Brian P Brooks1, Wadih M Zein2, Amy H Thompson3, Maryam Mokhtarzadeh2, Daniel A Doherty4, Melissa Parisi5, Ian A Glass4, May C Malicdan6, Thierry Vilboux7, Meghana Vemulapalli8, James C Mullikin8, William A Gahl9, Meral Gunay-Aygun10. 1. National Eye Institute, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland; National Human Genome Research Institute, Genetics and Molecular Biology Branch, Bethesda, Maryland; Office of the Clinical Director, National Eye Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: brooksb@mail.nih.gov. 2. National Eye Institute, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland. 3. National Eye Institute, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland; Columbus Technologies & Services, Inc., Greenbelt, Maryland. 4. Department of Pediatrics, University of Washington, Seattle, Washington; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington. 5. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. 6. National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 7. National Human Genome Research Institute, Genetics and Molecular Biology Branch, Bethesda, Maryland; Inova Translational Medicine Institute, Falls Church, Virginia. 8. National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 9. National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 10. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; Johns Hopkins University School of Medicine, Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland.
Abstract
PURPOSE: Joubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in JS patients, with correlation to systemic findings and genotype. DESIGN: Patients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial. PARTICIPANTS: Ninety-nine patients with JS examined at a single center. METHODS: All patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible. MAIN OUTCOME MEASURES: The VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG. RESULTS: Among patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified. CONCLUSIONS: We recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation. Published by Elsevier Inc.
PURPOSE: Joubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in JS patients, with correlation to systemic findings and genotype. DESIGN: Patients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial. PARTICIPANTS: Ninety-nine patients with JS examined at a single center. METHODS: All patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible. MAIN OUTCOME MEASURES: The VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG. RESULTS: Among patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified. CONCLUSIONS: We recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation. Published by Elsevier Inc.
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