Joubert Syndrome is a congenital condition with a triad of major clinical findings: hypotonia in infancy, global developmental delay, and pathognomonic cerebellar and brainstem malformation. Ocular phenotypes can present with oculomotor apraxia, strabismus, nystagmus, ptosis, retinal dystrophy, chorioretinal coloboma, optic nerve atrophy, and abnormal retinal pigmentation.
Joubert syndrome (JS) is a rare, genetically heterogeneous disorder belonging to a group of inherited diseases caused by defect(s) in the primary cilia, which are also known as ciliopathies. The disease affects multiple organs, including the eye, kidney, and brain.
First described by Marie Joubert in 1969 (Joubert, 1969), JS now is known to have multiple genetic causes and subtypes, all of which affect the structure and/or function of primary cilia. Primary cilia are a specialized non-motile, microtubule-based cellular structure that has important roles in development, sensory signaling, and tissue homeostasis in mammalian cells (Gerdes, 2009; Wheway, 2014). In the vertebral eye, primary cilia are found in the cornea, lens, trabecular meshwork, photoreceptors, and retinal pigment epithelium (May-Simera, 2018; Sugiyama, 2010; Luo, 2012; Grisanti, 2016). As a result, syndromic ciliopathies often present with variable ocular manifestations (May-Simera, 2018; Wang, 2018; Khan, 2008). Patients with JS classically present with the distinct cerebellar and brainstem malformation (“molar tooth sign” on MRI), hypotonia, and global developmental delay. Ophthalmic involvement includes oculomotor apraxia, strabismus, nystagmus, ptosis, retinal dystrophy, chorioretinal coloboma, and optic nerve atrophy (Wang, 2018).
JS is inherited primarily via an autosomal recessive pattern. The pathogenic variant OFD1 is reported to be inherited in an X-linked recessive manner (Coene, 2009).
Prevalence of JS is estimated to be 1 in 80,000 to 1 in 100,000, with notably higher prevalence in French Canadians (Parisi, 2003; Brancati, 2010; Wang, 2018). Other ethnic foci include the Dutch (Kroes, 2016), Ashkenazi Jews (Edvardson, 2010), Canadian Hutterites (Huang, 2011), and Japanese (Suzuki, 2016).
Molecular studies show that dysfunctional cellular processes that compromise the structural and/or functional integrity of the primary cilia lead to retinal ciliopathies (Wheway, 2013). Thirty-four genes have been reported to cause JS (Wang, 2018). The major genes associated with JS include: CEP290, AHI1, TMEM67, CSPP1, and CPLANE1; all of which play a developmental and/or regulatory role in the primary cilium (Wang, 2018; Parisi, 2003).
Retinal degeneration in JS is thought to be caused by abnormal photoreceptor development due to the defective primary cilia in the cells whose cellular processes are impaired, such as vesicular trafficking (AH1) (Westfall, 2010) and ciliogenesis (CEP290) (Rachel, 2012; May-Simera, 2018).
Classic JS consists of a triad of major clinical findings: hypotonia in infancy, global developmental delay, and pathognomonic cerebellar and brainstem malformation (“molar tooth sign” on MRI) (Parisi, 2003). Atypical breathing patterns (alternating tachypnea and/or apnea) and abnormal eye movements, especially oculomotor apraxia, are also associated with JS (Saraiva, 1992; Tusa, 1999).  As the patient ages, hypotonia progresses to truncal ataxia, but breathing abnormalities usually improve (Parisi, 2003). Depending on the organs affected, JS can also present with retinal dystrophy, ocular coloboma, renal disease (e.g., juvenile nephronophthisis), hepatic fibrosis, occipital encephalocele, polydactyly, oral hamartomas, endocrine disorders, and abnormal facies (Parisi, 2003; Wang, 2018).
Patients with JS ocular phenotypes present with oculomotor apraxia (80%), strabismus (74%), nystagmus (72%), ptosis (44%), retinal dystrophy (38%), chorioretinal coloboma (30%), optic nerve atrophy (22%), and abnormal retinal pigmentation (4.5%) (Wang, 2018).
Retinal dystrophy can vary from early-onset severe rod–cone dystrophy to late-onset cone–rod dystrophy (Wang, 2018; Brooks, 2018). Retinal dystrophy can be appreciated on the fundus exam and fundus autofluorescence image (Figure 1). JS patients with retinal degeneration are less likely to have coloboma, and JS patients with colobomas are less likely to present with retinal degeneration, except in two reported cases of CEP290-related JS where the two co-exist (Brooks, 2018). Optic nerve atrophy can occur independently of retinal degeneration in JS patients (Brooks, 2018). Optic disc drusen have also been observed (Sturm, 2010; Yilmaz, 2015; Apostolou, 2001). 
ERG studies may also be abnormal in JS patients. In one NIH study, the majority of JS patients exhibited abnormal ERG readings. JS patients who have severely reduced or non-recordable ERG readings are found to have mutations in CEP290, CEP164, AHI1, MKS1, and INPP5E (Brooks, 2018).
Children with JS have delayed development of best visual acuity compared to normal. Specifically, the transition from non-quantifiable acuity (e.g. fix and follow; central steady and maintained; blink to light) to quantifiable acuity is delayed (Brooks, 2018). Compared to a normal child who develops complete visual ability between age 2-3, children with JS visually mature around age 4-6 (Brooks, 2018). While visual acuity generally does not worsen with age, those with retinal degeneration experience declining visual acuity over time (Brooks, 2018).
In JS patients, oculomotor abnormalities are common, including oculomotor apraxia, decreased vestibulo-ocular reflex cancellation, decreased smooth pursuit, compensatory head thrusts or catch-up saccades, and nystagmus (Brooks, 2018; Sturm, 2010; Gill, 2011; Khan, 2008). Oculomotor apraxia may manifest as high frequency (~3Hz), small amplitude (5-10°), horizontal head titubation in the first months of life (Poretti, 2014).
The pathognomonic neuro-radiological sign on the brain MRI, the “molar tooth sign,” indicates the cerebellar vermis hypoplasia and brainstem abnormalities (deep interpeduncular fossa, and thick and elongated superior cerebellar peduncles) (Figure 2).
Targeted genetic testing of the common gene mutations can aid in the diagnosis of JS. If the gene panel returns negative, exon-sequencing or even whole-genome sequencing can be used to establish a genetic cause (Vilboux, 2017).
- Cerebellar vermis malformations without the Molar Tooth Sign (e.g. Dandy-Walker)
- X-linked cerebellar hypoplasia
- Meckel-Gruber syndrome
- Bardet–Biedl syndrome
- Leber congenital amaurosis
Ophthalmologic management includes corrective lenses for refractive errors and neuro-ophthalmological rehabilitation for oculomotor disorders. Regular ophthalmic monitoring throughout the amblyogenic period is recommended, which may last longer in JS patients (Brooks, 2018).
Genotyping can aid in disease diagnosis and monitoring disease trajectory. For example, because JS caused by mutations in CEP290, AHI1, and INPP5E commonly manifest with retinal degeneration, affected patients should have regular monitoring for retinal health (Brooks, 2018).
Because JS has different phenotypic subtypes that affect different organs, prognosis and mortality in JS is largely dependent on the severity of the organs affected. It has been reported that JS patients with retinal dystrophy are more likely to have multicystic renal disease and thus higher mortality rate than JS patients without retinal dystrophy (Saraiva, 1992). Children with JS are more likely to have delayed visual development and a longer amblyopic period (Brooks, 2018). Patients with JS who have retinal degeneration have worse visual acuity as they age (Brooks, 2018).
- Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology. 1969 Sep;19(9):813-25. doi: 10.1212/wnl.19.9.813. PMID: 5816874. https://pubmed.ncbi.nlm.nih.gov/30518138/
- Gerdes, J. M., Davis, E. E., & Katsanis, N. (2009). The vertebrate primary cilium in development, homeostasis, and disease. Cell, 137(1), 32–45. https://doi.org/10.1016/j.cell.2009.03.023.
- Wheway, G., Parry, D. A., & Johnson, C. A. (2014). The role of primary cilia in the development and disease of the retina. Organogenesis, 10(1), 69–85. https://doi.org/10.4161/org.26710 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049897/
- May-Simera, H. L., Wan, Q., Jha, B. S., Hartford, J., Khristov, V., Dejene, R., Chang, J., Patnaik, S., Lu, Q., Banerjee, P., Silver, J., Insinna-Kettenhofen, C., Patel, D., Lotfi, M., Malicdan, M., Hotaling, N., Maminishkis, A., Sridharan, R., Brooks, B., Miyagishima, K., … Bharti, K. (2018). Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells. Cell reports, 22(1), 189–205. https://doi.org/10.1016/j.celrep.2017.12.038 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166245/
- Sugiyama Y, Stump RJ, Nguyen A, Wen L, Chen Y, Wang Y, Murdoch JN, Lovicu FJ, McAvoy JW. Secreted frizzled-related protein disrupts PCP in eye lens fiber cells that have polarised primary cilia. Dev Biol. 2010 Feb 15;338(2):193-201. doi: 10.1016/j.ydbio.2009.11.033. Epub 2009 Dec 5. PMID: 19968984; PMCID: PMC2815166. https://pubmed.ncbi.nlm.nih.gov/19968984/
- Luo N, West CC, Murga-Zamalloa CA, Sun L, Anderson RM, Wells CD, Weinreb RN, Travers JB, Khanna H, Sun Y. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet. 2012 Aug 1;21(15):3333-44. doi: 10.1093/hmg/dds163. Epub 2012 Apr 27. PMID: 22543976; PMCID: PMC3392109. https://pubmed.ncbi.nlm.nih.gov/22543976/
- Grisanti L, Revenkova E, Gordon RE, Iomini C. Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway. Development. 2016 Jun 15;143(12):2160-71. doi: 10.1242/dev.132704. Epub 2016 Apr 27. PMID: 27122169; PMCID: PMC4920172. https://pubmed.ncbi.nlm.nih.gov/27122169/
- Wang SF, Kowal TJ, Ning K, Koo EB, Wu AY, Mahajan VB, Sun Y. Review of Ocular Manifestations of Joubert Syndrome. Genes (Basel). 2018 Dec 4;9(12):605. doi: 10.3390/genes9120605. PMID: 30518138; PMCID: PMC6315342. https://pubmed.ncbi.nlm.nih.gov/30518138/
- Khan AO, Oystreck DT, Seidahmed MZ, AlDrees A, Elmalik SA, Alorainy IA, Salih MA. Ophthalmic features of Joubert syndrome. Ophthalmology. 2008 Dec;115(12):2286-9. doi: 10.1016/j.ophtha.2008.08.005. PMID: 19041481. https://pubmed.ncbi.nlm.nih.gov/19041481/
- Coene, K. L., Roepman, R., Doherty, D., Afroze, B., Kroes, H. Y., Letteboer, S. J., Ngu, L. H., Budny, B., van Wijk, E., Gorden, N. T., Azhimi, M., Thauvin-Robinet, C., Veltman, J. A., Boink, M., Kleefstra, T., Cremers, F. P., van Bokhoven, H., & de Brouwer, A. P. (2009). OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. American journal of human genetics, 85(4), 465–481. https://doi.org/10.1016/j.ajhg.2009.09.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756557/
- Parisi M, Glass I. Joubert Syndrome. 2003 Jul 9 [Updated 2017 Jun 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1325/ https://www.ncbi.nlm.nih.gov/books/NBK1325/
- Kroes HY, Monroe GR, van der Zwaag B, Duran KJ, de Kovel CG, van Roosmalen MJ, Harakalova M, Nijman IJ, Kloosterman WP, Giles RH, Knoers NV, van Haaften G. Joubert syndrome: genotyping a Northern European patient cohort. Eur J Hum Genet. 2016 Feb;24(2):214-20. doi: 10.1038/ejhg.2015.84. Epub 2015 Apr 29. PMID: 25920555; PMCID: PMC4717206. https://pubmed.ncbi.nlm.nih.gov/25920555/
- Edvardson S, Shaag A, Zenvirt S, Erlich Y, Hannon GJ, Shanske AL, Gomori JM, Ekstein J, Elpeleg O. Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am J Hum Genet. 2010 Jan;86(1):93-7. doi: 10.1016/j.ajhg.2009.12.007. Epub 2009 Dec 31. Erratum in: Am J Hum Genet. 2010 Feb;86(2):294. Shanske, Alan L [added]. PMID: 20036350; PMCID: PMC2801745. https://pubmed.ncbi.nlm.nih.gov/20036350/
- Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, Frosk P, Li C, Willer JR, Chodirker BN, Greenberg CR, McLeod DR, Bernier FP, Chudley AE, Müller T, Shboul M, Logan CV, Loucks CM, Beaulieu CL, Bowie RV, Bell SM, Adkins J, Zuniga FI, Ross KD, Wang J, Ban MR, Becker C, Nürnberg P, Douglas S, Craft CM, Akimenko MA, Hegele RA, Ober C, Utermann G, Bolz HJ, Bulman DE, Katsanis N, Blacque OE, Doherty D, Parboosingh JS, Leroux MR, Johnson CA, Boycott KM. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet. 2011 Dec 9;89(6):713-30. doi: 10.1016/j.ajhg.2011.11.005. PMID: 22152675; PMCID: PMC3234373. https://pubmed.ncbi.nlm.nih.gov/22152675/
- Suzuki T, Miyake N, Tsurusaki Y, Okamoto N, Alkindy A, Inaba A, Sato M, Ito S, Muramatsu K, Kimura S, Ieda D, Saitoh S, Hiyane M, Suzumura H, Yagyu K, Shiraishi H, Nakajima M, Fueki N, Habata Y, Ueda Y, Komatsu Y, Yan K, Shimoda K, Shitara Y, Mizuno S, Ichinomiya K, Sameshima K, Tsuyusaki Y, Kurosawa K, Sakai Y, Haginoya K, Kobayashi Y, Yoshizawa C, Hisano M, Nakashima M, Saitsu H, Takeda S, Matsumoto N. Molecular genetic analysis of 30 families with Joubert syndrome. Clin Genet. 2016;90:526–35. https://pubmed.ncbi.nlm.nih.gov/27434533/
- Westfall JE, Hoyt C, Liu Q, Hsiao YC, Pierce EA, Page-McCaw PS, Ferland RJ. Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1. J Neurosci. 2010 Jun 30;30(26):8759-68. doi: 10.1523/JNEUROSCI.5229-09.2010. PMID: 20592197; PMCID: PMC2923804. https://pubmed.ncbi.nlm.nih.gov/20592197/
- Rachel, R. A., Yamamoto, E. A., Dewanjee, M., Munasinghe, J., May-Simera, H. L., Dong, L., & Swaroop, A. (2012). CEP290 is required for photoreceptor ciliogenesis and other cilia related functions. Cilia, 1(Suppl 1), P98. https://doi.org/10.1186/2046-2530-1-S1-P98 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555976/
- Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Med Genet. 1992 Jul 1;43(4):726-31. doi: 10.1002/ajmg.1320430415. PMID: 1341417. https://pubmed.ncbi.nlm.nih.gov/1341417/
- Tusa RJ, Hove MT. Ocular and oculomotor signs in Joubert syndrome. J Child Neurol. 1999 Oct;14(10):621-7. doi: 10.1177/088307389901401001. PMID: 10511333. https://pubmed.ncbi.nlm.nih.gov/10511333/
- Brooks BP, Zein WM, Thompson AH, Mokhtarzadeh M, Doherty DA, Parisi M, Glass IA, Malicdan MC, Vilboux T, Vemulapalli M, Mullikin JC, Gahl WA, Gunay-Aygun M. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018 Dec;125(12):1937-1952. doi: 10.1016/j.ophtha.2018.05.026. Epub 2018 Jul 25. PMID: 30055837. https://www.aaojournal.org/article/S0161-6420(18)30686-9/fulltext
- Sturm, V., Leiba, H., Menke, M. et al. Ophthalmological findings in Joubert syndrome. Eye 24, 222–225 (2010). https://doi.org/10.1038/eye.2009.116 https://www.nature.com/articles/eye2009116#citeas
- Yilmaz S, Biler ED, Solmaz AE, Serdaroglu G, Tekin HG, Gokben S. Optic disc drusen mimicking papilledema in an infant with Joubert syndrome. Genet Couns. 2015;26(1):35-9. PMID: 26043505. https://pubmed.ncbi.nlm.nih.gov/26043505/
- Apostolou T, Nikolopoulou N, Theodoridis M, Koumoustiotis V, Pavlopoulou E, Chondros D, Billis A. Late onset of renal disease in nephronophthisis with features of Joubert syndrome type B. Nephrol Dial Transplant. 2001 Dec;16(12):2412-5. doi: 10.1093/ndt/16.12.2412. PMID: 11733635. https://pubmed.ncbi.nlm.nih.gov/11733635/
- Gill H, Muthusamy B, Atan D, Williams C, Ellis M. Joubert syndrome presenting with motor delay and oculomotor apraxia. Case Rep Pediatr. 2011;2011:262641. doi:10.1155/2011/262641. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350021/
- Poretti A, Christen HJ, Elton LE, Baumgartner M, Korenke GC, Sukhudyan B, Hethey S, Cross E, Steinlin M, Boltshauser E. Horizontal head titubation in infants with Joubert syndrome: a new finding. Dev Med Child Neurol. 2014 Oct;56(10):1016-20. doi: 10.1111/dmcn.12489. Epub 2014 May 10. PMID: 24814865. https://pubmed.ncbi.nlm.nih.gov/24814865/
- Vilboux T, Doherty DA, Glass IA, Parisi MA, Phelps IG, Cullinane AR, Zein W, Brooks BP, Heller T, Soldatos A, Oden NL, Yildirimli D, Vemulapalli M, Mullikin JC, Nisc Comparative Sequencing Program, Malicdan MCV, Gahl WA, Gunay-Aygun M. Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. Genet Med. 2017 Aug;19(8):875-882. doi: 10.1038/gim.2016.204. Epub 2017 Jan 26. PMID: 28125082. https://pubmed.ncbi.nlm.nih.gov/28125082/
- Parisi M. A. (2009). Clinical and molecular features of Joubert syndrome and related disorders. American journal of medical genetics. Part C, Seminars in medical genetics, 151C(4), 326–340. https://doi.org/10.1002/ajmg.c.30229 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797758/
- Baba S, Takeshita E, Yamazaki H, Tarashima M, Sasaki M. Disruption of the Photoreceptor Inner Segment-Outer Segment Junction in a 6-Year-Old Girl with Joubert Syndrome. Neuroophthalmology. 2016 Oct 19;41(1):19-23. doi: 10.1080/01658107.2016.1236391. PMID: 28228833; PMCID: PMC5278790. https://pubmed.ncbi.nlm.nih.gov/28228833/