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 , 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. In the vertebral eye, primary cilia are found in the cornea, lens, trabecular meshwork, photoreceptors, and retinal pigment epithelium. As a result, syndromic ciliopathies often present with variable ocular manifestations. Patients with JS classically present with the distinct cerebellar and brainstem malformation (“molar tooth sign” on MRI), hypotonia, and global developmental delay.
Prevalence of JS is estimated to be 1 in 80,000 to 1 in 100,000, with notably higher prevalence in French Canadians. Other ethnic foci include the Dutch , Ashkenazi Jews, Canadian Hutterites, and Japanese.
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). JS is inherited primarily via an autosomal recessive pattern. Thirty-four genes have been reported to cause JS, although 10-40% of all cases have an unknown genetic cause. 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. Mutations in CEP290 have been implicated in approximately 50% of JS.
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) and ciliogenesis (CEP290).
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) . Atypical breathing patterns (alternating tachypnea and/or apnea) and abnormal eye movements, especially oculomotor apraxia, are also associated with JS.  As the patient ages, hypotonia progresses to truncal ataxia, but breathing abnormalities usually improve. Depending on the organs affected, JS can also present with renal disease (e.g., juvenile nephronophthisis), hepatic fibrosis, occipital encephalocele, polydactyly, oral hamartomas, endocrine disorders, and abnormal facies.
Patients with JS ocular phenotypes present with oculomotor apraxia (80% of patients), strabismus (74%), nystagmus (72%), ptosis (44%), retinal degeneration (38%), chorioretinal coloboma (30%), optic nerve atrophy (22%), and abnormal retinal pigmentation (4.5%).
Retinal dystrophy can vary from early-onset severe rod–cone dystrophy to late-onset cone–rod dystrophy. 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. Optic nerve atrophy can occur independently of retinal degeneration in JS patients. Optic disc drusen have also been observed. 
Electroretinogram (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.
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. Compared to a normal child who develops complete visual ability between age 2-3, children with JS visually mature around age 4-6. While visual acuity generally does not worsen with age, those with retinal degeneration experience declining visual acuity over time.
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. Head titubation, characterized by high frequency (~3Hz), small amplitude (5-10°), horizontal head tremor, may be observed in the first months of life.
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.
- 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.
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.
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. Children with JS are more likely to have delayed visual development and a longer amblyopic period.
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