Prevalence, multimodal imaging and genotype-phenotype assessment of trauma related subretinal fibrosis in stargardt disease.

BACKGROUND AND OBJECTIVES: Stargardt disease produces lipofuscin accumulation predisposing to subretinal fibrosis (SRFib) after ocular trauma. Noninvasive imaging techniques allow in vivo assessment. The purpose of this study is to determine the prevalence of SRFib in a cohort of Stargardt patients, the presence of history of ocular trauma, the clinical features and possible genotype-phenotype associations in Stargardt patients with SRFib. METHODS: We evaluated retrospectively 106 Stargardt patients and analysed the multimodal imaging and the genotype of patients with SRFib. RESULTS: Six patients exhibited SRFib, three of them with history of ocular trauma. Multimodal imaging showed extensive SRFib principally in the temporal midperipheral retina with no fluid associated. SRFib was better defined by short wavelength autofluorescence and spectral domain optical coherence tomography and appeared clinically stable over time. There was no particular genotype associated to SRFib. CONCLUSION: SRFib occurs in a significant percentage of patients with Stargardt disease and can be diagnosed through multimodal imaging regardless the history of trauma, further sustaining the importance of an appropriate imaging in such patients. No genotype-phenotype association has been established, supporting the traumatic etiology in half of cases. The remaining cases may be classified as idiopathic or have a minimal trauma occurring early in life that may be not recalled by the patients.

Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

Novel p.M96T variant of NRL and shRNA-based suppression and replacement of NRL mutants associated with autosomal dominant retinitis pigmentosa.

Mutations in the gene encoding the transcription factor neural retina leucine zipper (NRL) are known to cause autosomal dominant (adRP) or recessive (arRP) retinitis pigmentosa (RP). In an adRP Spanish family, we detected a novel sequence variation (c.287T>C) in the NRL gene that results in the p.M96T protein change. A functional test of the ability of NRL, in conjunction with cone-rod homeobox (CRX), to transactivate a human rhodopsin (RHO) promoter was used to evaluate the pathogenic mechanisms of NRL. We found upregulation of the RHO promoter by p.M96T protein similar to that shown by other missense NRL mutations that cause adRP. Affected RP patients of the family carry the nucleotide change, although two other family members that also carry the c.287T>C variation remain asymptomatic. This result complicates the genetic counselling of the family. The pathogenic mechanisms associated with adRP NRL mutations appear to be caused by a gain of function. To suppress the negative effect of an NRL mutant, the suppression and replacement strategy seems to be the most suitable therapeutic approach capable of overcoming the mutational heterogeneity associated with NRL-linked adRP. Thus, we evaluated this methodology in the NRL gene for the first time.

[Quantifying and classifying postsurgical pain in pterygium surgery with conjunctival autografts]. / Cuantificación y cualificación del dolor postquirúrgico en la cirugía de pterigión con autoinjerto conjuntival.

OBJECTIVE: Quantify and define post-surgical pain after pterygium surgery with conjunctival autografts. MATERIAL AND METHODS: The study included 17 patients. The parameters analysed were, gender, age, pterygium TCL classification, primary characteristics or relapse, usage of isolated tissue adhesive or extra fixation with stitches. A visual analogue pain scale was used immediately after surgery, on the days 2 and 3 post-surgery, and the characteristics of the pain and the frequency of it in days 2 and 3 following the surgery. RESULTS: A total of 17 eyes of 17 patients were operated. The majority of patients (52.9%) showed moderate pain on the visual analogue scale immediately after surgery. On day 2 after surgery the pain level was mild in the majority of patients with characteristics of sharp pain and lash pain predominantly. On day 3 after surgery, mild pain was also predominant, with characteristics of stinging and lash pain in majority of patients. CONCLUSIONS: Using scales and pain characteristics we can quantify and define post-surgical pain after pterygium surgery with conjunctival auto-grafts resection immediately after surgery and in the following days.

Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype--phenotype correlation.

Patients with Usher syndrome type II (USH2) show moderate-to-severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype-genotype correlation exists regarding the issue of progression of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1--21) was performed in twenty-eight Spanish USH2 patients. Ten different pathogenic mutations and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels.

Choroideremia, sensorineural deafness, and primary ovarian failure in a woman with a balanced X-4 translocation.

We present clinical and cytogenetic studies of a female patient affected with choroideremia, mild sensorineural deafness, and primary amenorrhea showing a balanced translocation between chromosomes X and 4. The breakpoint was precisely defined applying FISH techniques: 46,X,t(X;4)(q21.2;p16.3).ish t(X;4)(D4S96+, D4F26+; wcpX+). The X-chromosomal breakpoint was located within a region where both the choroideremia locus and a deafness locus (DFN3/POU3F4) have been mapped. The presence of X-linked disorders in this balanced carrier of X-autosomal translocations (XAT) can be explained either by the disruption of the structural coding or regulatory sequences of the gene(s) or by the submicroscopic deletion of this region leading to a contiguous gene deletion syndrome. The primary ovarian failure (POF) found in the present case has been already observed in XAT when the breakpoint is within a previously defined critical region (Xq13-26). A position effect is postulated as a possible explanation.

Homozygous and heterozygous gly-188-Arg mutation of the rhodopsin gene in a family with autosomal dominant retinitis pigmentosa.

Autosomal dominant retinitis pigmentosa (adRP) may be caused by point mutations in the rhodopsin gene in up to 20% of Spanish families. Most of the rhodopsin mutations causing adRP have been reported in the heterozygous state. We describe a patient with adRP who is homozygous for a missense mutation at codon 188 in the second intradiscal domain of rhodopsin. All her sons are heterozygous for the mutation and show an RP phenotype suggesting complete penetrance for this mutation. The homozygous carrier of the mutation Gly-188-Arg in the rhodopsin gene showed a later subjective onset of symptoms than the heterozygotes, suggesting that the photoreceptor degeneration induced by the mutation is not dramatically influenced by mutant allele dosage.

Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2).

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

Novel mutations in the TULP1 gene causing autosomal recessive retinitis pigmentosa.

PURPOSE: To assess the contribution of TULP1 to autosomal recessive retinitis pigmentosa (arRP). METHODS: Fifteen exons of the gene were screened by single-strand conformation polymorphism analysis of 7 (of 49) arRP pedigrees showing cosegregation with TULP1 locus markers. RESULTS: In one of the seven families two allelic mutations, IVS4-2delAGA and c.937delC, were found in exons 5 and 10, respectively. CONCLUSIONS: Two novel mutations in TULP1 were found to be associated with arRP. That they both compromise the gene product supports their pathogenicity. This gene was present in no more than 2% of a panel of 49 Spanish families affected by arRP.

[Asp-190-Tyr mutation in the rhodopsin gene in a Spanish family with autosomic dominant pigmentary retinosis]. / Mutación Asp-190-Tyr en el gen de la rodopsina en una familia española afectada de retinosis pigmentaria autosómica dominante.

Mutations in the rhodopsin cause of retinitis pigmentosa autosomal dominant (ADRP). We report a large family affected with ADRP. Analysis by denaturant gradient gel electrophoresis and direct DNA sequence detected an heterozygous G to T transversion in the exon 3 of the rhodopsin gene. This mutation damages a restriction site for Taq I enzyme and produces the change Asp-190-Tyr in rhodopsin. All carriers of the mutation show a regional RP phenotype. This mutation is responsible for the disease in this family.

Ser186Pro mutation of RHO gene in a Spanish autosomal dominant retinitis pigmentosa (ADRP) family.

A Spanish family affected with autosomal dominant retinitis pigmentosa (ADRP) with a diffuse phenotype showed a mutation in the rhodopsin gene. The mutation was the transition T-->C in codon 186, which has been reported once before in an American patient (Dryja et al., Proc Natl Acad Sci USA 1991;88:9370-9374). This change replaces a serine by a proline in the second intradiscal loop of the protein, generating a molecule that is probably folding- and transport-defective.

Retinitis pigmentosa, mental retardation, marked short stature, and brachydactyly in two sibs.

We present two siblings with retinitis pigmentosa, mental retardation, markedly short stature, and brachydactyly. This association of clinical findings appears to be distinct from previously described syndromes and seems to represent the pleiotropic effects of a single autosomal recessive gene.

Detection of a novel Cys628STOP mutation of the myosin VIIA gene in Usher syndrome type Ib.

A Spanish family with three Usher I syndrome-affected members was linked to markers located on chromosome 11q. A search for mutations on the myosin VIIA gene revealed a novel mutation (Cys628STOP) on exon 16 segregating with the disorder in a homozygous state. This nonsense mutation could be responsible for the disease since it leads to a truncated protein that presumably has no function.

[The Pro347Leu mutation of the rhodopsin gene in a Spanish family with autosomal dominant pigmentary retinosis]. / Mutación Pro347Leu del gen de la rodopsina en una familia española con retinosis pigmentaria autosómica dominate.

We present a Spanish family affected with autosomal dominant pigmentary retinosis in which we have identified the mutation responsible for the disease (Pro347Leu) within the rhodopsin (RHO) gene. Complete ophthalmological and electrophysiological studies were performed in 14 members of this family. The molecular study, performed by SSCP analysis of the 5 exon and the promotor region of the rhodopsin gene, direct sequentiation and restriction analysis with the enzyme Mspl, showed a C-->T change in the second base of 347 codon of RHO gene. This mutation predicts a change of proline by leucine at this position. Every patient with the mutation showed a phenotype of diffuse, early onset and severe pigmentary retinosis with a little intrafamiliar variation. The Pro347Leu mutation, that has been very frequently described among all the populations, has been identified as a cause of RP in an Spanish family.

Three novel RDS-peripherin mutations (689delT, 857del17, G208D) in Spanish families affected with autosomal dominant retinal degenerations. Mutations in brief no. 147. Online.

Among 43 unrelated Spanish patients affected with autosomal dominant (AD) photoreceptor disorders a study of RDS-peripherin gene was performed. We found three different unreported mutations 689delT, 857del17, corresponding to two macular dystrophy families and G208D in a retinitis pigmentosa (RP) family giving us a proportion of about 20% of RDS mutations in autosomal dominant Spanish macular dystrophies and 3% in ADRP.