Null mutation in the human 11-cis retinol dehydrogenase gene associated with fundus albipunctatus.

PURPOSE: Recent studies show that mutations in the gene encoding 11-cis retinol dehydrogenase are associated with fundus albipunctatus. The authors wanted to investigate whether additional, more severe, mutations in the 11-cis retinol dehydrogenase gene might be responsible for more severe forms of hereditary retinal diseases. DESIGN: Case-control molecular genetics study. PARTICIPANTS AND CONTROLS: Two index patients, 7 relatives, and 50 control individuals. METHODS: The authors screened two index patients diagnosed with fundus albipunctatus for mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene by direct sequencing. Control individuals were screened for the presence of the mutations using allele-specific oligonucleotide hybridization. MAIN OUTCOME MEASURES: Mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene. RESULTS: In a compound heterozygote, two novel mutations were found: a 4 bp insertion in exon 2 and a missense mutation Cys267Trp in exon 5. In a second pedigree, a homozygous frameshift mutation in codon 43 (Arg42ct[1-bpdel]) was detected. In both families, the mutations segregate with the disease. The mutations were not found in 50 control individuals. CONCLUSIONS: On the basis of our observations, it is unlikely that mutations in the 11-cis retinol dehydrogenase gene are associated with other, possibly more severe, retinal pathologic conditions/dystrophies or syndromic diseases in which the retina is also affected.

Predictive value of pattern VEP, pattern ERG and hole size in macular hole surgery.

OBJECTIVE: To describe pattern-reversal visual evoked response (PRVEP) and pattern electroretinogram (PERG) parameters in eyes with macular hole and their value for predicting postoperative visual outcome. METHODS: Prospectively we studied 27 eyes (27 patients) with a full-thickness macular hole. Preoperatively the hole and rim were measured and the PRVEP and PERG were recorded. The preoperative parameters were correlated with postoperative visual outcome. RESULTS: The macular hole was closed in 26 of 27 eyes. Sixteen eyes (59%) had an increase in visual acuity (VA) of two lines or more, 10 eyes (37%) remained within one line of preoperative VA and 1 eye (4%) had a decrease in VA of two lines. Duration of symptoms was negatively correlated with preoperative VA (R=-0.547, P=0.0038) and postoperative VA (R=-0.519, P=0.0065) and positively correlated with hole area (R=0.533, P=0.0061) and rim area R=0.633, P=0.0009). Only the PRVEP P100 latency of the 10' check size and the PERG N35 latency were significantly associated with visual outcome (P=0.022 and P=0.042 respectively). CONCLUSIONS: There was no association of either hole or rim size with postoperative visual outcome. Preoperative electrophysiology, however, is useful as a prognostic tool. Utilization is limited to the use of latency parameters of the response and is dependent on the check size of the stimulus.

Phenotypic variations in a family with retinal dystrophy as result of different mutations in the ABCR gene.

AIMS: To describe two phenotypic variations of autosomal recessive retinal dystrophy occurring in a consanguineous family in a pseudodominant pattern, resulting from mutations in the ATP binding cassette transporter (ABCR) gene. METHODS: Patients of this family underwent an extensive ophthalmic evaluation, including fundus photography, fluorescein angiography, and electroretinography (ERG). Genetic analysis comprised sequence analysis of the retina specific ABCR gene. RESULTS: Five patients presented with decreased visual acuity in the second decade, central chorioretinal atrophy associated with a central scotoma, and severely decreased photopic and scotopic ERG responses. This clinical picture, which in our opinion resembles a cone-rod dystrophy (CRD), was associated with compound heterozygosity for IVS30+ 1g -->t and IVS40+5g-->a mutations in the ABCR gene. The four remaining patients presented with night blindness in the first decade because of a retinitis pigmentosa-like (RP-like) dystrophy. In addition to a pale "waxy" optic disc, attenuated retinal vessels and bone spicule deposits, a widespread chorioretinal atrophy was observed. The scotopic ERG was extinguished and the photopic ERG was severely diminished. Genetic analysis revealed a homozygous 5' splice mutation IVS30+1g -->t in the ABCR gene. CONCLUSION: Mutations in the ABCR gene can cause clinical pictures resembling autosomal recessive RP and autosomal recessive CRD.

The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.

In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.

Refined mapping of the gene for autosomal dominant retinitis pigmentosa (RP17) on chromosome 17q22.

Linkage analysis was performed on a large Dutch family with autosomal dominant retinitis pigmentosa. Linkage was found to the RP17 locus on chromosome 17q22, which was previously described in two South African families by Bardien et al. (1995, 1997). Assuming that the disease phenotypes in these families are caused by the same gene, the RP17 critical region is refined to a 7.7-cM interval between markers D17S1607 and D17S948. Two positional candidate genes, the retina-specific amine oxidase (RAO) gene (AOC2) and the cone transducin gamma gene (GNGT2), were excluded.

Positional cloning of the gene for X-linked retinitis pigmentosa 2.

X-linked retinitis pigmentosa (XLRP) results from mutations in at least two different loci, designated RP2 and RP3, located at Xp11.3 and Xp21.1, respectively. The RP3 gene was recently isolated by positional cloning, whereas the RP2 locus was mapped genetically to a 5-cM interval. We have screened this region for genomic rearrangements by the YAC representation hybridization (YRH) technique and detected a LINE1 (L1) insertion in one XLRP patient. The L1 retrotransposition occurred in an intron of a novel gene that consisted of five exons and encoded a polypeptide of 350 amino acids. Subsequently, nonsense, missense and frameshift mutations, as well as two small deletions, were identified in six additional patients. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. Our data provide evidence that mutations in this gene, designated RP2, are responsible for progressive retinal degeneration.

Anomaloscope examination in macular gliosis, macular holes and central serous choroidopathy.

BACKGROUND: Surgery for macular gliosis and macular holes has become increasingly successful with regard to anatomical outcome. Assessment of the damage to the receptors by these processes is still difficult, but is important in predicting functional outcome. METHODS: Examination with the Nagel II or the Neitz OT anomaloscope was performed in 36 patients with macular gliosis, 23 patients with full-thickness macular holes and 47 patients with central serous choroidopathy. The anomaloscope matches were expressed as the quotient of anomaly. RESULTS: In macular gliosis the mid-matching point is usually 1.0; there is no pseudoprotanomaly. In macular holes the mid-matching point is 1.0 when visual acuity is 0.3 or greater; in eyes with lower visual acuity there may be signs of diminished red sensitivity, but anomaloscope examination becomes difficult. In central serous choroidopathy the mid-matching point is shifted towards red, and pseudoprotanomaly is present, even when visual acuity is normal. CONCLUSIONS: Diseases of the inner retina, in early stages, do not alter colour vision substantially, whereas diseases of the outer retina give rise to early colour vision deficiency. In macular gliosis and macular holes, anomaloscope examination enables estimation of macular receptor misalignment.

Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR.

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age-related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G->T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G->A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.

Two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia: Boucher-Neuhäuser syndrome.

We describe two sibs with chorioretinal dystrophy, hypogonadotrophic hypogonadism, and cerebellar ataxia, Boucher-Neuhäuser syndrome, a rare but distinct pleiotropic single gene disorder with an autosomal recessive pattern of inheritance. The cases presented illustrate that this syndrome is still poorly recognised. We provide a review and analysis of previously reported cases and the differential diagnosis, which might aid in the identification of additional cases.

Prognostic value of pattern reversal visual-evoked potentials in idiopathic epiretinal membrane.

BACKGROUND: Prognostically favorable factors for epiretinal membrane removal have been described in the literature by several authors. Little information, however, is available about the objective assessment of the preoperative macular function. This study reports the results of idiopathic epiretinal membrane removal and the prognostic value of preoperative, pattern reversal visual-evoked potentials (PRVEPS) in recovery of visual acuity (VA). METHODS: In 60 patients (60 eyes) with idiopathic epiretinal membrane we performed PRVEP examination preoperatively. All eyes were operated on by standard three-port vitrectomy with membrane removal. Two eyes were excluded because of postoperative complications. Follow-up VA was compared with preoperative VA for the 58 study eyes and correlated with preoperative PRVEP parameters. RESULTS: The mean preoperative VA was 0.2, the mean postoperative VA, 0.4. The PRVEP was recordable in 74%, 67% and 36% of cases for check sizes of 17, 10 and 7 arcmin respectively. Twenty patients (50%) had an increase in VA of two lines or more, in 25 patients (43%) VA remained within one line of the preoperative value, and in 4 patients (7%) VA decreased by two lines or more. The mean preoperative VA was not significantly different between the group with an improved VA and the group that did not benefit from membrane removal. Of the PRVEP parameters, only the N80 latency for the 17' check size was significantly associated with postoperative visual outcome. CONCLUSION: The PRVEP is applicable as a predictor for visual outcome in cases of epiretinal membrane removal. For the 17' pattern size we found a significant association of the combination of recordability and delayed N80 latency with visual outcome.

Localization of a novel X-linked progressive cone dystrophy gene to Xq27: evidence for genetic heterogeneity.

Clinical reexamination and DNA linkage analysis were carried out in an X-linked progressive cone dystrophy (XLPCD) family, previously described by Pinckers and Timmerman in 1981. In a large pedigree segregating XLPCD, by use of > or = 27 markers spanning the entire X chromosome, a novel locus for XLPCD was identified in Xq27. All other regions on the chromosome could be excluded. Since this novel locus is distinct from previously identified genes or regions involved in XLPCD, we further establish genetic heterogeneity underlying this disease entity.

Reticular dystrophy of the retinal pigment epithelium and choroidal neovascularization. A fluorescein and ICGV study.

We report the clinical history of 2 patients affected with reticular dystrophy of the retinal pigment epithelium and central choroidal neovascularization. With time, spontaneous reduction of the subretinal fluid associated with consequent improvement of the visual acuity has been noted in our first case. The second patient showed a stable fibrotic subfoveal choroidal neovascularization. Conventional fluorescein angiography and indocyanine green videoangiography findings are illustrated. The differential diagnosis between other reticular pigmented lesions often associated with choroidal neovascularization is discussed.

Pattern reversal visual evoked potentials in eyes with macular holes and their fellow eyes.

PURPOSE: To investigate whether the pattern reversal visual evoked potential can be useful in the diagnosis and management of macular hole patients. METHODS: The pattern reversal visual evoked potential was measured in 66 patients with a macular hole and in 43 healthy control subjects. Check sizes of 34', 17' and 10' were applied. RESULTS: Results showed that, for the check sizes of 34', 17' and 10', eyes with a macular hole had significantly prolonged N80 and P100 latencies and a significantly reduced P100 amplitude as compared to their fellow eyes. Furthermore, for the 10' check size, the fellow eyes appeared to have a significantly reduced P100 amplitude in comparison with the control eyes, whereas N80 and P100 latencies of the fellow eyes of the macular hole patients were not prolonged. CONCLUSION: Significant pattern reversal visual evoked potential alterations were shown in eyes with macular holes and fellow eyes for small check sizes.

Pattern-reversal visual evoked potentials in patients with epiretinal membrane.

PURPOSE: To determine the extent of pattern-reversal visual evoked potential parameter alteration by epiretinal membranes and to investigate the use of pattern-reversal visual evoked potential in the estimation of macular function in eyes with epiretinal membrane and in the fellow eyes. METHODS: In both eyes of 162 patients with epiretinal membrane, 92 of primary and 70 of secondary origin, pattern-reversal visual evoked potentials were recorded. Check sizes of 17', 10', and 7' (minutes of arc) were used. Parameters investigated were N80 and P100 latencies and P100 amplitude. RESULTS: No significant difference was detected between eyes with epiretinal membrane of primary and secondary origin regarding visual acuity and the pattern-reversal visual evoked potential parameters for the different check sizes. Compared with the fellow eyes, the eyes with epiretinal membrane had a significantly reduced visual acuity, prolonged N80 and P100 latencies, and a reduced P100 amplitude for the different check sizes. Compared with a separate control group (N = 20) with patients 50 to 59 years old, eyes with epiretinal membrane (N = 9) showed the same features as in the total group, but only for the 17' and 10' check sizes. The fellow eyes (N = 9) showed a significant reduction of the P100 amplitude (P < .05) for the pattern sizes of 17' and 10', but no difference in visual acuity or pattern-reversal visual evoked potential latency was found. CONCLUSIONS: In eyes with epiretinal membrane, pattern-reversal visual evoked potential latencies are prolonged, and amplitude is reduced. Relationships between clinical parameters and pattern-reversal visual evoked potential parameters require further study.

Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene.

Choroideremia (CHM) is an X-linked recessive eye disease that results from mutations involving the Rab escort protein-1 (REP-1) gene. In 18 patients deletions of different sizes have been found. Two females suffering from CHM were reported to have translocations that disrupt the REP-1 gene. In 22 patients, small mutations have been identified. Interestingly, these are all nonsense, frameshift or splice-site mutations; with one possible exception, missense mutations have not been found. This comprises all the known mutations in the disease.

Stable and progressive hearing loss in type 2A Usher's syndrome.

Audiograms were traced or additionally performed on 23 Usher's syndrome patients in 10 Dutch multi-affected families, all linked to chromosome 1q (USH2A locus). Serial audiograms, available in 13 patients, were used for a regression analysis of binaural pure tone average on age (follow-up, 9 to 32 years) to test for "significant progression," ie, a significant regression coefficient, here called the "annual threshold increase" (ATI, expressed in decibels per year). A significant ATI (> 1 dB/y) was observed in 3 patients. Analysis of variance of ATI demonstrated significant heterogeneity; hearing loss was either stable or progressive. This implies a significant clinical heterogeneity. A similar analysis performed on our progressive USH2A cases and "type III" cases previously reported by others (ATI of 1 to 5 dB/y), some of which were recently linked to chromosome 3q (USH3 locus), failed to show any significant heterogeneity in the progression of hearing loss.

Genetic fine mapping of the gene for recessive Stargardt disease.

Stargardt disease (STGD) is one of the most frequent causes of macular degeneration in childhood. Linkage analysis in families with recessive STGD has recently shown genetic homogeneity and a location of the underlying gene at 1p22-p21 in a 4-cM interval. Haplotype analysis in seven Dutch STGD families with 11 highly polymorphic markers spanning the critical region has enabled us to refine the location of the underlying gene to a 2-cM region flanked by the loci D1S406 and D1S236. We have identified one 45-year-old nonpenetrant individual who carries two disease alleles. In another family, an affected individual inherited the paternal but not the maternal disease chromosome, suggesting genetic heterogeneity or a different mechanism leading to the disease in this family.

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1.

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide-exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.