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Purpose: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. Materials and methods: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. Results: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. Conclusion: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers. [ABSTRACT FROM AUTHOR]

Map-dot-fingerprint basement-membrane abnormalities of the cornea are common in the general population, affecting as many as 76% of persons over age 50 and 42% of persons of all ages. The prevalence of this condition in the general population is not significantly different from that found in families of patients with recurrent corneal erosions and map-dot-fingerprint corneal changes. Despite this extremely high prevalence of basement-membrane changes the incidence of recurrent erosive symptoms in total groups of patients with basement-membrane changes is quite rare, suggesting that these 2 entities are possibly not related. Although previous observers have suggested an autosomal dominant mode of inheritance of these basement-membrane changes, our data raise the possibility that map-dot-fingerprint basement-membrane changes represent an age-dependent, degenerative condition of the cornea. We were unable, however, to prove either hypothesis. [ABSTRACT FROM PUBLISHER]

Three middle-aged male patients are described with a peculiar patterned dystrophy of the macula. The basic lesions are discrete yellow plaques typically confined to the macular area and radiating from the fovea. They appear to be located at the level of the retinal pigment epithelium (RPE). With the passage of time some of the yellow plaques altered in extent and configuration, and atrophic changes appeared or extended. Visual acuity and electrophysiological tests are either normal or only moderately affected. The lesions appear to be distinct from the patterned dystrophies of the retina already described and from other conditions characterised by yellow or white deposits at the level of the RPE. [ABSTRACT FROM PUBLISHER]

Bilateral symmetry of disorders of vision is examined in 60 typical patients with retinitis pigmentosa. We observed a very high degree of interocular congruence in the patterns of both kinetic visual field defects and threshold profiles and in abnormalities of foveal colour discrimination and visual acuity. Abnormalities of foveal colour vision are highly correlated with the extent of visual field loss. [ABSTRACT FROM PUBLISHER]

Purpose: To describe a family with X-linked congenital nystagmus and identify the genetic interval within which the gene is located., Methods and Design: Clinical examination with genotyping of 30 individuals from a multi-generational Caucasian family with congenital nystagmus inherited in an X-linked pattern using markers from Xq26-q27, followed by linkage analysis and sequencing of a candidate gene, solute carrier family 25, member 14 (SLC25A14), in four affected individuals from four families linked to this region., Results: The pattern of inheritance in the family was consistent with X-linkage with incomplete penetrance among carrier females. No affected males had affected sons. Based on the extended pedigree, the estimated penetrance among obligate female carriers (daughters of affected males) was 29% (6 of 21). Visual acuity among 15 affected individuals ranged from 20/20 to 20/70 (median 20/30). Clinical examinations, including electroretinography in two individuals, were otherwise normal except for the presence of nystagmus. Significant LOD scores (theta = 0) were found with markers DXS8057, DXS8044, DXS1047, DXS1062, DXS8072, and DXS8078, placing the gene within a approximately 5 cM interval flanked by DXS9909 and DXS1211 on the long arm of the X chromosome. Sequencing the candidate gene SLC25A14 in four affected individuals from four families linked to this region failed to reveal any mutations., Conclusions: NYS1 appears to be a common gene for familial congenital idiopathic nystagmus. Linkage analysis of this family further reduces the interval in which NYS1 is located.

Purpose: We present a macular phenotype resulting from 1 or more abnormalities in the developmental pathway of the central retina., Methods: We describe the clinical and genetic characteristics of 7 patients observed since shortly after birth with regard to visual acuity, refractive error, anterior segment status, retinal findings including foveal structure, and natural history., Results: The patients varied in age from 18 months to 18 years. All patients were examined for the first time during their first year of life and by us at the age of 5 years or younger. The longest follow-up period was 16 years. The abnormal appearance of the macula consisted of thinning of the retina, rarefication of the pigment epithelium with excess visibility of the large choroidal vessels, and absence of the foveal reflex. The visual acuities varied from 20/20 in the better eye to light perception. A retinal detachment was noted in 1 patient at age 2 1/2 years. The refractive errors varied from -2.50 to -16.50 diopters of spherical equivalent. The disease was limited to the retina in 4 patients. In 2 patients, however, developmental abnormalities of the anterior segment were also present; they consisted of malformation of the iris in 1 patient and Peters' anomaly in the other. The electroretinogram (ERG) showed reduced but not absent photopic responses and some reduction in scotopic responses., Conclusion: The phenotype of ateliotic macula is being defined as characterized by an unfinished or primordial appearance. In the 7 patients studied, visual loss was noted shortly after birth. The visual outcome was variable with regard to visual acuity, but many patients showed improvement. There was no evidence of significant worsening of the disease with age except in 1 patient who had a retinal detachment. The ERG responses showed primarily photopic but also scotopic changes. The better-preserved ERG differentiates this disorder from Leber's congenital amaurosis.

Unlabelled: Leber congenital amaurosis (LCA, MIM 204001) is a clinically and genetically heterogeneous retinal disorder characterized by severe visual loss from birth, nystagmus, poor pupillary reflexes, retinal pigmentary or atrophic changes, and a markedly diminished electroretinogram (ERG)., Purpose: To examine 100 consecutive patients with LCA in order to assess the relative burden of the three known genes involved in LCA, namely retinal guanylyl cyclase (GUCY2D), retinal pigment epithelium protein ( RPE65), and the cone-rod homeobox (CRX), and to define their clinical correlates., Methods: Mutational analysis and detailed clinical examinations were performed in patients diagnosed with LCA at the Johns Hopkins Center for Hereditary Eye Diseases and the Montreal Children's Hospital., Results: Mutations were identified in 11% of our patients: GUCY2D mutations accounted for 6%, while RPE65 and CRX gene mutations accounted for 3% and 2%, respectively. The clinical presentation was variable; however, the visual evolution in patients with mutations in GUCY2D and CRX remained stable, while individuals with mutations in the RPE65 gene showed progressive visual loss., Conclusions: This study suggests that molecular diagnosis of Leber congenital amaurosis could provide important information concerning prognosis and course of treatment.

Purpose: To identify and characterize new cone rod homeobox (CRX) mutations associated with the Leber congenital amaurosis phenotype., Methods: The human CRX gene was sequenced in 74 consecutive patients carrying the diagnosis of Leber congenital amaurosis., Results: Two mutations were identified in CRX that cause frameshifts and predict severe truncations of the encoded protein. One of these, a 1-bp insertion, spares only nine N-terminal amino acids, removing the homeodomain, WSP motif, and conserved OTX domain at the C terminus. Of the CRX mutations described in the literature, this is the first that convincingly represents a null allele of the gene. Although the patient heterozygous for this null allele is affected with Leber congenital amaurosis, it was surprising that her father, who had normal vision, was heterozygous for the same mutation., Conclusions: These results strongly suggest that haploinsufficiency of CRX is not sufficient to cause a retinal disorder. Loss of function alleles of CRX appear to cause Leber congenital amaurosis through a recessive or multigenic mechanism.

Complete achromatopsia is a rare, autosomal recessive disorder characterized by photophobia, low visual acuity, nystagmus and a total inability to distinguish colours. In this disease, cone photoreceptors, the retinal sensory neurons mediating colour vision, seem viable but fail to generate an electrical response to light. Achromatopsia, or rod monochromatism, was first mapped to 2p11-2q12 (MIM 216900; ref. 3), where it is associated with missense mutations in CNGA3 (ref. 4). CNGA3 encodes the alpha-subunit of the cone cyclic nucleotide-gated cation channel, which generates the light-evoked electrical responses of cone photoreceptors. A second locus at 8q21-q22 has been identified among the Pingelapese islanders of Micronesia, who have a high incidence of recessive achromatopsia (MIM 262300). Here we narrow the achromatopsia locus to 1.4 cM and show that Pingelapese achromatopsia segregates with a missense mutation at a highly conserved site in CNGB3, a new gene that encodes the beta-subunit of the cone cyclic nucleotide-gated cation channel. Two independent frameshift deletions establish that achromatopsia is the null phenotype of CNGB3. Combined with earlier findings, our results demonstrate that both alpha- and beta-subunits of the cGMP-gated channel are essential for phototransduction in all three classes of cones.

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy and the most frequent cause of inherited blindness in children. LCA is usually inherited in an autosomal recessive fashion, although rare dominant cases have been reported. One form of LCA, LCA4, maps to chromosome 17p13 and is genetically distinct from other forms of LCA. We recently identified the gene associated with LCA4, AIPL1 (aryl-hydrocarbon interacting protein-like 1) and identified three mutations that were the cause of blindness in five families with LCA. In this study, AIPL1 was screened for mutations in 512 unrelated probands with a range of retinal degenerative diseases to determine if AIPL1 mutations cause other forms of inherited retinal degeneration and to determine the relative contribution of AIPL1 mutations to inherited retinal disorders in populations worldwide. We identified 11 LCA families whose retinal disorder is caused by homozygous or compound heterozygous AIPL1 mutations. We also identified affected individuals in two apparently dominant families, diagnosed with juvenile retinitis pigmentosa or dominant cone-rod dystrophy, respectively, who are heterozygous for a 12-bp AIPL1 deletion. Our results suggest that AIPL1 mutations cause approximately 7% of LCA worldwide and may cause dominant retinopathy., (Copyright 2000 Academic Press.)

Purpose: To determine the distribution and structure of fibrillin microfibrils in the three fibrillin-rich lens capsule zones of subjects with the Marfan syndrome., Methods: Capsules were dissected from nine lenses extracted intracapsularly from Marfan syndrome patients. The capsules were divided and mounted flat on gelatin-coated glass slides. ABC immunoperoxidase staining with monoclonal anti-fibrillin antibody was used to visualize and localize fibrillin in these specimens. The staining patterns and microscopic structure of microfibrils were compared to those of normal controls., Results: There were no bundles of fibrillin fibers in Zone I - a 0.75-mm wide peripheral ring of the anterior capsule that normally contains radial bunches of fibrillin fibers; instead, fine disorganized fibrillin-positive fragments were dispersed in this region. The size and shape of the fragments varied among patients. In contrast to normal lenses, there was only light staining for fibrillin in Zone II - a 1-mm wide meshwork of normally fibrillin-rich fibers that encircles the equator and serves as an insertion platform for most zonular fibers. The radial periodic bands of Zone III - a 0.1-mm wide ring on the most peripheral part of the normal posterior capsule - were identifiable in some samples, but stained only faintly for fibrillin., Conclusion: Fibrillin microfibrils are disrupted and fragmented in the lens capsule of patients with the Marfan syndrome. The qualitative, quantitative, and structural abnormalities of fibrillin deposition in the lens capsule of these patients support a causal relationship to lens abnormalities in this disease.

Purpose: To report postsurgical findings in patients with Marfan syndrome and retinal detachment (RD)., Methods: The authors identified and retrospectively reviewed the charts of one cohort of 12 patients (15 eyes) with Marfan syndrome and RD who were operated on at the Wilmer Institute and a second cohort of 16 such patients (24 eyes) who were operated several years earlier and elsewhere., Results: First cohort--Final visual acuity (VA) was 20/80 or better and the retina was flat in all five phakic eyes (100%). The RD occurred after the eye had undergone lens removal in 10 eyes, 6 of which (60%) had a final VA of 20/80 or better, and 9 of which (90%) had a final VA of 5/200 or better (P = 0.20). Second cohort--The final VA was 20/80 or better and the retina was flat in 6 of the 7 phakic eyes (86%). Among 17 aphakic or pseudophakic eyes, only 5 (29%) had a flat retina and VA of 20/80 or better, whereas 12 (71%) had no light perception (P = 0.03)., Conclusions: The results of RD operations done in the past in Marfan patients were worse when the eye was aphakic. In most cases operated more recently, the prognosis for successful RD repair was good regardless of whether the eye was phakic.