Irene H. Maumenee

Gene Therapy in Patient-specific Stem Cell Lines and a Preclinical Model of Retinitis Pigmentosa With Membrane Frizzled-related Protein Defects

Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naïve human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrp(rd6)/Mfrp(rd6) mice--an established preclinical model of RP--and long-term improvement in visual function was observed in AAV-Mfrp-treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines, and the Mfrp(rd6)/Mfrp(rd6) preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.

Biometry Characteristics in Adults and Children With Marfan Syndrome: From the Marfan Eye Consortium of Chicago

PURPOSEnTo report on the biometric findings of adults and children with Marfan syndrome (MFS) recruited from 2 annual National Marfan Foundation conferences (2012 and 2015).nnnDESIGNnCross-sectional study.nnnMETHODSnSubjects diagnosed with MFS by Ghent 2 nosology were included for analysis. Subjects were divided into adults (≥16 years of age) and children (5-15 years of age). Biometric data included values for refractive error, axial length (AL), corneal curvature, anterior chamber depth, lens thickness, and central corneal thickness.nnnRESULTSnOf the 117 subjects evaluated, 74 (35 adults, 32 children, and 7 children <5 years of age) had a definite diagnosis of MFS and were included in the study. The AL was longer (25.25 ± 0.32xa0mm vs 24.24 ± 0.33xa0mm, Pxa0= .03) and the lens was thicker (3.94 ± 0.09xa0mm vs 3.62 ± 0.10xa0mm, Pxa0= .03) in adults. Both groups had flat corneas (average keratometry [Kmed] of 41.59 ± 0.35 diopters [D] in adults vs 40.89 ± 0.36 D in children, Pxa0= .17). A negative correlation was found between AL and Kmed (-0.33, P < .001). The corneas of patients with MFS with ectopia lentis (EL) were significantly flatter and with higher degree of corneal astigmatism compared to patients without EL (Kmed of 40.68 ± 0.31 D vs 41.75 ± 0.28 D, P < .01 and corneal astigmatism of 1.68 ± 0.16 D vs 1.13 ± 0.14 D, Pxa0= .01).nnnCONCLUSIONSnChildren with established MFS have flat corneas at least to the same degree as adults. Corneas of patients with MFS with EL are flatter and have a higher degree of corneal astigmatism. We strongly suggest that corneal parameters should be measured if MFS is suspected, especially in children that may not yet have developed EL.

Osteogenesis Imperfecta and the Eye

While the many skeletal, auditory, dental and other anomalies in osteogenesis imperfecta (OI) have been well documented in the medical literature, the eye and the visual system are also commonly affected in patients with OI. As type I collagen fibers are also found in ocular structures including the cornea and sclera, eyes in OI patients may have corneal thinning and blue sclerae to different degrees related to the severity of altered type I collagen synthesis as a result of OI. More severe ocular and visual system problems may also be related to OI and lead to significant visual impairment. Ocular and visual pathway problems reported in OI patients include corneal disorders, glaucoma, retinal detachment, optic neuropathy and others. This chapter provides an overview of the range of eye and vision-related pathologies found in patients with OI. This chapter (1) reviews the basic anatomy of the eye and visual system for background, (2) provides a literature review of case reports, case series and clinical studies that relate to the eye and visual pathways in OI, (3) shares results from an eye survey of OI patients from the Kennedy Krieger Institute and (4) makes general recommendations regarding eye care for OI patients.

Retinal disease in marfan syndrome: From the marfan eye consortium of Chicago

BACKGROUND AND OBJECTIVEnTo study the prevalence of peripheral retinal disease in patients with Marfan Syndrome (MFS).nnnPATIENTS AND METHODSnIn this observational, cross-sectional case series, patients with MFS were recruited by the Marfan Eye Consortium of Chicago during the National Marfan Foundations annual conference. Patients underwent a fully dilated exam by vitreoretinal specialists in addition to ultra-widefield fundus photography using a scanning laser ophthalmoscope (Optos 200Tx; Optos PLC, Dunfermline, Scotland, United Kingdom).nnnRESULTSnClinical examination revealed posterior segment pathology in 18% of eyes with increased incidence to 70% in patients with a subluxed lens. In six out of 10 subjects in whom the clinical exam was suboptimal (young age, small pupil, and limited cooperation), the Optos provided a superior view of the peripheral retina compared to clinical exam alone.nnnCONCLUSIONnClinical exam of MFS patients revealed similar posterior segment pathology as noted in previous literature, with improved detection of peripheral retinal disease with the use of ultra-widefield imaging.

Systemic diagnostic testing in patients with apparently isolated uveal coloboma.

PURPOSEnTo investigate the frequency and types of systemic findings in patients with apparently isolated uveal coloboma.nnnDESIGNnCross-sectional observational study.nnnMETHODSnsetting: Single-center ophthalmic genetics clinic. study population: Ninety-nine patients with uveal coloboma seen at the National Eye Institute. observational procedure: Results of audiology testing, echocardiogram, brain magnetic resonance imaging, renal ultrasound, and total spine radiographs. main outcome measure: Prevalence of abnormal findings on systemic testing.nnnRESULTSnUveal coloboma affected only the anterior segment in 8 patients, only the posterior segment in 23 patients, and both anterior and posterior segments in 68 patients. Best-corrected visual acuity (BCVA) of eyes with coloboma was ≥20/40 in 45% of eyes; 23% of eyes had BCVA of ≤20/400. The majority of patients (74%) had good vision (>20/60) in at least 1 eye. Ten of the 19 patients (53%) who underwent echocardiography had abnormalities, with ventral septal defects being the most prevalent. Abnormal findings were observed in 5 of 72 patients (7%) who had a renal ultrasound and in 5 of 29 patients (17%) who underwent a brain MRI. Audiology testing revealed abnormalities in 13 of 75 patients (17%), and spine radiographs showed anomalies in 10 of 77 patients (13%). Most findings required no acute intervention.nnnCONCLUSIONSnAlthough some patients with coloboma had evidence of extraocular abnormalities, the majority of findings on routine clinical examination did not require acute intervention, but some warranted follow-up. Results from the systemic evaluation of patients with coloboma should be interpreted with caution and in view of their clinical context.

Congenital cavitary optic disc anomaly and Axenfeld’s anomaly in Wolf-Hirschhorn syndrome: A case report and review of the literature

ABSTRACT Background: Wolf-Hirschhorn syndrome is a rare genetic syndrome caused by a heterozygous deletion on chromosome 4p16.3 and is characterized by a “Greek warrior helmet” facies, hypotonia, developmental delay, seizures, structural central nervous system defects, intrauterine growth restriction, sketelal anomalies, cardiac defects, abnormal tooth development, and hearing loss. A variety of ocular manifestations may occur in up to 40% of patients. Materials/methods: We report the genetic testing results, systemic findings, and complete ophthalmologic examination findings in a patient with Wolf-Hirschhorn syndrome, including external photography, RetCam3 (Clarity Medical Systems, Pleasonton, CA) goniography, and fundus photography. In addition, we review the literature on ocular manifestations of Wolf-Hirschhorn syndrome. Results: Microarray analysis revealed an unbalanced translocation between 4p16.3–15.3 and Xp22.33-p22.2. Systemic findings included “Greek warrior helmet” facies, hypotonia, cleft palate, neonatal tooth eruption, talipes equinovarus, bilateral clinodactyly, clitoromegaly, partial agenesis of the corpus callosum, bilateral renal hypoplasia, and two atrial septal defects. Ocular findings included normal intraocular pressures and corneal diameters, large-angle exotropia, downward slanting of the palpebral fissures, absent eyelid creases, upper and lower eyelid retraction with shortage of the anterior eyelid lamellae, euryblepharon, lagophthalmos with poor Bell’s reflex and exposure keratopathy, hypertelorism, Axenfeld’s anomaly, megalopapillae, and cavitary optic disc anomaly. Conclusions: We describe the ocular phenotype of a patient with Wolf-Hirschhorn syndrome, including the rare descriptions and photographs of Axenfeld’s anomaly, megalopapilla, and cavitary optic disc anomaly in this condition.

Comparative data on SD-OCT for the retinal nerve fiber layer and retinal macular thickness in a large cohort with Marfan syndrome

ABSTRACT Purpose: To report the distribution of macular and optic nerve topography in the eyes of individuals with Marfan syndrome aged 8–56 years using spectral domain optical coherence tomography (SD-OCT). Methods: Thirty-three patients with Marfan syndrome underwent a full eye examination including slit-lamp biomicroscopy, indirect ophthalmoscopy, and axial length measurement; and SD-OCT measurements of the retinal nerve fiber layer (RNFL) and macular thickness. Results: For patients between the ages of 8 and 12 years, the average RNFL thickness is 98 ± 9 μm, the vertical cup to disc (C:D) ratio is 0.50 ± 0.10, the central subfield thickness (CST) is 274 ± 38 μm, and the macular volume is 10.3 ± 0.6 mm3. For patients between the ages of 13 and 17 years, the average RNFL is 86 ± 16 μm, the vertical C:D ratio is 0.35 ± 0.20, the CST is 259 ± 15 μm, and the macular volume is 10.1 ± 0.5 mm3. For patients 18 years or older, the average RNFL is 89 ± 12 μm, the vertical C:D ratio is 0.46 ± 0.18, the CST is 262 ± 20 μm, and the macular volume is 10.2 ± 0.4 mm3. When the average RNFL data are compared to a normative, age-adjusted database, 6 of 33 (18%) were thinner than the 5% limit. Conclusion: This study reports the distribution of SD-OCT data for patients with Marfan syndrome. Compared to a normative database, 18% of eyes with Marfan syndrome had RNFL thickness < 5% of the population.