Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center

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.

Trial registration: ClinicalTrials.gov NCT00068224.

Published by Elsevier Inc.

Figures

Figure 1.

Best-corrected visual acuity (BCVA), coloboma, retinal dystrophy, and optic nerve atrophy occur across a spectrum of genotypes in Joubert syndrome (JS). For each genotype, BCVA (A) and the age at most recent visit(C) are shown as box and whisker plots representing the median value (bar), upper and lower quartile values (boxes), and extreme data points (whiskers). Outliers are denoted by circles. The visual acuity (VA) shown inA is the value for the best eye: Both eyes are listed in Table S1 (available at www.aaojournal.org). The number of patients with nonquantifiable VA in each genotype is in B. D, The number of patients with coloboma for each genotype (28/99 patients); location of coloboma is indicated using color-coded bars. E, Retinal dystrophy observed in 20 of 83 patients. F, Optic nerve atrophy observed in 8 of 86 patients. Where the denominator of a parameter does not equal 99, it is an indication that not all patients could be assessed for that parameter, and the number assessed is the denominator. G, Electroretinography (ERG) results are reported as color-coded bars for patients for whom data were available. D-G, Grey bars indicate the total number of patients in each genotype. logMAR = logarithm of the minimum angle of resolution; ON = optic nerve.

Figure 2.

Ptosis and ocular alignment defects are prevalent in patients with Joubert syndrome (JS) of many genotypes. A, Bar graph displaying ptosis in the worst eye as measured by marginal reflex distance (MRD); severity is indicated by color-coded bars. Yellow bars indicate ptosis without indication of severity when no MRD was recorded. Six patients with ptosis received surgery to correct ptosis. B, A 4-year-old (KIAA0586, patient 368) displaying esotropia with inferior oblique overaction.C, Mild unilateral ptosis in a 20-year-old(INPP5E, patient 7503). Best eye visual acuity (VA) was 0.3 logMAR. D, Severe bilateral ptosis in a 4-year-old(TMEM67, patient 557). This patient has not had surgery, and best eye visual acuity (VA) was fix and follow (FF) at most recent visit.E, Severe ptosis in a 2-year-old (MKS1, patient 537). Vision in both eyes was FF.

Figure 3.

Coloboma in Joubert syndrome (JS) is mainly a visually inconsequential manifestation limited to the retina but may involve the optic nerve and (rarely) the iris as well. A, Small (left) and forme fruste (right) coloboma in a 29-year-old(TMEM67, patient 560). Best eye visual acuity (VA) was 0.4 logarithm of the minimum angle of resolution (logMAR) in the right eye and 0.6 logMAR in the left eye (Snellen 20/50, 20/80). B, Larger coloboma in a 14-year-old (TMEM67, patient 303). This patient had a VA of 0.1 logMAR in the right eye and 0.18 in the left eye (20/25, 20/32, Snellen) and an abnormal electroretinography (ERG) at most recent visit. C, Coloboma with optic nerve involvement in a 14-year-old (TMEM67, patient 252). This patient’s VA at last ophthalmic visit was 0.6 logMAR in the right eye and 0.8 logMAR in the left eye (20/80, 20/125 Snellen), and ERG was normal. D, A rare coloboma affecting iris, retina, and optic nerve in a 3-year-old (INPP5E, patient 372). The VA was 1.3 logMAR in the right eye (20/400 Snellen) and not reportable in the left eye. An ERG before the National Institutes of Health (NIH) visit was noted as “profoundly abnormal.” Note the ciliary processes adherent to the lens margin and ectopia lentis in the left eye.

Figure 4.

In Joubert syndrome (JS), affected patients can show straightforward retinal dystrophy or atypical or subtle alterations. Fundi photographs in color (left of panel) and fundus autofluorescence (rightof panel) are shown for each patient. A, Typical diffuse retinal dystrophy and vascular tortuosity in the left eye in a 14-year-old(INPP5E, patient 352). The electroretinography (ERG) showed no response, and visual acuity (VA) was not assessable. B, Advanced retinal degeneration in a 17-year-old (AHI1, patient 540). The best-corrected visual acuity (BCVA) at this visit was 0.8 in the right eye and 0.7 in the left eye (20/125 and 20/100 Snellen), and ERG showed no response. Inset is widefield Optos photograph (Dunfermline, Scotland, UK). C, A particularly unusual crescent-shape area of retinal degeneration in the right eye adjacent to the macula in a 15-year-old (CC2D2A, patient 565). The dystrophy to this point did not appear progressive, leading us to think that this finding may represent a focal developmental anomaly. The BCVA was 0.3 logarithm of the minimum angle of resolution (logMAR) in the right eye and 0 logMAR in the left eye (20/40 and 20/20 Snellen), and patient had severe ptosis in the right eye and mild ptosis in the left eye (MRD −1, +3).D, A rare combination of coloboma including the optic nerve and retinal degeneration in the right eye in a 23-year-old (CEP290, patient 441). This patient had BCVA of 1.2 logMAR (20/250 Snellen).E, Optic nerve atrophy without retinal degeneration in a 13-year-old (KIAA0586, patient 531). Although this patient did not have retinal degeneration as defined for this study, the authors would not call this patient’s (and several others in the study) retinal architecture completely normal either. This patient had most recent BCVA of 0 logMAR in both eyes (20/20) and did not have any additional ocular manifestations of JS.

Figure 5.

The transition from nonquantifiable to quantifiable acuity is delayed in Joubert syndrome (JS)-affected patients. This stacked bar chart (A)displays the number of patient visits in each age group and the visual acuity (VA) range at visit, coded by color. On the secondary axis, the percentage of patients with quantifiable VA (logarithm of the minimum angle of resolution [logMAR] 0–2.0) and the percentage of patients with nonquantifiable VA (fix and follow [FF] through no light perception) at each age range are displayed. Both National Institutes of Health (NIH) and historical visits from outside examinations were included. The pie charts (B,C) on theright report on the visual status of the 24-patient subset in our cohort who had visits both before (primarily from historical records) and after age 5 years. If a patient had multiple visits before age 5 years, the visit closest to age 3 years was selected for pie chart B. The visits displayed on pie chart C were the most recent visit for each patient (NIH on-site visit). The genotype of each patient in each section of the pie is listed, followed by the number of patients of that genotype in parentheses. Patients with retinal dystrophy at the most recent NIH visit are denoted by an asterisk next to the number. BTL = blink to light; CUSM = central unsteady maintained; NLP = no light perception.

Figure 6.

The visual acuity (VA) of patients with Joubert syndrome (JS) is often reduced to some degree even without retinal dystrophy, and patients with retinal dystrophy with quantifiable acuity can retain a degree of functional VA into adulthood. Patients were grouped on the scatter plot (A) according to retinal dystrophy status at most recent National Institutes of Health (NIH) ophthalmic examination. Both NIH and historical visits from outside examinations were included. Patients without retinal dystrophy are shown inblue. Patients with dystrophy are shown in red. Each dot represents the VA at 1 visit for 1 patient, and multiple acuity measurements of the same patient are connected by lines. Trend lines representing mean VAs for patients with and without dystrophy are shown in bold with accompanying 95% confidence intervals as dashed lines of same color. A random-effects mode was used to account for the within-person correlation and cubic spline terms to account for the nonlinearity over time. Scatter plotB is displaying the VA of only patients with retinal dystrophy. Each dot represents the acuity at 1 visit for 1 patient; multiple visits of the same patient are connected by lines. Colors represent individual genotypes. FF = fix and follow; logMAR = logarithm of the minimum angle of resolution.