TY - JOUR
T1 - Joubert Syndrome
T2 - Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center
AU - Brooks, Brian P.
AU - Zein, Wadih M.
AU - Thompson, Amy H.
AU - Mokhtarzadeh, Maryam
AU - Doherty, Daniel A.
AU - Parisi, Melissa
AU - Glass, Ian A.
AU - Malicdan, May C.
AU - Vilboux, Thierry
AU - Vemulapalli, Meghana
AU - Mullikin, James C.
AU - Gahl, William A.
AU - Gunay-Aygun, Meral
N1 - Funding Information:
The authors thank the Joubert Syndrome and Related Disorders Foundation for their extensive support and the individuals with JS and their families who generously participated in this investigation. Thanks to the NISC Comparative Sequencing Program staff for their work and dedication. This research was supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Clinical Center. The authors also thank Richard E. Thompson, PhD, of the Biostatistics Department at the Johns Hopkins Bloomberg School of Public Health (Baltimore, MD) for statistical assistance.
Funding Information:
The authors thank the Joubert Syndrome and Related Disorders Foundation for their extensive support and the individuals with JS and their families who generously participated in this investigation. Thanks to the NISC Comparative Sequencing Program staff for their work and dedication. This research was supported by the Intramural Research Program of the National Human Genome Research Institute and the NIH Clinical Center. The authors also thank Richard E. Thompson, PhD, of the Biostatistics Department at the Johns Hopkins Bloomberg School of Public Health (Baltimore, MD) for statistical assistance.
Publisher Copyright:
© 2018
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ophtha.2018.05.026
DO - 10.1016/j.ophtha.2018.05.026
M3 - Article
C2 - 30055837
AN - SCOPUS:85050339097
SN - 0161-6420
VL - 125
SP - 1937
EP - 1952
JO - Ophthalmology
JF - Ophthalmology
IS - 12
ER -