BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

Ultrasonographic features of PMEL17 ( Silver ) mutant gene-associated multiple congenital ocular anomalies (MCOA) in Comtois and Rocky Mountain horses

OBJECTIVE: (1) To describe the ultrasonographic appearance of multiple congenital ocular anomalies (MCOA) in the eyes of horses with the PMEL17 (Silver) mutant gene. (2) To compare the accuracy of B-mode ocular ultrasound to conventional direct ophthalmoscopy. ANIMALS STUDIED: Sixty-seven Comtois and 18 Rocky Mountain horses were included in the study. PROCEDURES: Horses were classified as being carriers or noncarriers of the PMEL17 mutant allele based on coat color or genetic testing. Direct ophthalmoscopy followed by standardized ultrasonographic examination was performed in all horses. RESULTS: Seventy-five of 85 horses (88.24%) carried at least one copy of the Silver mutant allele. Cornea globosa, severe iridal hypoplasia, uveal cysts, cataracts, and retinal detachment could be appreciated with ultrasound. Carrier horses had statistically significantly increased anterior chamber depth and decreased thickness of anterior uvea compared with noncarriers (P < 0.05). Uveal cysts had a wide range of location and ultrasonographic appearances. In 51/73 (69.86%) carrier horses, ultrasound detected ciliary cysts that were missed with direct ophthalmoscopy. CONCLUSIONS: In this study, ultrasonography was useful to identify uveal cysts in PMEL17 mutant carriers and to assess anterior chamber depth.

Deletion 5q12: Delineation of a Phenotype Including Mental Retardation and Ocular Defects

Array-CGH enables the detection of submicroscopic chromosomal deletions and duplications and leads to an accurate delineation of the imbalances, raising the possibility of correlating genotype to phenotype and mapping minimal critical regions associated with particular patterns of clinical features. We report here on four patients sharing common clinical features (psychomotor retardation, coarse facies and ocular anomalies), with proximal 5q deletions identified by oligo array-CGH. The deletions range from 5.75 to 17.26-Mb in size and occurred de novo. A common 2.63-Mb region between the deletions described here can be defined in 5q12.1 (59,390,122-62,021,754 bp bp from 5pter, hg18) and includes 12 genes. Among them, KIF2A, which encodes a kinesin superfamily protein, is a particularly interesting candidate for the phenotype, as it suppresses the growth of axonal collateral branches and is involved in normal brain development. Ocular defects, albeit unspecific, seem to be common in the 5q12.1 deletion. Identification of additional cases of deletions involving the 5q12.1 region will allow more accurate genotype-phenotype correlations. (C) 2011 Wiley-Liss, Inc.

Decreased Perifoveal Sensitivity Detected by Microperimetry in Patients Using Hydroxychloroquine and without Visual Field and Fundoscopic Anomalies

Purpose. To evaluate the usefulness of microperimetry in the early detection of the ocular anomalies associated with the use of hydroxychloroquine. Methods. Prospective comparative case series study comprising 14 healthy eyes of 7 patients (group A) and 14 eyes of 7 patients under treatment with hydroxychloroquine for the treatment of rheumatologic diseases and without fundoscopic or perimetric anomalies (group B). A comprehensive ophthalmological examination including microperimetry (MP) and spectraldomain optical coherence tomography was performed in both groups. Results. No significant differences were found in mean MP foveal sensitivity between groups (P = 0.18). However, mean MP overall sensitivity was significantly higher in group A (29.05 ± 0.57 dB versus group B, 26.05 ± 2.75 dB; P < 0.001). Significantly higher sensitivity values were obtained in group A in comparison to group B for the three eccentric loci evaluated (P < 0.001). Conclusion. Microperimetry seems to be a useful tool for the early detection of retinal damage in patients treated with hydroxychloroquine.

Clinical evaluation and COL2A1 gene analysis in 21 Brazilian families with Stickler syndrome: Identification of novel mutations, further genotype/phenotype correlation, and its implications for the diagnosis

We present clinical and molecular evaluation from a large cohort of patients with Stickler syndrome: 78 individuals from 21 unrelated Brazilian families. The patients were selected in a Hospital with a craniofacial dysmorphology assistance service and clinical diagnosis was based on the presence of cleft palate associated to facial and ocular anomalies of Stickler syndrome. Analysis of COL2A1 gene revealed 9 novel and 4 previously described pathogenic mutations. Except for the mutation c.556G>T (p.Gly186X), all the others were located in the triple helical domain. We did not find genotype/phenotype correlation in relation to type and position of the mutation in the triple helical domain. However, a significantly higher proportion of myopia in patients with mutations located in this domain was observed in relation to those with the mutation in the non-tripe helical domain (c.556G>T; P < 0.04). A trend towards a higher prevalence of glaucoma, although not statistically significant, was observed in the presence of the mutation c.556G>T. It is possible. that this mutation alters the splicing of the mRNA instead of only creating a premature stop codon and therefore it can lead to protein products of different ocular effects. One novel DNA variation (c.1266+7G>C) occurs near a splice site and it was observed to co-segregate with the phenotype in one of the two families with this DNA variation. As in silico analysis predicted that the c.1266+7G>C DNA variation can affect the efficiency of the splicing, we still cannot rule it out as non-pathogenic. Our study also showed that ascertainment through cleft palate associated to other craniofacial signs can be very efficient for identification of Stickler syndrome patients. Still, high frequency of familial cases and high frequency of underdevelopment of distal lateral tibial epiphyses observed in our patients suggested that the inclusion of this information can improve the clinical diagnosis of Stickler syndrome. (C) 2008 Elsevier Masson SAS. All rights reserved.

Avaliação psico-educacional de uma adolescente portadora da síndrome de Sturge-Weber

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Importance of early diagnosis of Stickler syndrome in newborns

Objective: The study aims to investigate a possible correlation between the main clinical and ophthalmological characteristics, age and Robin sequence in patients with the Stickler syndrome. Introduction: The Stickler syndrome is an autosomal dominant genetic disorder, characterised by ocular, orofacial and skeletal anomalies and/or auditory loss. Patients with Robin sequence features and respiratory complications are frequently diagnosed with the Stickler syndrome. The heterogeneous phenotypic manifestations may present a challenge for early clinical diagnosis. Methods: We performed a retrospective study of the 98 patients with the Stickler syndrome, between November 1995 and June 2009. The data were compared to investigate their ocular alterations and association with the Robin sequence. To be included, patients had to present with the following triad: cleft palate, facial features (hypoplastic midface, micrognathia and prominent eyes) and ocular anomalies (myopia and/or abnormalities of the retina). Results: Fifty-one percent of the patients presenting with Robin sequence features had been diagnosed with the Stickler syndrome. Ocular alterations were found in 50% of the patients. Discussion: The Robin sequence may appear as an isolated condition or associated with other features, or else as part of other known syndromes. Currently, the diagnosis of the Stickler syndrome is based on clinical signs. Affected individuals eventually develop hearing loss, retinal detachment and blindness. The ophthalmological complications associated are usually progressive and can lead to blindness.

Aniridia congénita familiar : caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

School vision screening, ages 5-16 years:The evidence-base for content, provision and efficacy

The optometric profession in the UK has a major role in the detection, assessment and management of ocular anomalies in children between 5 and 16 years of age. The role complements a variety of associated screening services provided across several health care sectors. The review examines the evidence-base for the content, provision and efficacy of these screening services in terms of the prevalence of anomalies such as refractive error, amblyopia, binocular vision and colour vision and considers the consequences of their curtailment. Vision screening must focus on pre-school children if the aim of the screening is to detect and treat conditions that may lead to amblyopia, whereas if the aim is to detect and correct significant refractive errors (not likely to lead to amblyopia) then it would be expedient for the optometric profession to act as the major provider of refractive (and colour vision) screening at 5-6 years of age. Myopia is the refractive error most likely to develop during primary school presenting typically between 8 and 12 years of age, thus screening at entry to secondary school is warranted. Given the inevitable restriction on resources for health care, establishing screening at 5 and 11 years of age, with exclusion of any subsequent screening, is the preferred option. © 2004 The College of Optometrists.

Malformations of Cortical Development in Patients With Mid line Facial Defects and Ocular Hypertelorism

Objectives: We studied the neuroimaging and neurophysiological aspects of 17 patients with midline facial defects with ocular hypertelorism (MFDH). Methods: The investigation protocol included a previous semistructured questionnaire about family history; gestational, neonatal, and postnatal development; and dysmorphologic and neurologic evaluation. Recognized monogenic disorders and individuals with other well-known conditions were excluded. All patients had high resolution magnetic resonance imaging (MRI) with multiplanar reconstruction (MPR) and routine electroencephalograms (EEGs). Results: We detected abnormalities in five patients whose MRIs had been previously reported as normal. MRI showed central nervous system (CNS) structural abnormalities in all patients, which included commissural alterations in 16/17 (94%), malformations of cortical development in 10/17 (58%), disturbances of neural tube closure in 7/17(42%), and posterior fossa anomalies in 6/17 (35%). Some patients had more than one type of malformation occurring at different stages of the embryonary process. EEGs showed epileptiform activity in 4/17 (24%) and background abnormalities in 5/17 (29%) of patients. Conclusion: This study clearly demonstrated the presence of structural and functional neurologic alterations related to MFDH. Therefore, the CNS anomalies cannot be considered incidental findings but an intrinsic part of this condition, which could be related to environmental effects and/or genetic mutations. These findings would provide a basis for future investigations on MFDH and should also be considered when planning rehabilitation.

Reading performance in children with visual function anomalies

Aims - To compare reading performance in children with and without visual function anomalies and identify the influence of abnormal visual function and other variables in reading ability. Methods - A cross-sectional study was carried in 110 children of school age (6-11 years) with Abnormal Visual Function (AVF) and 562 children with Normal Visual Function (NVF). An orthoptic assessment (visual acuity, ocular alignment, near point of convergence and accommodation, stereopsis and vergences) and autorefraction was carried out. Oral reading was analyzed (list of 34 words). Number of errors, accuracy (percentage of success) and reading speed (words per minute - wpm) were used as reading indicators. Sociodemographic information from parents (n=670) and teachers (n=34) was obtained. Results - Children with AVF had a higher number of errors (AVF=3.00 errors; NVF=1.00 errors; p<0.001), a lower accuracy (AVF=91.18%; NVF=97.06%; p<0.001) and reading speed (AVF=24.71 wpm; NVF=27.39 wpm; p=0.007). Reading speed in the 3rd school grade was not statistically different between the two groups (AVF=31.41 wpm; NVF=32.54 wpm; p=0.113). Children with uncorrected hyperopia (p=0.003) and astigmatism (p=0.019) had worst reading performance. Children in 2nd, 3rd, or 4th grades presented a lower risk of having reading impairment when compared with the 1st grade. Conclusion - Children with AVF had reading impairment in the first school grade. It seems that reading abilities have a wide variation and this disparity lessens in older children. The slow reading characteristics of the children with AVF are similar to dyslexic children, which suggest the need for an eye evaluation before classifying the children as dyslexic.

Ocular biocompatibility of a poly(ortho ester) characterized by autocatalyzed degradation.

The biocompatibility of autocatalyzed poly(ortho ester) (POE(70)LA(30)), a viscous, hydrophobic, bioerodible polymer, was investigated. POE(70)LA(30) was synthesized, sterilized by gamma irradiation, and injected in rabbit eyes at adequate volumes through subconjunctival, intracameral, intravitreal, and suprachoroidal routes. Clinical examinations were performed postoperatively at regular time points for 6 mo, and histopathologic analysis was carried out to confirm tissular biocompatibility. After subconjunctival injection, the polymer was well tolerated and persisted in the subconjunctival space for about 5 weeks. In the case of intracameral injections, polymer biocompatibility was good; the POE(70)LA(30) bubble was still present in the anterior chamber for up to 6 mo after injection. No major histopathologic anomalies were detected, with the exception of a localized Descemet membrane thickening. After intravitreal administration, POE(70)LA(30) biocompatibility was excellent, and no inflammatory reaction could be detected during the observation period. The polymer was degraded in approximately 3 mo. Suprachoroidal injections of POE(70)LA(30) were reproducible and well tolerated. POE(70)LA(30) triggered a slight elevation of the retina and choroid upon clinical observation. The polymer was detectable in the suprachoroidal space for about 6 mo. No inflammatory reaction and no major retinal anomalies could be detected by histology. In conclusion, POE(70)LA(30) appears to be a promising biomaterial for intraocular application, potentially providing sustained drug delivery over an extended period of time, with a good tolerance.

UBE2A Deficiency Syndrome: Mild to Severe Intellectual Disability Accompanied by Seizures, Absent Speech, Urogenital, and Skin Anomalies in Male Patients

We describe three patients with a comparable deletion encompassing SLC25A43, SLC25A5, CXorf56, UBE2A, NKRF, and two non-coding RNA genes, U1 and LOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures, and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge. These clinical features overlap with those described in two patients from a family with a similar deletion at Xq24 that also includes UBE2A, and in several patients of Brazilian and Polish families with point mutations in UBE2A. Notably, all five patients with an Xq24 deletion have ventricular septal defects that are not present inpatients with a point mutation, which might be attributed to the deletion of SLC25A5. Taken together, the UBE2A deficiency syndrome in male patients with a mutation in or a deletion of UBE2A is characterized by ID, absent speech, seizures, urogenital anomalies, frequently including a small penis, and skin abnormalities, which include generalized hirsutism, low posterior hairline, myxedematous appearance, widely spaced nipples, and hair whorls. Facial dysmorphisms include a wide face, a depressed nasal bridge, a large mouth with downturned corners, thin vermilion, and a short, broad neck. (C) 2010 Wiley-Liss, Inc.

The role of LMX1B and PITX2 in anterior segment development and adult ocular function

Several congenital syndromes associated with anterior segment (AS) anomalies can lead to impaired vision and glaucoma, such as nail-patella syndrome (NPS), caused by mutations in the LIM homeodomain transcription factor LMX1B and Axenfeld-Rieger's syndrome (ARS), caused by mutations in the bicoid-related homeodomain transcription factor PITX2. Targeted mutations in lmx1b and pitx2 and RNA in situ analysis reveal that both genes are required for AS development and are co-expressed within the periocular mesenchyme, suggesting they participate in a shared genetic pathway. Lmx1b homozygous mutants display iris and corneal stroma hypoplasia, and defects in ciliary body formation. In contrast, pitx2 homozygous mutants exhibit a more severe phenotype: the AS chamber, corneal endothelium, and extraocular muscles (EOM) fail to develop. The absence of EOM in pitx2 mutants suggests pitx2 acts upstream of lmx1b, or that other lmx1b family members, such as lmx1a, can compensate for lmx1b function. Lmxla/lmx1b double homozygous mutants have a reduced capacity to generate EOM, implying that lmx1 gene products have a redundant function in EOM development and that lmx1 family members may act downstream of pitx2. However, analysis of pitx2 expression in the AS tissues of lmx1b mutants and reciprocal studies of lmx1b expression in pitx2 mutants indicate that these genes do not function in a simple linear pathway. Instead, lmx1b and pitx2 may regulate a shared set of downstream targets or both genes may work in parallel transcribing unique targets required for a common biological process. Ultrastructural analysis of lmx1b and pitx2 mutant corneas indicates that collagen fibrillogenesis is perturbed, revealing a common role for both genes in the deposition of extracellular matrix. Furthermore, lmx1b/pitx2 double heterozygotes develop corneal opacities not observed in single heterozygotes demonstrating that lmx1b and pitx2 genetically interact. Data suggests that defects in the basement membrane of the corneal endothelium underlie the opacities observed in double heterozygotes. Additionally, double heterozygotes develop anterior synechias that occlude the trabecular meshwork, potentially blocking aqueous humor drainage. These data suggest that lmx1b and pitx2 are responsible for ECM deposition in multiple cell types and imply that such defects may contribute to the glaucomas observed in NPS and ARS patients. ^