Maria Carolina Ortube

Ocular manifestations of oblique facial clefts.

Introduction:In the Tessier classification, craniofacial clefts are numbered from 0 to 14 and extend along constant axes through the eyebrows, eyelids, maxilla, nostrils, and the lips. We studied a patient with bilateral cleft 10 associated with ocular abnormalities. Method:Clinical report with orbital and cranial computed tomography. Results:After pregnancy complicated by oligohydramnios, digoxin, and lisinopril exposure, a boy was born with facial and ocular dysmorphism. Examination at age 26 months showed bilateral epibulbar dermoids, covering half the corneal surface, and unilateral morning glory anomaly of the optic nerve. Ductions of the right eye were normal, but the left eye had severely impaired ductions in all directions, left hypotropia, and esotropia. Under anesthesia, the left eye could not be rotated freely in any direction. Bilateral Tessier cleft number 10 was implicated by the presence of colobomata of the middle third of the upper eyelids and eyebrows. As the cleft continued into the hairline, there was marked anterior scalp alopecia. Computed x-ray tomography showed a left middle cranial fossa arachnoid cyst and calcification of the reflected tendon of the superior oblique muscle, trochlea, and underlying sclera, with downward and lateral globe displacement. Discussion:Tessier 10 clefts are very rare and usually associated with encephalocele. Bilateral 10 clefts have not been reported previously. In this case, there was coexisting unilateral morning glory anomaly and arachnoid cyst of the left middle cranial fossa but no encephalocele. Conclusions:Bilateral Tessier facial cleft 10 may be associated with alopecia, morning glory anomaly, epibulbar dermoids, arachnoid cyst, and restrictive strabismus.

Whole exome sequencing detects homozygosity for ABCA4 p.Arg602Trp missense mutation in a pediatric patient with rapidly progressive retinal dystrophy

BackgroundA pediatric patient presented with rapidly progressive vision loss, nyctalopia and retinal dystrophy. This is the first report of homozygosity for the p.Arg602Trp mutation in the ABCA4 gene. The child became legally blind within a period of 2 years.Case presentationAn eight year-old Hispanic female presented with bilateral decreased vision following a febrile gastrointestinal illness with nausea and vomiting. Extensive workup involved pediatric infectious disease and rheumatology consultations.Initial visual acuity was 20/60 at distance and 20/30 at near in both eyes. Rapidly progressive vision loss occurred during a 2-year period resulting in visual acuities of 20/200 at distance in both eyes. Fundus exam disclosed attenuated vessels and multiple subretinal blister-like elevations. Optical coherence tomography showed far more lesions than were clinically evident with different levels of elevation. Autofluorescence imagery showed dramatic and widespread geographic areas of atrophy. The deposits that appeared drusen-like on clinical exam were hyperfluorescent, consistent with lipofuscin deposits containing A2e (N-retinylidene-N-retinylethanolamine) indicative of RPE cell dysfunction. Electroretinography was consistent with cone dystrophy, with relative preservation of rod function. Blood analysis and rheumatology evaluation found no evidence of a diffuse post-infectious/inflammatory process. The unique and rapid progression of her subretinal blister-like lesions was documented by fluorescein angiography, optical coherence tomography, autofluorescence imagery, and fundus photography. Family pedigree history disclosed consanguinity, her parents being first cousins. DNA analysis by whole exomic sequencing revealed homozygosity of p.Arg602Trp in the ABCA4 gene.ConclusionThe pediatric patient presented with a striking clinical appearance and dramatic rate of progression that was clinically more characteristic of an infectious or inflammatory process. This case expands the diverse range of phenotypes attributed to ABCA4 mutations and further supports the role of whole exome sequencing as a powerful new tool available to aid clinicians in establishing diagnosis for challenging cases.

Comparative regional pupillography as a noninvasive biosensor screening method for diabetic retinopathy.

PURPOSE We describe infrared regional pupillometry as an objective comparative assessment of midperipheral to central retinal sensitivity and to correlate with midperipheral retinal ischemia in diabetic subjects. METHODS We tested 12 normal and 17 diabetic subjects using bilateral infrared pupillometry. The diabetic cohort included seven subjects without, five with mild, three with moderate, and two with severe non-proliferative diabetic retinopathy (NPDR). Central and annular stimuli of varying intensity were presented to one eye, and pupillary amplitude and constriction velocity were measured from both eyes. Light stimulus of increasing intensity was presented as 20 consecutive trials (stimulus duration of 300 ms with 3000 ms intervals). The ratio of central to peripheral responses (Q values) was calculated for each stimulus configuration. Average responses with respect to the stimulus strength were regressed with Gompertz sigmoid function. RESULTS Control and moderate/severe NPDR cases comparison showed statistically significant differences in amplitude (Q(A)) and constriction velocity (Q(CV)) (Wilcoxon rank sum test P = 0.002, respectively). Age difference for these groups was not statistically significant (Wilcoxon rank sum test P = 0.15). The comparison of control and diabetic subjects without NPDR/mild NPDR was statistically significant for Q(A) and Q(CV) (Wilcoxon rank sum test P = 0.0002 and P = 0.001, respectively). Q(A) and Q(CV) differences were statistically significant between moderate/severe NPDR cases and subjects without or mild NPDR cases (Wilcoxon rank sum test P = 0.013). CONCLUSIONS Q(A) and Q(CV) values correlated highly with the severity of diabetic retinopathy, but not with the duration of diabetes.

Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease

The key to reducing the individual and societal burden of age-related macular degeneration (AMD)-related vision loss, is to be able to initiate therapies that slow or halt the progression at a point that will yield the maximum benefit while minimizing personal risk and cost. There is a critical need to find clinical markers that, when combined with the specificity of genetic testing, will identify individuals at the earliest stages of AMD who would benefit from preventive therapies. These clinical markers are endophenotypes for AMD, present in those who are likely to develop AMD, as well as in those who have clinical evidence of AMD. Clinical characteristics associated with AMD may also be possible endophenotypes if they can be detected before or at the earliest stages of the condition, but we and others have shown that this may not always be valid. Several studies have suggested that dynamic changes in rhodopsin regeneration (dark adaptation kinetics and/or critical flicker fusion frequencies) may be more subtle indicators of AMD-associated early retinal dysfunction. One can test for the relevance of these measures using genetic risk profiles based on known genetic risk variants. These functional measures may improve the sensitivity and specificity of predictive models for AMD and may also serve to delineate clinical subtypes of AMD that may differ with respect to prognosis and treatment.

A Novel Web-Based Clinical Research Tool for a Nationwide Research Study

Objective: To describe a web-based clinical research tool designed for a nationwide genetic study aiming to enroll individuals with Age-Related Macular Degeneration (ARM) and their adult children. Materials and Methods: The web-based system incorporates an IRB-approved online Informed Consent (IC) process and can handle multiple participants with simultaneous online surveys. The web interface is scripted in Hypertext Preprocess format (PHP), Asynchronous JavaScript and XML (AJAX) and integrated into a FileMaker (v11.0) backend database that allows for research staff customization. The system complies with Health Insurance Portability and Accountability Act (HIPAA) and works with a Secure Socket Layer (SSL). It provides a firewalled intranet for communication with the participants and addresses the design of a comprehensive family pedigree as well as the integration of branch logic questionnaires. Results: The web based observational study (url: https://jseiclinres.jsei.ucla.edu/garm/) was launched in August 2009 and a total of 543 participants were enrolled in the study as of December 2012. Physicians are able to upload participant’s eye records and images to the system using an encrypted File Transfer Protocol (FTP) server. Discussion: The current system requires FileMaker programming expertise in order to be used for other studies. Future enhancements include the creation of simple templates to customize the database and automatic scripts for exporting de-identified clinical data to a central repository. Conclusion: Our web-based research tool complies with federal guidelines for electronic protected health information. It offers a useful approach to conduct a web-based research study or disease-registry while creating a user-friendly interface for the participants. Journal of Clinical Research Bioethics J o u r n a l o f C lin ical Resrch& Bioe t h i c s

Orbital ectopic brain tissue in Aicardi syndrome.

Background:Aicardi syndrome is a cerebroretinal disorder originally described in 1965. Its salient clinical features are infantile spasms, agenesis of corpus callosum, hypsarrhythmia, and a pathognomonic optic disc appearance consisting of multiple depigmented chorioretinal lacunae clustered around the disc. Methods:Clinical report with cranial computed tomography and biopsy results. Results:A 3-year-old female patient presented with Aicardi syndrome and progressive proptosis of the left eye since birth. Visual acuity was light perception only in the right eye. Ocular motility examination showed large angle of left exotropia. Direct funduscopy showed a large optic nerve head and chorioretinal lacunae in the right eye; the left eye was not visible. Magnetic resonance imaging detected a large retrobulbar cyst and left microphthalmia. The patient underwent neurosurgery. Intraoperative microscopic dissection of the dural membrane led to exposure of an underlying cyst, which was 80% resected. Biopsies of walls of the orbital cyst showed fragments of neuroglial and meningothelial tissues with some calcification and mild chronic inflammation. Psammoma bodies were identified. The diagnosis was heterotopic brain tissue. Conclusions:Heterotopia of brain tissue within the orbits is a very rare finding. Two previous reports have described an orbital cyst in association with Aicardi syndrome, both attributed to encephaloceles. We report a very rare case of heterotopia of brain tissue in Aicardi syndrome. The patient did not have an encephalocele.

Genetic ME–a visualization application for merging and editing pedigrees for genetic studies

BackgroundIn order to study the genetics of diseases more accurately and effectively, one often collects large families. Different members of a large family may provide differing information about the structure and make-up of their pedigree. Thus, software is needed to facilitate reconciliation of pedigrees collected independently from multiple informants from a single large family to create a unified pedigree that is based on the best composite information available.FindingsOur implementation demonstrates that Genetic ME performs merging in terms of adding, replacing and combining information from two pedigrees. Through a tracking process, all of the changes made to the data set for the individuals can be traced back to their original source material. A new pedigree structure can be easily visualized while reconciling disparate information from multiple pedigrees.MethodsWe developed the Genetic Merging & Editing (Genetic ME) program, an open source Java application built on top of CraneFoot and Ghostscript, to support comparing, editing and merging of pedigrees collected from multiple sources in a visually-oriented manner.ConclusionsGenetic ME constitutes an ideal addition to software packages for reconciling pedigree information from multiple sources. Genetic ME provides a friendly graphical user interface, traces the changes made by users, and produces viewable merged pedigree structures able to be further used by other popular analysis programs.