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.