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Congenital nystagmus (CN) is a common oculomotor disorder (frequency of 1/1,500 live births) characterized by bilateral uncontrollable ocular oscillations, with onset typically at birth or within the first few months of life. This condition is regarded as idiopathic, after exclusion of nervous and ocular diseases. X-linked, autosomal dominant, and autosomal recessive modes of inheritance have been reported, but X-linked inheritance is probably the most common. In this article, we report the mapping of a gene for X-linked dominant CN (NYS1) to the short arm of chromosome X, by showing close linkage of NYS1 to polymorphic markers on chromosome Xp11.4-p11.3 (maximum LOD score of 3.20, over locus DXS993). Because no candidate gene, by virtue of its function, has been found in this region of chromosome Xp, further studies are required, to reduce the genetic interval encompassing the NYS1 gene. It is hoped that the complete gene characterization will address the complex pathophysiology of CN.

Our purpose was to search for mutations in the apolipoprotein E (apoE) gene and to evaluate the role of apoE polymorphisms in the occurrence of autosomal dominant retinitis pigmentosa (ADRP). The ApoE gene coding sequence was analyzed in 51 unrelated patients affected with ADRP. A screening for mutations by SSCP and an analysis of the apoE polymorphisms were performed using PCR and restriction enzymatic digestion. No abnormal patterns of migration were observed by SSCP analysis. No significant statistical difference was seen between our ADRP population and the French general population for apoE allele frequency. From these results we report that the apoE gene does not seems to be involved in our ADRP population.

Stargardt disease (STGD) and late-onset fundus flavimaculatus (FFM) are autosomal recessive conditions leading to macular degenerations in childhood and adulthood, respectively. Recently, mutations of the photoreceptor cell-specific ATP binding transporter gene (ABCR) have been reported in Stargardt disease. Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM families and we show that mutations truncating the ABCR protein consistently led to STGD. Conversely, all mutations identified in FFM were missense mutations affecting uncharged amino acids. These results provide the first genotype-phenotype correlations in ABCR gene mutations.

Purpose: To report the identification of two novel RDS mutations in the peripherin/RDS gene of two unrelated French patients affected by autosomal dominant retinitis pigmentosa (ADRP)., Methods: Fifty-eight unrelated patients affected by ADRP were analyzed. Our diagnostic for RP were bilateral fundus involvement, concentric depression of the visual field and severe involvement on electroretinogram. Transmission of the trait was unambiguous. Our strategy was to analyze the coding sequence of the gene using a combination of single-strand conformation polymorphism (SSCP) and direct sequence analysis of the exons of the gene. Exons that displayed conformational polymorphisms were sequenced on an automated DNA sequencer., Results: The sequence analyses revealed two previously unreported missense mutations: Cys165Tyr and Phe211Leu in exons 1 and 2, respectively. None of the 70 controls analyzed carried these base changes. Cosegregation of the base substitution with the disease could be tested in both families presenting the Cys165Tyr and Phe211Leu mutations., Conclusions: Several lines of evidence support the idea that these base substitutions are disease-causing mutations. To the best of our knowledge, no peripherin/RDS gene analysis has been previously reported in ADRP in France.

Leber's congenital amaurosis (LCA) is the earliest and most severe of all inherited retinal dystrophies. Recently, we mapped an LCA gene to chromosome 17p13.1 (LCA1) and ascribed the disease to mutations of the retinal guanylate cyclase (ret GC) gene in a subset of families of North African ancestry. Owing to the genetic heterogeneity of LCA and considering that LCA1 results from an impaired production of cGMP in the retina (with permanent closure of cGMP-gated cation channels), we hypothesized that the activation of the cGMP phosphodiesterase (PDE) could trigger the disease by lowering the intracellular cGMP level in the retina. The rod and cone cGMP-PDE inhibitory subunits were regarded therefore as candidate genes in LCA. Here, we report the exclusion of five rod and cone cGMP-PDE subunits in LCA families unlinked to chromosome 17p13.

Purpose: Apolipoprotein E (ApoE) is a polymorphic protein that plays a central part in plasma metabolism of lipids and in central nervous system lipid homeostasis. Our purpose was to evaluate the potential role of ApoE polymorphism in the occurrence of exudative age-related macular degeneration associated with drusen, which contain lipids., Methods: We analyzed apolipoprotein E genotypes in 116 unrelated patients with exudative age-related macular degeneration in one eye and hard drusen (n = 39) or soft drusen (n = 77) in the other eye, and compared the results with those of age-matched and sex-matched control subjects (n = 168). Apolipoprotein E alleles were detected by a ploymerase chain reaction-based method., Results: A lower frequency of the epsilon4 allele carriers was observed in the exudative age-related macular degeneration group compared with control subjects (12.1% vs 28.6%, respectively; P < .0009). The epsilon4 allele was less frequent in the age-related macular degeneration group compared with control subjects (0.073 vs 0.149, respectively; P < .006). This decreased frequency of the epsilon4 allele was mainly observed in the soft drusen subgroup compared with control subjects (0.045 vs 0.149, respectively; P < .0009)., Conclusion: This lower relative frequency of the epsilon4 allele supports the hypothesis that the ApoE gene is a genetic protective factor identified in age-related macular degeneration.

Glutathione is a ubiquitous antioxidant in mammalian tissues. The first step of its synthesis is catalyzed by the glutamate-cysteine ligase (GLCL) which consists of a heavy, catalytic subunit and a light, regulatory subunit (GLCLR). Previous genetic analyses have revealed frequent losses of chromosome 1p22-->p21 in human malignant mesothelioma and the shortest region of overlapping deletions has been narrowed between the two loci D1S435 and D1S236. An expressed sequence tag of the GLCLR gene was found within a YAC contig encompassing the same interval aoffwas therefore considered as a good candidate gene for predisposition to human mesothelioma. We report here the characterization of the genomic structure of the GLCLR gene and the refine its physical mapping to chromosome 1p22.1.

Introduction: Leber's hereditary optic neuropathy (LHON) is a bilateral optic atrophy, more common in males than in females. No specific clinical feature or biologic test exists to evidence LHON. We report here the case of a man affected with a nonfamilial bilateral optic atrophy, whose diagnostic remained uncertain for 17 years., Patient and Methods: This patient was hospitalized at the age of 27 in order to establish diagnosis. He had an ophthalmologic examination once a year. He was also affected with chronic renal failure. Detection of the G to A mutation at position 11778 of the DNA was assessed by restriction enzyme digestion of amplified genomic DNA., Results: The 11778 mitochondrial DNA mutation was evidenced, in homoplasmic condition in white blood cells., Discussion: Molecular biology allows to substantiate the diagnosis of LHON and is relatively easy and cheap. Assessment of mitochondrial DNA provides a useful diagnostic tool for nonfamilial or atypical cases of LHON.

Leber's congenital amaurosis (LCA, MIM 204,000), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digito-ocular sign of Franceschetti). Hypermetropia and keratoconus frequently develop in the course of the disease. The observation by Waardenburg of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.

Hereditary retinal dystrophies can be subdivised into central (macular) and peripheral degenerations. Stargardt disease, Best disease, cone dystrophy and retinoschisis, affecting children or young adults, are the 4 commonest macular dystrophies. Retinitis pigmentosa, with primary affects photoreceptors, presents a wide clinical, genetic and molecular heterogeneity. It is certainly the most representative cause of peripheral degeneration. Recent advances in molecular biology allow a more complete clinical definition of these inheritable retinal diseases.

Purpose: We have previously identified rhodopsin gene mutations in France in autosomal dominant (ADRP) retinitis pigmentosa in France, using a combination of SSCP (single-strand conformation polymorphism) and direct sequence analysis. The aim of this study was to perform a more rapid tool to identify a mutation in a ADRP family, when this mutation has been identified for one affected member of this family., Methods: We looked for a restriction site, created or abolished by a mutation in the rhodopsin gene. We performed in vitro DNA amplification using PCR (polymerase chain reaction), enzymatic digestion, and migration on agarose gel., Results: Abnormal patterns of migration were observed for affected ADRP members., Discussion: This technique is useful and rapid (less than 5 hours) to recognize a previously identified mutation. However, previous precise identification of the mutation in one member of the family is needed.

Purpose: To screen for mutations in the rhodopsin, peripherin/RDS, and ROM1 genes in a family affected with retinitis punctata albescens. Because clinical heterogeneity was observed in this family, with some members affected with retinitis punctata albescens and one member affected with features typical of retinitis pigmentosa, we analyzed the apolipoprotein E gene to elucidate this unusual intrafamilial heterogeneity., Methods: The coding sequences of these genes were analyzed with a combination of single-strand conformation polymorphism and direct sequence analysis. Haplotypes of the apolipoprotein E gene were analyzed by polymerase chain reaction and enzymatic digestion., Results: The Arg135Trp mutation in the rhodopsin gene was observed in all affected members of this family, but no mutation was detected in the peripherin/RDS or ROM1 genes. The e4 allele of the apolipoprotein E gene apparently cosegregated with the albescens phenotype in this family., Conclusions: The albescent phenotype in retinal dystrophy appears to not be caused exclusively by a peripherin/RDS gene mutation, and we suggest that the apolipoprotein E gene may play a role in the albescent phenotype.

Stargardt's disease is an autosomal recessive infantile macular degeneration of unknown origin whose gene has been recently mapped to chromosome 1p21-p13 by linkage analysis in eight multiplex families. Since the cone-specific alpha-subunit of the transducin gene (GNAT2) has been mapped to chromosome 1p13, we tested GNAT2 as the disease-causing gene in our series. Using a novel intragenic polymorphism, we show here that GNAT2 is most probably located centromeric to the genetic interval encompassing the disease gene (D1S424-D1S236, location score = 3.54). In addition, single-strand conformation polymorphism and sequence analyses of the eight exons of the GNAT2 gene was performed in our probands. No evidence of a deleterious base substitution was observed in any affected individual. Taken together, these results support the exclusion of GNAT2 as the causal disease gene of Stargardt's disease. come. The pathogenesis is unknown and the treatment is limited to ultraviolet ray protection with dark glasses. Stargardt's disease has been recently mapped to chromosome 1p21-p13 in the genetic interval defined by loci D1S424 and D1S236. In addition, our previous study has suggested that Stargardt's disease is genetically homogeneous (Kaplan et al. 1993). With respect to the physical mapping of the proteins specific to the retinal pigmentary epithelium or to cones we noted that the cone-specific alpha-subunit of the transducin gene (GNAT2) has been mapped to chromosome 1p13 (Wilkie et al. 1992). The human GNAT2 is 9967 bp in length and consists of eight exons with seven introns (Morris and Fong 1993). In the present study, we examined this gene as the candidate gene in eighteen unrelated patients affected with Stargardt's disease.

A familial association between juvenile macular dystrophy and congenital hypotrichosis is described in two siblings aged 25 and 23 years. We put forward arguments for locating the retinal alteration at the level of the retinal pigment epithelium and suggest that the hair disorder could be a Marie-Unna type hypotrichosis. This association is transmitted as an autosomal recessive condition.

Acute blurred vision is a usual clinical setting which could be related to many different etiologies. The ophthalmologist has to precise the symptomatology to differentiate long or short visual acuity loss, troubles of accommodation, metamorphopsia or central scotomas. Then a complete ophthalmologic examination will try to localise the causative lesion in the cornea, the lens, the chorio-retina or in the intraocular media.

Fundus flavimaculatus with macular dystrophy is an autosomal recessive disease responsible for a progressive loss of visual acuity in adulthood, with pigmentary changes of the macula, perimacular flecks, and atrophy of the retinal pigmentary epithelium. Since this condition shares several clinical features with Stargardt disease, which has been mapped to chromosome 1p21-p13, we tested the disease for linkage to chromosome 1p. We report here the mapping of the disease locus to chromosome 1p13-p21, in the genetic interval defined by loci D1S435 and D1S415, in four multiplex families (maximum lod score 4.79 at recombination fraction 0 for probe AFM217zb2 at locus D1S435). Thus, despite differences in the age at onset, clinical course, and severity, fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders. This result supports the view that allelic mutations produce a continuum of macular dystrophies, with onset in early childhood to late adulthood.