Extensive macular atrophy with pseudodrusen-like appearance: a new clinical entity.

PURPOSE: To describe a previously unreported clinical entity of progressive extensive macular atrophy and pseudodrusen-like appearance in middle-aged patients. DESIGN: Clinical, electrophysiologic, and molecular retrospective study. METHODS: The database of an outpatient clinic unit for genetic sensory diseases was screened for patients older than 40 years with uncharacterized macular dystrophy. Patients with extensive macular atrophy and pseudodrusen-like appearance were included. RESULTS: Eighteen patients of 45 records (40%) matched the inclusion criteria. Bilateral polycyclic well-delineated chorioretinal atrophy extending to the temporal vascular arcades, with a larger vertical axis and without sparing of the fovea featured the macular lesion. The pseudodrusen-like appearance was widespread throughout the posterior pole and the peripheral retina. In the extreme periphery, paving stone lesions were located mostly in the inferior quadrants. In contrast to age-related macular degeneration, a rapid progression of the atrophy was observed with an early involvement of the foveal zone, thus leading to a severe visual loss. All the patients except 2 were legally blind at the end of the follow-up. Unlike age-related macular degeneration, in none of these patients did choroidal neovascularization develop. In all patients, the scotopic and photopic electroretinography responses were reduced. CONCLUSIONS: Extensive macular atrophy with pseudodrusen should be considered as a possible pattern of severe macular dystrophy occurring in the middle-aged adult.

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.

Homozygous deletion related to Alu repeats in RLBP1 causes retinitis punctata albescens.

PURPOSE: Retinitis punctata albescens (RPA) is an infrequently occurring form of autosomal recessive (and rarely dominant) retinal dystrophy featuring early-onset severe night blindness and tiny, dotlike, white deposits in the fundus. RPA is associated mostly with mutations in RLBP1 and occasionally in RHO, RDS, and RDH5. In this study, mutations were sought in RLBP1, which encodes the retinol binding protein CRALBP in patients with typical RPA. METHODS: Clinical investigation included funduscopy, visual field testing, electroretinogram recording, and adaptometry. The 7 coding exons (3-9) of RLBP1 and the 15th (last) exon of ABDH2 were PCR amplified and sequenced. Long-distance PCR and cloning of genomic DNA were performed to characterize the deletion. RESULTS: The study involved a 24-year-old Moroccan patient with typical RPA, born of first-cousin parents. He carried a 7.36-kb homozygous deletion encompassing the last 3 exons of RLBP1 (7, 8, and 9) and part of the intergenic region between RLBP1 and ABHD2, which lies downstream of RLBP1. This deletion abolishes the retinal binding site of CRALBP. The telomeric breakpoint of the deletion (in RLBP1 intron 6) is embedded in an Alu element, whereas the centromeric breakpoint (in the intergenic region) lies between two Alu elements placed in the opposite orientation. CONCLUSIONS: Because of the high density of Alu elements in RLBP1, a systematic search should be made for deletions in this gene when one or both alleles lack point mutations, in the case of RPA or flecked retinal dystrophy.

Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis.

PURPOSE: To evaluate the mutation prevalence and phenotype in genes involved in the ocular retinoid metabolism. DESIGN: We analyzed LRAT, encoding the lecithin retinol acyltransferase, and RDH10, a retinal pigment epithelium-specific retinol dehydrogenase. METHODS: We screened by denaturing-high performance liquid chromatography (D-HPLC) and direct sequencing all coding exons of LRAT and RDH10 in 216 patients, including 134 with simplex or multiplex retinitis pigmentosa and 82 with various types of flecked retinal dystrophies. RESULTS: Only nonpathogenic variants were found in this series. In an additional 2.5-year-old patient presenting with an "RPE65" phenotype (night blindness, photoattractivity, and visual improvement several months after birth), we discovered a homozygous deletion in LRAT (c.217_218delAT) leading to a premature stop at codon 120. CONCLUSIONS: The phenotype of patients with mutations in LRAT is similar to that of patients with mutations in RPE65, suggesting the need to systematically screen both genes in case of typical phenotype.

Retinal electrophysiological results in patients receiving lamotrigine monotherapy.

PURPOSE: To evaluate the effects on vision in patients receiving lamotrigine (LTG) monotherapy. METHODS: Twenty-four consecutive patients taking LTG for partial seizures were referred for a routine ophthalmologic examination including visual acuity testing, tonometry, slit lamp, and fundus examination. Automated kinetic perimetry, electrooculogram (EOG), and electroretinogram were performed after informed consent was obtained. RESULTS: In 18 patients finally included, the clinical ophthalmologic examination showed no abnormality. Four patients complained of blurring; among them, one patient had a visual field constriction in both eyes, which, however, was of unclear clinical significance (poor compliance) and a reduced light/dark ratio of the electrooculogram. One other patient with blurred vision had a reduced EOG, but the visual field was normal. Two patients had a reduced EOG but no visual symptoms. Considering the whole group of patients receiving LTG therapy, the light/dark ratio of the EOG was reduced in a dose-dependent fashion (p < 0.0001). The electroretinogram was normal in all patients. CONCLUSIONS: No irreversible visual field impairment in patients treated with LTG was encountered, although a dose-dependent retinal toxicity may have been present. The exact cellular mechanism of the electrophysiologic changes in patients taking LTG remain to be explained.

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

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.

Effect of acetazolamide on ocular hemodynamics in pseudotumor cerebri associated with inflammatory bowel disease.

PURPOSE: To describe the hemodynamic effect of oral acetazolamide administration on ocular perfusion in a patient with pseudotumor cerebri associated with Crohn disease. DESIGN: Interventional case report. METHODS: A 20-year-old woman with a 5-year history of Crohn disease presented with a 2-week history of headache and blurred vision in both eyes. Ophthalmologic examination was normal. Fluorescein angiography showed a profound delay in retinal and choroidal perfusion. Lumbar puncture showed an opening pressure of 320 mm water. Therapy was initiated with oral acetazolamide 750 mg per day. RESULTS: A subjective improvement of symptoms was noted over 4 days. Repeat fluorescein angiography showed resolution of the ocular perfusion deficit. No recurrent symptoms were noted 19 months after cessation of therapy. CONCLUSIONS: Crohn disease may present with pseudotumor cerebri and severe ocular perfusion deficits that are reversible with oral acetazolamide therapy.

BIGH3 (TGFBI) Arg124 mutations influence the amyloid conversion of related peptides in vitro.

Amyloid deposits with Arg124 mutated TGFBI protein have been identified in autosomal dominant blinding corneal dystrophies. We assessed in vitro the mechanisms determining TGFBI protein amyloid transformation involving mutations of Arg124. Eight peptides synthesized following the TGFBI protein sequence, centered on codon Arg124 holding the previously reported amyloidogenic mutations and the respective controls were studied. Cys124 and His124 mutated peptide preparations contained significantly higher amounts of amyloid than the native peptide. Blocking the SH group of Cys124 and deleting the first four NH2-terminal amino acids including Val112-Val113 resulted in a decrease in amyloid fibril formation while deletion of the nine CONH2-terminal residues increased amyloid fibril concentration. Fourrier transformed-infrared spectroscopy analysis of the different peptide solutions showed an increase in beta-pleated sheet structures in those with enhanced amyloid yielding. We designed a peptide (BB1) likely to counteract the role of Val112-Val113 in amyloid fibril formation. Incubation of Cys124 peptide with BB1 indeed resulted in a 35% inhibition of amyloid fibril formation. Our results are in keeping with the clinical observations of Arg124 mutation-linked amyloidosis and show the importance of Val112-Val113, disulfide and hydrogen bonding in increasing the beta-pleated conformation and amyloid formation. These findings shed new light on the molecular mechanisms of TGFBI protein amyloidogenesis and encourage further research on the use of specifically designed peptides as putative therapeutic agents for these disabling diseases.

Macroglial alterations after isolated optic nerve sheath fenestration in rabbit.

PURPOSE: To study the modifications undergone by the macroglial cells after meningeal breach of the optic nerve in the rabbit, without optic neuropathy. METHODS: The optic nerve sheath fenestration technique carried out in humans was adapted to rabbit without axonal injury in the optic nerve. The effects of meningeal fenestration on glial cells were examined by immunocytochemical procedures (day 15) using the antibodies against two astrocyte markers: glial fibrillary acidic protein (GFAP) and vimentin. Proliferation of glial cells was evaluated with single 5-bromodeoxyuridine (BrdU) labeling or double GFAP and BrdU labelings. Qualitative data on glial cells were evaluated with the electron microscope. RESULTS: Optic nerve sheath fenestration on healthy adult rabbits resulted in a decrease of volume of the subarachnoid space located at the level of the meningeal scar, with a significant increase of the optic nerve area. The meninges presented a fibrous scar. In the optic nerve parenchyma, astrocytes appeared hypertrophic in the vicinity of the fenestration. The whole nerve contains numerous BrdU-labeled mitotic cells, a number of which double-labeled for both BrdU and GFAP belong to the astrocyte line. There was no loss of optic nerve axons. CONCLUSIONS: The inflammation produced by the surgical breach of the peri-optic meningeal sheaths induces a significant reactivity, including proliferation of astrocytes in the optic nerve. Reactive astrocytes may interact positively with axons and may modify the extracellular environment in the optic nerve.

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.