cataract or lens abnormality in the left eye. Endocrine studies revealed normal serum hormone levels. There were no colobomatous lesions and systemic anomalies suggestive of a coloboma syndrome. This case represents the rare association of septo-optic dysplasia with complex microphthalmos.
TL;DR: It was found that there was not a significant difference in the incidence of new and recurrent retinoblastoma among eyes treated with external beam radiation versus focal modalities.
Abstract: Patients with germinal retinoblastoma (those with bilateral disease or positive family history) have a mutation which puts them at risk for developing new tumors. It is unclear whether the frequency of new tumor development is effected by the type of treatment employed. It may be hypothesized that external beam radiation ‘sterilizes’ the whole retina, and thus decreases the risk of new and recurrent tumors. We reviewed our experience with 66 eyes in 47 patients over the past ten years. We did not find a significant difference in the incidence of new and recurrent retinoblastoma among eyes treated with external beam radiation versus focal modalities.
TL;DR: The authors report the first case of primary retinal telangiectasis with a concomitant diffuse central nervous system venous abnormality.
Abstract: Primary retinal telangiectasis or Coats' disease is a non-hereditary retinal vascular abnormality consisting of incompetent telangiectatic and aneurysmal retinal vessels. It is characteristically found unilaterally in boys and occasionally may be associated with other systemic disorders. The authors report the first case of primary retinal telangiectasis with a concomitant diffuse central nervous system venous abnormality.
TL;DR: Two novel mutations detected in patients with the classical eye features of Norrie disease predict a functional 'null allele', i.e. the complete absence of the corresponding gene product.
Abstract: Norrie disease (ND) is a rare X-linked recessive disorder characterized by congenital blindness due to a degenerative and proliferative dysplasia of the neuroretina and, occasionally, by deafness and mental handicap. Here, we report two novel mutations detected in patients with the classical eye features of ND. Both the one-base pair insertion in exon II (544/545 insA) and the two-base pair deletion in the start codon (418delTG) of the ND gene predict a functional ‘null allele’, i.e. the complete absence of the corresponding gene product.
TL;DR: Two Hispanic families with this disease showed genetic heterogeneity with respect to autosomal dominant, juvenile-onset, primary open angle glaucoma and the disease gene was excluded from this region by genetic linkage analysis.
Abstract: A gene for autosomal dominant, juvenile-onset, primary open angle glaucoma (GLCIA) has been previously mapped to 1q21-31 in several Caucasian pedigrees. We studied two Hispanic families with this disease to determine if their disease genes also map to this region. Individuals were considered as being affected if they had 1OP > 30 mmHg (without treatment) and glaucomatous optic nerve damage or visual field defects. Persons older than 40 years with intraocular pressures < or = 21 mmHg and no evidence of optic nerve damage or visual field loss were scored as unaffected. Individuals not falling into these two categories were considered unknown. Genomic DNA was extracted from blood samples and subjected to PCR-based microsatellite marker analysis. Computer-based linkage analysis was used to determine if the disease gene mapped to chromosome 1q2I-31. In the family from the Canary Islands, the disease gene was linked to the chromosome 1q2I-31 region previously identified by other researchers. Markers D1S212 and D1S218 produced maximum lod scores of 3.38 and 2.99, respectively. In the family from the Balearic Islands, the disease gene was excluded from this region by genetic linkage analysis. Haplotype analysis also excluded the disease gene from chromosome 1q21-31. Our Hispanic families showed genetic heterogeneity with respect to autosomal dominant, juvenile-onset, primary open angle glaucoma.
TL;DR: In ADRP7, a mutation in neighboring codon 173 produced RP with an atypical fundus pattern and macular involvement within the first decade of life, confirming the established clinical and genetic heterogeneity involved in this form of RP.
Abstract: A study was made of two families with autosomal dominant retinitis pigmentosa (ADRP) from Valencia (Spain). One family (ADRP15) was found to have a mutation in codon 114 of the rhodopsin gene that led to a substitution of a glycine for an aspartic acid. The second family (ADRP7) substituted an aspartic acid for valine in codon 173 of the peripherin-RDS gene. Rhodopsin is involved in 25% of ADRP cases and many mutations of this gene have been described as causing different forms of the disease, with variable severity and age at onset, ADRP has been classified as RP with a milder symptom evolution, a typical RP fundus pattern, and macular involvement occurring after the second decade of life. Peripherin-RDS gene mutations lead to RP or other retinopathies. Furthermore, two mutations in codon 172 have been described as causing macular dystrophy. In ADRP7, a mutation in neighboring codon 173 produced RP with an atypical fundus pattern and macular involvement within the first decade of life. These observations...
TL;DR: Eight children presented who suffered from pathological changes of the anterior chamber as part of Axenfeld-Rieger syndrome and all of them had associated hypermetropia, which may have resulted from disturbed development of the posterior segment of the eyes during fetal life.
Abstract: Eight children presented who suffered from pathological changes of the anterior chamber as part of Axenfeld-Rieger syndrome All of them had associated hypermetropia Hypermetropia in these cases may have resulted from disturbed development of the anterior segment of the eyes during fetal life