PRPH2 mutation c.582-1G>A causing adult-onset macular dystrophy with a benign concentric annular macular dystrophy phenotype in a family / Mutação c.582-1G>A do gene PRPH2 causando distrofia macular de início adulto com fenótipo de distrofia macular anular concêntrica benigna em uma família

ABSTRACT The peripherin gene (PRPH2) mutation is associated with photoreceptor cell dysfunction as well as in several inherited retinal dystrophies. The PRPH2 mutation c.582-1G>A is a rare variant reported in retinitis pigmentosa and pattern dystrophy. Here Case 1 was of a 54-year-old woman with bilateral atrophy of the perifoveal retinal pigmentary epithelium and choriocapillaris with central foveolar respect. Autofluorescence and fluorescein angiography revealed perifoveal atrophy of the retinal pigmentary epithelium with an annular window effect without the "dark choroid" sign. Case 2 (mother of Case 1) presented with extensive atrophy of the retinal pigmentary epithelium and choriocapillaris. PRPH2 was evaluated and the c.582-1G>A mutation was identified in heterozygosity. An advanced adult-onset benign concentric annular macular dystrophy diagnosis was thereby proposed. The c.582-1G>A mutation is poorly known and not present in all common genomic databases. This case report is the first one to report a c.582-1G>A mutation associated with benign concentric annular macular dystrophy.

RESUMO Mutações do gene da periferina (PRPH2) estão associadas à disfunção das células fotorreceptoras e estão envolvidas em várias distrofias retinianas hereditárias. A mutação c.582-1G>A do gene PRPH2 é uma variante rara, relatada na retinite pigmentosa e nas distrofias em padrão. O caso 1 foi de uma mulher de 54 anos com atrofia bilateral do epitélio pigmentar da retina perifoveal e da coriocapilar, com acometimento foveolar central. A autofluorescência e a angiofluoresceinografia revelaram atrofia perifoveal do epitélio pigmentar da retina, com efeito de janela anular, sem o sinal da "coroide escura". O caso 2 (mãe) apresentava extensa atrofia do epitélio pigmentar da retina e da coriocapilar. Foi feito um estudo do gene PRPH2, que identificou a mutação c.582-1G>A em heterozigose. Foi proposto um diagnóstico de distrofia macular anular concêntrica benigna de início adulto em estágio avançado. A mutação c.582-1G>A é pouco conhecida e não está presente em todos os bancos de dados genômicos usuais. Este é o primeiro relato de caso publicado de uma mutação c.582-1G>A associada à distrofia macular anular concêntrica benigna.

PRPH2 mutation c.582-1G>A causing adult-onset macular dystrophy with a benign concentric annular macular dystrophy phenotype in a family.

The peripherin gene (PRPH2) mutation is associated with photoreceptor cell dysfunction as well as in several inherited retinal dystrophies. The PRPH2 mutation c.582-1G>A is a rare variant reported in retinitis pigmentosa and pattern dystrophy. Here Case 1 was of a 54-year-old woman with bilateral atrophy of the perifoveal retinal pigmentary epithelium and choriocapillaris with central foveolar respect. Autofluorescence and fluorescein angiography revealed perifoveal atrophy of the retinal pigmentary epithelium with an annular window effect without the "dark choroid" sign. Case 2 (mother of Case 1) presented with extensive atrophy of the retinal pigmentary epithelium and choriocapillaris. PRPH2 was evaluated and the c.582-1G>A mutation was identified in heterozygosity. An advanced adult-onset benign concentric annular macular dystrophy diagnosis was thereby proposed. The c.582-1G>A mutation is poorly known and not present in all common genomic databases. This case report is the first one to report a c.582-1G>A mutation associated with benign concentric annular macular dystrophy.

Unilateral recurrent macular hole in a patient with retinitis pigmentosa: a case report.

INTRODUCTION: Several macular complications related to abnormalities of the vitreoretinal interface have been classically attributed to retinitis pigmentosa of which cystoid macular edema is the most common. Other less frequent complications are as follows: epiretinal membranes, vitreomacular traction syndrome and macular holes. CASE PRESENTATION: A 64-year-old woman, with the previous diagnosis of retinitis pigmentosa, was referred to our department with a complaint of central visual loss in her left eye for 12 months. A fundoscopy and optical coherence tomography examination revealed the presence of a macular hole more than 500 microns in diameter. The patient underwent 20-gauge pars plana vitrectomy. Closure of the hole was observed after surgery, but reopening occurred at 2 years postoperatively. CONCLUSION: The pathogenesis of macular hole formation in patients with retinitis pigmentosa is unclear. Surgical outcomes may not always be favorable, and the possibility of reopening must be taken into account, even after a long time.

Vitreoretinal surgery for bilateral macular holes after laser-assisted in situ keratomileusis for the correction of myopia: a case report.

INTRODUCTION: Laser-assisted in situ keratomileusis surgery may induce postoperative changes in the vitreomacular interface due to the mechanical stretch of the vitreous produced by the suction ring and the shock waves generated by the excimer laser and, subsequently, may provoke macular hole formation. CASE PRESENTATION: A 53-year-old Spanish woman who had undergone a laser-assisted in situ keratomileusis for the correction of myopia in her right and left eye (10 years ago) was referred to our department with a complaint of decreased visual acuity in both eyes. A fundoscopy and optical coherence tomography examination revealed a bilateral full-thickness macular hole. A 23-gauge sutureless pars plana vitrectomy was performed in both eyes, and 1 month after surgery her visual acuity improved and the hole closed. CONCLUSION: The development of a bilateral full-thickness macular hole after laser-assisted in situ keratomileusis has been reported once. This case study enhances our understanding of the vitreoretinal pathology induced by laser-assisted in situ keratomileusis, showing the importance of a rigorous follow-up, because complications may occur even a decade later. In this case study we must also consider the contribution of the underlying myopia to the development of the bilateral macular holes.

Spontaneous closure of stage IV idiopathic full-thickness macular hole and late reopening as a lamellar macular hole: a case report.

INTRODUCTION: Spontaneous closure of traumatic macular holes is described as a common event in the peer-reviewed literature. However, the spontaneous closure of stage III and IV full-thickness idiopathic macular holes has been reported in less than 15 cases in the literature, this being an extremely rare event, with their reopening being even more infrequent. We report a case of a spontaneous closure of stage IV idiopathic full-thickness macular hole and late reopening as a lamellar macular hole. CASE PRESENTATION: A 67-year-old Spanish man was referred to our hospital with a complaint of decreased vision in his right eye and metamorphopsia for approximately 11 months. He did not report any trauma. Diagnosis was based on fundoscopic and optical coherence tomography. They revealed a stage IV full-thickness idiopathic macular hole and a small epiretinal membrane. Three months later the hole spontaneously closed, and two years later we appreciated its reopening as a lamellar macular hole. CONCLUSIONS: The contraction of the epiretinal membrane could have contributed to cystic spaces and their fusion, subsequently, to the formation of a lamellar macular hole. To the best of our knowledge this is the first report in the literature of a spontaneously closed full-thickness idiopathic macular hole with reopening as a partial thickness macular defect.

Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1.

PURPOSE: To identify the genetic basis of a large consanguineous Spanish pedigree affected with autosomal recessive retinitis pigmentosa (arRP) with premature macular atrophy and myopia. METHODS: After a high-throughput cosegregation gene chip was used to exclude all known RP and Leber congenital amaurosis (LCA) candidates, genome-wide screening and linkage analysis were performed. Direct mutational screening identified the pathogenic mutation, and primers were designed to obtain the RT-PCR products for isoform characterization. RESULTS: Mutational analysis detected a novel homozygous PROM1 mutation, c.869delG in exon 8 cosegregating with the disease. This variant causes a frameshift that introduces a premature stop codon, producing truncation of approximately two-thirds of the protein. Analysis of PROM1 expression in the lymphocytes of patients, carriers, and control subjects revealed an aberrant transcript that is degraded by the nonsense-mediated decay pathway, suggesting that the disease is caused by the absence of the PROM1 protein. Three (s2, s11 and s12) of the seven alternatively spliced isoforms reported in humans, accounted for 98% of the transcripts in the retina. Given that these three contained exon 8, no PROM1 isoform is expected in the affected retinas. CONCLUSIONS: A remarkable clinical finding in the affected family is early macular atrophy with concentric spared areas. The authors propose that the hallmark of PROM1 truncating mutations is early and severe progressive degeneration of both rods and cones and highlight this gene as a candidate of choice to prioritize in the molecular genetic study of patients with noncanonical clinical peripheral and macular affectation.

Comprehensive SNP-chip for retinitis pigmentosa-Leber congenital amaurosis diagnosis: new mutations and detection of mutational founder effects.

Fast and efficient high-throughput techniques are essential for the molecular diagnosis of highly heterogeneous hereditary diseases, such as retinitis pigmentosa (RP). We had previously approached RP genetic testing by devising a chip based on co-segregation analysis for the autosomal recessive forms. In this study, we aimed to design a diagnostic tool for all the known genes (40 up to now) responsible for the autosomal dominant and recessive RP and Leber congenital amaurosis (LCA). This new chip analyzes 240 single nucleotide polymorphisms (SNPs) (6 per gene) on a high-throughput genotyping platform (SNPlex, Applied Biosystems), and genetic diagnosis is based on the co-segregation analysis of SNP haplotypes in independent families. In a single genotyping step, the number of RP candidates to be screened for mutations is considerably reduced, and in the most informative families, all the candidates are ruled out at once. In a panel of RP Spanish pedigrees, the disease chip became a crucial tool for selecting those suitable for genome-wide RP gene search, and saved the burdensome direct mutational screening of every known RP gene. In a large adRP family, the chip allowed ruling out of all but the causative gene, and identification of an unreported null mutation (E181X) in PRPF31. Finally, on the basis of the conservation of the SNP haplotype linked to this pathogenic variant, we propose that the E181X mutation spread through a cohort of geographically isolated families by a founder effect.

Identification of an intronic single-point mutation in RP2 as the cause of semidominant X-linked retinitis pigmentosa.

PURPOSE: A large family with 11 males and 2 females with X-linked retinitis pigmentosa (XLRP) was analyzed in search of pathologic mutations. METHODS: Of the two major XLRP genes, RPGR was analyzed by SNP cosegregation and RP2 was directly screened for mutations. The pathogenicity of a new variant was assessed in silico, in vivo, and in vitro. RESULTS: The results of cosegregation analysis with SNPs closely located to RPGR excluded this gene as the cause of the disease in this family. Sequencing of RP2 showed a putative pathogenic variant in intron 3 at the conserved polypyrimidine tract (c.1073-9T>A). This substitution cosegregated with the disease and was not found in 220 control chromosomes. In silico analyses using online resources indicated a decreased score of intron 3 acceptor splice site for the mutated sequence. Real-time RT-PCR analysis of the RP2 splicing pattern in blood samples of patients and carrier females showed skipping of exon 4, causing a frame shift that introduced a premature stop codon. Further verification of the pathogenicity of this point mutation was obtained by expression of a minigene RP2 construct in cultured cells. CONCLUSIONS: A transversion (T>A) at position -9 in intron 3 of RP2 causes XLRP by altering the splicing pattern and highlights the pathogenicity of intronic variants. The single point RP2 mutation leads to a wide range of phenotypic traits in carrier females, from completely normal to severe retinal degeneration, thus supporting that RP2 is also a candidate for semidominance in XLRP.