Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration.

OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (RP) plus noncongenital and progressive hearing loss, ataxia, or both, respectively. METHODS: A whole exome sequencing (WES) analysis was performed in 2 families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon-intron boundaries of the ABHD12 gene. To establish a genotype-phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists, and otologists. MAIN OUTCOME MEASURES: DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging, and audiography. RESULTS: After a WES analysis, we identified 4 new mutations (p.Arg107Glufs*8, p.Trp159*, p.Arg186Pro, and p.Thr202Ile) in ABHD12 in 2 families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which cosegregated with the disease among the family members. Another homozygous mutation (p.His372Gln) was detected in 1 affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the 4 affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract (PHARC) syndrome. CONCLUSIONS: Null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract. Our study allowed us to report 5 new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.

A corneal dystrophy associated with transforming growth factor beta-induced Gly623Asp mutation an amyloidogenic phenotype.

PURPOSE: To present the light and electron microscopic findings of a unique corneal dystrophy never before described in a German family carrying the Gly623Asp Mutation of the TGFBI gene with late clinical onset. DESIGN: Experimental study. PARTICIPANTS: Four affected and 6 nonaffected family members. METHODS: Slit-lamp examination, photographic documentation, and isolation of genomic DNA from peripheral blood leucocytes obtained from each family member examined. Exons 3, 4, 5, and 11 to 14 of the TGFBI gene were amplified and sequenced in these family members. Five corneal buttons of 3 affected siblings were excised at the time of penetrating keratoplasty. Light and electron microscopic examination were performed including immunohistochemistry with antibodies against keratoepithelin (KE) 2 and 15. MAIN OUTCOME MEASURES: Clinical and histologic characteristics of corneal opacification in affected patients and presence of coding region changes in the TGFBI gene. RESULTS: The specimens showed destructive changes in Bowman's layer and the adjacent stroma. Patchy Congo red-positive amyloid deposits were found within the epithelium in 1 cornea, in Bowman's layer and in the anterior stroma of all specimens also showing KE2, but not KE15, immunostaining. Electron microscopy revealed deposits mainly located in the anterior stroma and Bowman's layer and in small amounts in the basal area of some epithelial cells. The destroyed areas were strongly Alcian blue-positive, the Masson Trichrome stain proved mainly negative for the deposits. All affected but none of the unaffected family members had a heterozygous missense mutation in exon 14 of the TGFBI gene (G-->A transition at nucleotide 1915) replacing glycin by aspartic acid amino acid (Gly623Asp) at position 623 of the KE protein. CONCLUSIONS: In contrast with the patient carrying the Gly623Asp mutation of the TGFBI gene described by Afshari et al, our cases presented with Salzmann's nodular degeneration-like clinical features and their specimens contained KE2-positive amyloid. The reason for this now "meeting the expectation histologic phenotype" is unclear. The histologic findings emphasize that this is a unique corneal dystrophy, which shares no clinical characteristics with Reis-Bücklers' dystrophy and should be treated as a distinct entity. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Is there a common factor for vision?

In cognition, common factors play a crucial role. For example, different types of intelligence are highly correlated, pointing to a common factor, which is often called g. One might expect that a similar common factor would also exist for vision. Surprisingly, no one in the field has addressed this issue. Here, we provide the first evidence that there is no common factor for vision. We tested 40 healthy students' performance in six basic visual paradigms: visual acuity, vernier discrimination, two visual backward masking paradigms, Gabor detection, and bisection discrimination. One might expect that performance levels on these tasks would be highly correlated because some individuals generally have better vision than others due to superior optics, better retinal or cortical processing, or enriched visual experience. However, only four out of 15 correlations were significant, two of which were nontrivial. These results cannot be explained by high intraobserver variability or ceiling effects because test-retest reliability was high and the variance in our student population is commensurate with that from other studies with well-sighted populations. Using a variety of tests (e.g., principal components analysis, Bayes theorem, test-retest reliability), we show the robustness of our null results. We suggest that neuroplasticity operates during everyday experience to generate marked individual differences. Our results apply only to the normally sighted population (i.e., restricted range sampling). For the entire population, including those with degenerate vision, we expect different results.

Severe occlusive vasculitis as a complication of cat scratch disease

BACKGROUND: The purpose of this communication is to report a severe occlusive vasculitis as a complication of cat scratch. HISTORY AND SIGNS: A 34-year-old Hispanic woman presented with a sudden visual loss of the right eye associated with shivers, high fever and arthritis which developed 2 months after a cat's bite. Fundus examination showed papillitis and a palor of the paramacular zone of the retina. Fluorescein angiography revealed multiple arterial and venous vasculitic occlusions. THERAPY AND OUTCOME: Auto-immune disease and endocarditis were ruled out by an extensive medical work-up.The diagnosis of Bartonella henselae was confirmed by a positive serology. A systemic antibiotherapy with azithromycin, doxycyclin, rifampicin and steroid therapy resulted in a good clinical response, including a rapid visual recovery with a visual acuity of 20/20 and no relapse of the disease at 6 months follow-up. CONCLUSIONS: Ocular complications associated with cat scratch disease may include vasculitis with both arterial and venous occlusions causing severe visual loss.

Bilateral uveal pigmented alterations with remarkable evolution: long term follow-up in a case of possible bilateral diffuse uveal melanocytic proliferation

Purpose: to describe a case of probable bilateral diffuse uveal melanocytic proliferation (BDUMP) with scleral involvement, free from systemic malignancies and cataract. Methods: fifty months of follow up with recurrent complete ophthalmological examinations, including fundus photography, fluorescein/indocyanine green angiography (FA) and optical coherence tomography (OCT). Investigations also included an electroretinography (ERG) and histological examination of scleral biopsy. Extraocular malignancies were repeatedly searched. Results: the patient was a 61 year-old Italian man with chronic hepatitis type C. At first visit his best corrected visual acuity (BCVA) was 20/32 in OS and 20/25 in OD. Funduscopy showed multiple patch-shaped pigmented alterations involving macular region and mid retinal periphery. FA showed corresponding areas of late-phase hyperfluorescent pinpoints (figure 1a, OS) and intemediate-phase hypocyanescence (figure 1b, OS), with subtle serous neurosensory retinal detachment confirmed by OCT. Photopic and scotopic ERG tested normal. Systemic prednisone was administered for one month without any improvement. After ten months round pigmentary lesions appeared also in superior scleral surface of both eyes. Biopsy allowed to disclose slightly pigmented spindle cells. BCVA worsened for further 10 months, with enlargement of FA alteration areas but lenses still clear. After 30 months spontaneous coalescence and atrophy of retinal lesions started, paralleled by progressive visual recovery. At the end of our follow up BCVA was 20/25 in OU while scleral pigmentary lesions remained unchanged. Conclusions: we report the case of a patient with main features of BDUMP and some unusual findings. Although not all classical diagnostic criteria were fulfilled, the presence of scleral pigmented lesions and spontaneous visual recovery may enlarge clinical spectrum of the disease.

Role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma.

PURPOSE: To assess the role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma and to evaluate its safety. METHODS: Retrospective chart study on 21 patients (2% of a total of 1,005 treated by proton therapy between January 2003 and August 2007) who had developed a complication requiring vitreoretinal surgery. Mean/median total follow-up after irradiation was 43/43 months (range, 12-70 months). RESULTS: Indications for surgery included vitreous hemorrhage (n = 13), epimacular membrane (n = 5), rhegmatogenous retinal detachment (n = 1), combined vitreous hemorrhage with total serous retinal detachment (n = 1), and vitritis (n = 1). Mean/median interval for vitreoretinal surgery after irradiation was 21/20 months (range, 4-45 months), and mean/median follow-up after pars plana vitrectomy was 22/23 months (range, 2-56 months). Pars plana vitrectomy was combined with retinal photocoagulation (n = 5), air/gas (n = 5), or silicone oil tamponade (n = 1). Mean Snellen visual acuity was 20/200 (0-20/40) before and 20/100 (0-20/25) after pars plana vitrectomy. A transient postoperative rise in intraocular pressure was measured in seven patients. Four patients developed phthisis bulbi. CONCLUSION: Vitreoretinal surgery was efficient in maximizing treatment outcome after proton therapy, as it allowed a better oncologic follow-up. Pars plana vitrectomy permitted panretinal photocoagulation to avoid neovascular glaucoma or retinal detachment repair. Macular surgery improved visual acuity, especially in anterior melanoma, whereas repeated surgery may increase the risk of enucleation.

Anomalies et complications vasculaires dans les drusen du nerf optique [Vascular anomalies and complications of optic nerve drusen]

BACKGROUND: Drusen of the optic disc are associated with slowly progressive optic neuropathy, characterized by accumulation of acellular laminated concretions in the prelaminar portion of the optic nerve. Papillary hemorrhages and vascular shunts have been reported with disc drusen but their frequency and clinical significance is not well known. METHODS: Retrospective study of fundus photographs of 116 patients with disc drusen referred to the National Hospital for Neurology and Neurosurgery, London, between 1965 and 1991. RESULTS: Hemorrhages were found in 23 eyes from 16/116 (13.8%) patients. Most cases (68.8%, 11/16 cases) occurred in patients with buried drusen, and most hemorrhages were deeply located. Vascular shunts were present in 6.9% (8/116 cases), most frequently in patients with exposed drusen (6/8 cases), most being of the venous type (7/8 cases). DISCUSSION: Vascular anomalies are not rare in disc drusen, as 20.7% (24/116 cases) of our patients presented either disc hemorrhages or shunt vessels. Their presence supports the hypothesis of the slowly progressive nature of disc drusen and the more advanced stage of optic neuropathy in such eyes.

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy.

Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.

Variable phenotypic expressivity in a Swiss family with autosomal dominant retinitis pigmentosa due to mutation T494m in the Prpf3 gene

Purpose:to describe the clinical features in a five generations family segregating autosomal dominant retinitis pigmentosa and to identify the causative gene Patient and Methods:Twenty five individuals of a large five-generation family originating from Western Switzerland were ascertained for phenotypic and genotypic characterization. Ophthalmologic evaluations included color vision testing, Goldman perimetry and digital fundus photography. Some patients had autofluorescence (AF) imaging, ocular coherence tomography (OCT) and ISCEV-standard full-field electroretinography (ERG). Blood samples were collected from 10 affected (4 to 70 years of age) and 15 unaffected members after informed consent. DNA was isolated and exons and intron-exons junctions of known adRP genes were sequenced using a Big Dye sequencing kit 1.1. Results:Age of onset of nightblindness and severity of progression of the disease was variable between members of the family. Some patients had early onset of nightblindess aged 3, others at mid-twenties. Most patients had visual acuity above 0.6 for the first 4 decades. Two older patients still had good vision (0.4) in their seventies. Myopia (range: -2 to -5) was noticed in most affected subjects. Fundus findings showed areas of atrophy along the arcades. The AF imaging showed a large high density ring bilaterally. A T494M change was found in exon 11 of PRPF3 gene. The change segregates with the disease in the family. Conclusion: A mutation in the PRPF3 gene is rare compared with other genes causing ADRP. Although a T494M change has been reported, our family is the first one with a variable expressivity. Mutations in PRPF3 gene can cause a variable phenotype of ADRP unlike the previously described Danish and English families. Our report gives a better understanding as to the phenotype/genotype description of ADRP due to PRPF3 mutation.

Intravitreal Ranibizumab in the Treatment of Predominantly Hemorrhagic Lesions in Exudative Age-Related Macular Degeneration.

BACKGROUND: Submacular hemorrhage is a manifestation of neovascular age-related macular degeneration (AMD) that has a very poor natural history leading to severe visual loss. We have evaluated the safety and efficacy of intravitreal ranibizumab in the treatment of predominantly hemorrhagic AMD. PATIENTS AND METHODS: A retrospective study of patients with predominantly hemorrhagic AMD treated with intravitreal ranibizumab at the Jules Gonin Eye Hospital between December 2006 and December 2008 was undertaken. Baseline and monthly follow-up exams included visual acuity (VA), fundus exam and optical coherence tomography (OCT) while fluorescein and indocyanine green angiography were performed at least every three months. RESULTS: The study included 8 eyes. The mean follow-up was 13 months (SD: 6.3). The mean number of intravitreal injections administered for each patient was 6.4 (SD: 2). 50 % of the patients demonstrated stable or improved VA. The size of hemorrhage at baseline was inversely correlated to the final VA (two-tailed p value = 0.038) and positively correlated to the final central macular thickness (two-tailed p value = 0.021). Anticoagulation treatment was inversely correlated to the time of hemorrhage resolution (two-tailed p value = 0.039). CONCLUSIONS: Intravitreal ranibizumab may be an effective treatment for predominantly hemorrhagic lesions due to neovascular AMD.

Three Generation Family With Pattern Dystrophy and a Successful Treatment of Subfoveal Cnv Related to Pattern Dystrophy With Anti-vegf Intravitreal Injections

Purpose: To phenotype a large 3 generation Swiss family with pattern dystrophy and to report a successful result of treatment with ranibizumab of a subfoveal choroidal neovascularisation (CNV) associated with pattern dystrophy in 1 patient Patients and methods: 4 affected and 3 unaffected patients (3 female 4 male, age range: 19 - 80 years) were assessed with a complete ophthalmologic examination. AF images were taken using Heidelberg Retina Angiograph and the digital color photos, fluorescein angiogragraphy (FFA) using the same TOPCON 501 camera. Electroretinogram (full-field and multifocal) was performed in 1 affected patient. One 48 years old patient developed a subfoveal CNV, which was treated with 2 injections of ranibizumab, at 3 months interval. Blood sample was taken for molecular analysis (screening of the gene RDS). Results: Two patients had a typical fundoscopic appearance of pattern dystrophy with butterfly shaped deposit at the fovea and some peripheral flecks, as shown with AF imaging.. Two others affected patients had a more unusual appearance with some macular atrophy in one or both eyes, surrounded by flecks. The visual acuity ranged from 1.0 to 0.1 according to Snellen EDTRS chart. The patient with subfoveal CNV presented a drop of vision form 1.0 to 0.6 within 10 days prior to the diagnosis and also reported some metamorphopsia. FFA and optical computerized tomography (OCT) confirmed a classic CNV. After the 1st injection her vision improved to 1.0 but persistent metamorphopsia and fluid on OCT motivated a second injection. One month after the second injection the OCT was flat and the patient had no symptoms. The results of RDS screening will be presented at the meeting. Conclusion: We present a family with pattern dystrophy, with some members having an unusual fundus appearance, which was mistaken for an early onset dry AMD. The AF imaging is a useful tool in diagnosing this condition. A CNV associated with pattern dystrophy a rare. This is the first report of a successful treatment of the CNV with anti-VEGF intravitreal injections.

Recurrent idiopathic neuroretinitis: natural history and effect of treatment.

BACKGROUND: Previous reports have emphasized the self-limited nature of idiopathic neuroretinitis. There is less information about a subgroup of patients who suffer recurrent episodes with worse visual outcome. We sought to better characterize the clinical features of recurrent idiopathic neuroretinitis including the effects of immunosuppressive treatment. METHODS: Retrospective chart review of neuroretinitis patients from a single institution from 1983 to 2008. Inclusion criteria included two or more episodes of acute visual loss with disc oedema and macular exudates in a star pattern. Cases due to a specific infectious or inflammatory aetiology were excluded. RESULTS: Forty-one patients were included with an average follow up of 67 months. Median age at the time of the first episode was 28 years (range 10-54 years). Attacks were bilateral sequential in 34 patients (83%). We documented a total of 147 episodes in 75 eyes with an average of 3.6 attacks per patient. The average interval between attacks was 3 years. Visual field loss had a nerve fibre bundle pattern in most cases. Only 36% of eyes retained 6/12 or better visual acuity and greater than two-thirds of their visual field. Long-term immunosuppressive treatment in 13 patients decreased the attack rate by 72%. CONCLUSIONS: Recurrent idiopathic neuroretinitis typically affects young adults, with no gender preference. Recovery is limited and visual loss is cumulative with repeated attacks, often resulting in severe permanent visual loss. Immunosuppressive treatment appears to lessen the attack frequency.

Long-term stability of retinal function despite retained intraocular metallic foreign body.

BACKGROUND: Persisting metallic intraocular foreign bodies (IOFB) with a ferrous content have been associated with ocular siderosis and retinal degeneration. We describe two patients in whom a metallic IOFB containing iron was left embedded for many years in the choroid and sclera after having penetrated through the vitreous and the retina. HISTORY AND SIGNS: Two male patients, aged 41 and 48 years, presented with a metallic IOFB sustained during a work accident involving metal tools. THERAPY AND OUTCOME: For the first patient it was deemed unwise to operate, as the IOFB was also lodged very deeply in the choroid and sclera in the inferior temporal quadrant. The second patient underwent pars plana vitrectomy, but the IOFB could not be removed surgically as it was too deeply embedded in the sclera and choroid. After a period of 6 years (Case 1) and 4 years (Case 2) of follow-up, visual acuity remained at 1.0 and the IOFB was encased in a fibrotic capsule in both cases. Full-field and multifocal electroretinograms showed an inter-ocular asymmetry at baseline, which remained stable during the follow-up. CONCLUSIONS: Ocular siderosis may not develop in patients with a deeply embedded metallic IOFB. Regular monitoring of both visual function and the electroretinogram is mandatory when the IOFB is left inside the eye.

Expansion of intraocular gas bubbles due to altitude: do meteorological factors play a role?

BACKGROUND: Intraocular gas bubbles expand as patients move up to higher altitude. This may cause an acute intraocular pressure (IOP) rise with associated vascular obstructions and visual loss. MATERIALS AND METHODS: Two pseudophakic patients underwent a pars plana vitrectomy and 23% SF6 gas tamponade for a pseudophakic retinal detachment. During the immediate post-operative phase, the patients travelled daily up to their domicile, which was situated approximately 600 m higher than the level where they had been operated on. These travels were always without any pain or visual loss. However 1 week after surgery both patients developed severe ocular pain, and one patient had complete temporary loss of vision after ascending to altitude levels, which had previously presented no problem. Both episodes occurred in parallel with a change in barometric pressure. RESULTS: Treatment with acetazolamide reduced the increased IOP to normal levels, and visual acuity recovered. CONCLUSIONS: Although the post-operative size of an intraocular gas bubble decreases progressively over time, problems with bubble expansion may still occur even at a late stage if meteorological factors, that may increase the bubble size, change.

. Phenotype/genotype correlation associated with a novel nonsense Glu20stop mutation in the Rp2 gene in a three-generation family with x-linked retinitis pigmentosa

Purpose: To assess the phenotype of patients in a large 3 generation Swiss family with X-linked retinitis pigmentosa (XLRP) due to a novel nonsense mutation Glu20stop in RP2 gene and to correlate with the genotype. Methods: 6 affected patients (1 male, 5 females, age range: 23 - 73 years) were assessed with a complete ophthalmologic examination. All had fundus autofluorescence images, standardised electroretinography, Goldmann visual fields and Optical Coherence Tomography. In addition, medical records of 2 affected male patients were reviewed. Blood sample was taken for molecular analysis. Results: The male patients were severely affected at a young age with early macular involvement. The youngest 23 y old male had also high myopia and vision of less than 0.05 according to Snellen EDTRS chart bilaterally. All 5 female carriers had some degree of rod-cone dystrophy, but no macular involvement. The visual acuity was 1.0 in the younger carriers, while the 73 years old had VA of 0.5. Two females had mild myopia (range -0.75 to -2) and one had anisometropia of 3.5D, with the more severely affected eye being myopic. Three out of 5 female carriers had optic nerve drusen. Conclusions: We report a novel Glu20stop mutation in RP2 gene, which is a rare cause of XLRP. Our description of severe phenotype in male patients with high myopia and early macular atrophy confirms previous reports. Unlike previous reports, all our female carriers had RP, but not macular involvement or high myopia. The identifiable phenotype for RP2-XLRP aids in clinical diagnosis and targeted genetic screening.