Bernard Arnaud

Nuclear gene OPA1 , encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy

Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy occurring in 1 in 50,000 individuals that features progressive loss in visual acuity leading, in many cases, to legal blindness. Phenotypic variations and loss of retinal ganglion cells, as found in Leber hereditary optic neuropathy (LHON), have suggested possible mitochondrial impairment. The OPA1 gene has been localized to 3q28–q29 (refs 13–19). We describe here a nuclear gene, OPA1, that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria. We found four different OPA1 mutations, including frameshift and missense mutations, to segregate with the disease, demonstrating a role for mitochondria in retinal ganglion cell pathophysiology.

Keratectasia induced by laser in situ keratomileusis in keratoconus.

PURPOSE Corneal thinning disorders weaken the mechanical strength of affected corneas, suggesting that photorefractive procedures may be contraindicated in keratoconus. Few cases have been reported to confirm this hypothesis. METHODS A 45-year-old man had two laser in situ keratomileusis (LASIK) procedures and one photorefractive keratectomy (PRK) performed on his left eye, and three LASIK procedures on his right eye. After these surgeries, a dramatic corneal ectasia and grade III haze occurred in both eyes, with a clinical diagnosis of keratoconus. The changes in his corneas were followed with videokeratography and slit-lamp microscopy. RESULTS Preoperative videokeratograph of both eyes suggested keratoconus. After multiple refractive procedures, the best spectacle-corrected visual acuity was as low as 20/1200 bilaterally. Both eyes displayed dramatic corneal protrusion with corneal scarring. CONCLUSIONS This case emphasizes the need for preoperative corneal thickness measurement and detailed analysis of videokeratographs. Thinning corneal disorders such as keratoconus, keratoconus suspects, or pellucid marginal degeneration are a contraindication for excimer laser ablative refractive procedures.

Autosomal recessive retinal dystrophy associated with two novel mutations in the RPE65 gene.

Retinal dystrophies are a complex set of hereditary diseases of the retina that result in the degeneration of photoreceptors. Recent studies have shown that mutations in RPE65, a gene that codes for a retinal pigment epithelium (RPE)-specific protein thought to be involved in the 11-cis-retinoid metabolism, a key process in vision, cause severe, early onset retinal dystrophy. We describe two novel missense RPE65 mutations, L22P and H68Y, in a compound heterozygote with autosomal recessive retinal dystrophy. The relatively mild phenotype associated with these mutations suggests a possible link between the severity of the disease and the type of mutations in the RPE65 gene.

A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness.

PURPOSE To describe a French family with the incomplete type of X-linked congenital stationary night blindness (CSNB2) associated with a novel mutation in the retina-specific calcium channel alpha(1) subunit gene (CACNA1F). DESIGN Interventional case report. METHODS Two family members with a history of nonprogressive night blindness and subnormal visual acuity were clinically examined and the genotype determined by molecular genetic analysis. RESULT Both patients had clinical manifestations characteristic of CSNB2. Electrophysiologically, we found a predominant reduction of the ERG B-wave in the maximal response. Both rod and cone function were subnormal, with the latter tending to be more attenuated. We identified a C deletion at nucleotide position 4548, resulting in a frameshift with a predicted premature termination at codon 1524. CONCLUSIONS The clinical and genetic study of a novel mutation in the CACNA1F gene adds further support to the contention that CSNB2 represents a genetically distinct retinal disorder of a calcium channel.

Novel Mutations in MYO7A and USH2A in Usher Syndrome

Purpose: Usher syndrome is an autosomal recessive disease associating retinitis pigmentosa and neurosensory deafness. Three clinical types (USH1, USH2, USH3) and 11 mutated genes or loci have been described. Mutations in MYO7A and USH2A are responsible for about 40% and 60% of Usher syndromes type 1 and 2, respectively. These genes were screened in a series of patients suffering from Usher syndrome. Methods: We performed SSCP screening of MYO7A in 12 unrelated patients suffering from Usher syndrome type 1 (USH1) and USH2A in 28 unrelated patients affected by Usher syndrome type 2 (USH2). Results/conclusions: Six mutations in MYO7A were found in five patients, including two novel mutations c.397C>G (His133Asp) and 1244-2A>G (Glu459Stop), accounting for 42% of our USH1 patients. Twelve mutations in USH2A were found in 11 patients, including four new mutations c.850delGA, c.1841-2A >G, c.3129insT, and c.3920C>G (Ser1307Stop), accounting for 39% of our USH2 patients.

Keratographic analysis of a family with keratoconus in identical twins

&NA; We screened family members of monozygotic twins with keratoconus to search for a corneal thinning disorder using clinical, videokeratographic, and pachymetric analyses. The parents had bilateral astigmatism of a symmetric bow‐tie pattern with normal videokeratographic and pachymetric indices. The 8‐year‐old sister had slightly asymmetric astigmatism in both eyes with normal pachymetry values. No family member was suspected of a corneal thinning disorder. We discuss the mode of inheritance of keratoconus in this family.

Lateralization in haptic processing : an apparatus for analyzing manual strategies

We describe an apparatus for testing laterality in haptic processing in the discrimination of nonsense shapes in humans or monkeys. The system, which permits either mono- or dichhaptic discrimination, automatically provides data on the measurement of accuracy along with information on hand exploratory strategies.

Accuracy of IRAS GT interferometer and potential acuity meter prediction of visual acuity after phacoemulsification prospective comparative study

Purpose: To assess and compare the accuracy of 2 methods of predicting visual acuity after phacoemulsification. Setting: Department of Ophthalmology, Montpellier, France. Methods: This prospective study evaluated 47 eyes of 47 patients having uneventful phacoemulsification over a 1‐month period. All the patients had mild to moderate cataract. Visual acuity recovery was predicted using the white‐light IRAS GT® interferometer on the 3‐ and 8‐degree wide test area and the Guyton‐Minkowski potential acuity meter (PAM). Best corrected visual acuity was evaluated 1 day before and 1 month after surgery. Results: Both the interferometer and PAM underestimated the retinal visual capacity. Three‐degree white‐light interferometry gave significantly better mean predicted results than 8‐degree interferometry and the PAM. There was no statistically significant disparity between predicted and postoperative results with 3‐degree interferometry (1.04 ± 0.57 logMAR; −0.09 ± 0.27 decimal) (P = .0647) and a statistically significant disparity with 8‐degree interferometry (0.89 ± 0.59 logMAR; −0.13 ± 0.27 decimal) and the PAM (0.66 ± 0.62 logMAR; −0.22 ± 0.24 decimal) (P = .0001). The predicted values were widely dispersed; the correlation indices were 0.38 with the PAM (P = .091), 0.39 with 3‐degree interferometry (P = .001), and 0.49 with 8‐degree interferometry (P = .0005). Conclusions: Three‐degree white‐light interferometry gave more accurate results than 8‐degree interferometry and the PAM. The wide dispersion of results and unsatisfactory correlation indices show the tests are poor predictors of individual acuity. They should be used semiquantitatively and the results interpreted in relation to the clinical data. Qualitative methods may be useful in confirming or refuting visual recovery capacity ascertained by quantitative systems.

Different Mutations in RPE65 Are Associated with Variability in the Severity of Retinal Dystrophy

RPE65 encodes a retinal pigment epithelium (RPE)-specific protein thought to be involved in the 11 -cis retinoid metabolism, a key process in vision.To evaluate the visual implications of defects in this gene, we screened patients with various types of inherited retinal dystrophies. We found two nonsense mutations, 1121delA and R234X, in two sibs with Leber’s congenital amaurosis. The presence of either one of the two mutations on each allele indicates that they were compound heterozygotes. In a subsequent screening, two missense mutations, L22P and H68Y, were found in a patient with autosomal recessive retinitis pigmentosa.This individual was also a compound heterozygote. These results suggest that the level of impairment of the RPE65 protein, presumably abnormal activity in the case of amino acid substitutions and absence of protein in the case of null mutations, controls the rate at which the photoreceptors degenerate, and hence the severity of the phenotype.

RRH, Encoding the RPE-Expressed Opsin-Like Peropsin, Is Not Mutated in Retinitis Pigmentosa and Allied Diseases

Many genes from retinoid metabolism cause retinitis pigmentosa. Peropsin, an opsin-like protein with unknown function, is specifically expressed in apical retinal pigment epithelium microvilli. Since rhodopsin and RGR, another opsin-like protein, cause retinitis pigmentosa, we used D-HPLC to screen for the peropsin gene RRH in 331 patients (288 with retinitis pigmentosa and 82 with other retinal dystrophies). We found 13 nonpathogenic variants only, among which a c.730_731delATinsG that truncates the last two transmembrane-spanning fragments and the Lys284 required for retinol binding, but does not segregate with the disease phenotype. We conclude that RRH is not a frequent gene in retinitis pigmentosa.