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Joubert Syndrome: for professionals

Overview

PrevalenceEstimated at 1 in 80,000 to 100,000 individuals
InheritanceAutosomal recessive (mostly), X-linked recessive (OFD1-related)
Genes Involved (OMIM No.)CEP290, AHI1, TMEM67, CSPP1, CPLANE1 (OMIM #213300)
SymptomsVariable visual acuity
Nystagmus
Strabismus
Oculomotor apraxia
Ptosis
Developmental delay
Hypotonia
Episodic hyperpnoea
Apnoea
Ataxia
Intellectual disability
Seizures
Dysphagia
Polydactyly
Scoliosis
Hearing loss
Ocular FeaturesRetinal dystrophy
Chorioretinal coloboma
Optic nerve atrophy
Optic disc drusen
Abnormal retinal pigmentation
Morning glory disc anomaly
Systemic FeaturesCongenital respiratory control issues
Renal manifestations
Hepatic fibrosis
Endocrine abnormalities
Hirschsprung disease
Congenital heart disease
Key InvestigationsOcular:
Fundus autofluorescence imaging
Optical coherence tomography
Electroretinography
Ocular motility testing

Systemic:
Brain
MRI
Systemic imaging and blood tests
Molecular DiagnosisWhole genome sequencing with retinal or ciliopathy panel
ManagementOcular: Regular ophthalmic monitoring, Refractive correction, Surgical interventions (ptosis, severe coloboma)

Systemic: Neurological support (physical and occupational therapy), Respiratory management, Renal and hepatic monitoring by specialists Genetic counselling, Family planning advice (prenatal testing, preimplantation genetic diagnosis), Emotional and practical support from Eye Clinic Liaison Officers (ECLOs)
Therapies Under ResearchTargeted therapies addressing cilium-related pathways, Gene therapies, Understanding genetic modifiers influencing phenotypic variability

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Clinical phenotype

Joubert syndrome (JS) is a rare genetic disorder characterized by a distinctive cerebellar and brainstem malformation known as the “molar tooth sign” on MRI, along with hypotonia and developmental delays. It affects multiple organ systems, including the eyes, kidneys, and liver, reflecting its nature as a ciliopathy. Ophthalmic manifestation may be present and vary in severity based the different genotypes.1-3

Presenting features

Ocular:

  • Visual disturbances: Variable visual acuity, often impacted by developmental or neurological issues.4,5
  • Nystagmus: Observed in approximately 70% of patients.6
  • Strabismus: Present in about 70% of cases.
  • Oculomotor apraxia: Seen in 80% of patients, involving head thrusting to shift gaze.
  • Ptosis: Affects around 40%, can be unilateral or bilateral.

Systemic:

  • Neurological: Hypotonia evolving to ataxia, dysphagia, developmental delay, intellectual disability, and seizures in at least 10% of patients.7,8
  • Respiratory: Congenital respiratory control issues including episodic hyperpnoea and apnoea, which generally improve with age.9
  • Renal: Approximately 25% have renal manifestations like nephronophthisis or cystic dysplasia, leading to renal failure.
  • Hepatic: 15% present with congenital hepatic fibrosis.10
  • Skeletal: Polydactyly in 15%, scoliosis in over 5%.
  • Other: Endocrine abnormalities, hearing loss, Hirschsprung disease, and congenital heart disease.

Fundus

  • Retinal dystrophy:
    • Varies from early-onset severe rod–cone dystrophy to late-onset cone–rod dystrophy.1-3
    • May show diffuse retinal dystrophy and vascular tortuosity.
  • Chorioretinal coloboma:
    • Present in approximately 30% of patients.
    • Often associated with an increased risk for liver disease.
  • Optic nerve atrophy:
    • Seen in about 22% of cases.
    • Can occur independently of retinal degeneration.
  • Optic disc drusen:
    • Occasionally observed, contributing to optic nerve abnormalities.
  • Abnormal retinal pigmentation:
    • Reported in about 4.5% of patients.
    • Can present with changes visible on fundus examination.
  • Morning glory disc anomaly:
    • Described in some patients with specific genetic mutations, such as TMEM237 variants.

Genetics

Genes: Over 35 genes implicated, with major ones including CEP290, AHI1, TMEM67, CSPP1, and CPLANE1.

  • OMIM No.: #213300
  • Inheritance Pattern: Mostly autosomal recessive, except for OFD1-related disease which is X-linked recessive.
  • Function: These genes encode proteins localising at the basal body or ciliary transition zone of primary cilia, classifying JS as a ciliopathy. Mutations lead to significant clinical heterogeneity.1,11

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Fundus autofluorescence imaging: Helps to appreciate retinal dystrophy and optic disc drusen.12-15
  2. Optical coherence tomography: Thinning of the retinal layers, especially the outer layers. Atrophy of the photoreceptor layer, leading to reduced retinal thickness.16
  3. Electroretinography (ERG): Abnormal ERG readings in most JS patients, with severely reduced or non-recordable readings associated with mutations in CEP290, CEP164, AHI1, MKS1, and INPP5E.
  4. Ocular motility testing: Abnormalities including decreased vestibulo-ocular reflex cancellation, decreased smooth pursuit, compensatory head thrusts or catch-up saccades, and nystagmus.
  5. Genetic testing: whole genome sequencing with retinal or ciliopathy panel depending on phenotype.

Systemic

  1. Brain MRI: The pathognomonic “molar tooth sign,” indicating cerebellar vermis hypoplasia and brainstem abnormalities (deep interpeduncular fossa, thick and elongated superior cerebellar peduncles). The fourth ventricle may appear as ‘bat wing.’1-3
  2. Other systemic investigations by appropriate specialists: renal ultrasound, renal function tests, sleep studies, EEG, endocrine evaluation, abdominal ultrasound, skeletal survey, etc.17-19

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Diagnosis

Diagnosis is based on clinical features including developmental delay, hypotonia, abnormal eye movements, and the characteristic molar tooth sign on MRI. Genetic testing confirms the diagnosis by identifying pathogenic variants in JS-associated genes.

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Differential Diagnoses

Differential diagnoses include other ciliopathies such as Senior-Løken syndrome, Bardet-Biedl syndrome, Meckel syndrome, and cerebellar and brainstem congenital defects like Dandy-Walker malformation.

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Management

Management of JS requires a multidisciplinary approach due to its multisystem involvement.

Ocular

  1. Regular Ophthalmic Monitoring: For progression of retinal degeneration and management of visual impairment.
  2. Refractive Correction: Use of glasses or contact lenses.
  3. Surgical Interventions: For ptosis or severe coloboma if vision is significantly impacted.1

Systemic

  1. Neurological Support: Including management of hypotonia, ataxia, and developmental delay with physical and occupational therapy.
  2. Respiratory Management: Monitoring and managing congenital respiratory control issues.
  3. Renal and Hepatic Monitoring: Regular assessments and management by nephrology and hepatology specialists.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research. Patients may be referred to the Bardet-Beidl service in Great Ormond Street Hospital if additional support is required.

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Current research

Current research in JS involves exploring targeted therapies addressing cilium-related pathways, gene therapies, and understanding the genetic modifiers influencing the phenotypic variability observed in JS patients. Ongoing studies aim to improve diagnostic techniques, refine genotype-phenotype correlations, and develop novel interventions, offering hope for enhanced patient outcomes.

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Further information and support

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References

  1. Parisi M, Glass I. Joubert Syndrome. 2003 Jul 9 [Updated 2017 Jun 29]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1325/
  2. 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;19:813-25.
  3. Valente EM, Brancati F, Dallapiccola B. Genotypes and phenotypes of Joubert syndrome and related disorders. Eur J Med Genet. 2008;51:1-23.
  4. Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet Part C Semin Med Genet. 2009;151C:326-40.
  5. Brancati F, Dallapiccola B, Valente EM. Joubert Syndrome and related disorders. Orphanet J Rare Dis. 2010;5:20.
  6. Tusa RJ, Hove MT. Ocular and oculomotor signs in Joubert syndrome. J Child Neurol. 1999;14:621-7.
  7. Summers AC, Snow J, Wiggs E, et al. Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center. Am J Med Genet A. 2017;173:1796-812.
  8. Deonna T, Ziegler AL. Cognitive development and behavior in Joubert syndrome. Biol Psychiatry. 1993;33:854-5.
  9. Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Med Genet. 1992;43:726-31.
  10. Doherty D. Joubert syndrome: Insights into brain development, cilium biology, and complex disease. Semin Pediatr Neurol. 2009;16:143-54.
  11. Vilboux T, Doherty DA, Glass IA, et al. Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. Genet Med. 2017;19:875-82.
  12. Wang SF, Kowal TJ, Ning K, et al. Review of Ocular Manifestations of Joubert Syndrome. Genes (Basel). 2018;9(12):605. doi: 10.3390/genes9120605. PMID: 30518138; PMCID: PMC6315342.
  13. Brooks BP, Zein WM, Thompson AH, et al. Joubert Syndrome: Ophthalmological Findings in Correlation with Genotype and Hepatorenal Disease in 99 Patients Prospectively Evaluated at a Single Center. Ophthalmology. 2018;125(12):1937-1952.
  14. Sturm V, Leiba H, Menke M, et al. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010;24:222-5.
  15. Yilmaz S, Biler ED, Solmaz AE, et al. Optic disc drusen mimicking papilledema in an infant with Joubert syndrome. Genet Couns. 2015;26(1):35-9.
  16. Vilboux T, Doherty DA, Glass IA, et al. Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. Genet Med. 2017;19(8):875-82.
  17. Apostolou T, Nikolopoulou N, Theodoridis M, et al. Late onset of renal disease in nephronophthisis with features of Joubert syndrome type B. Nephrol Dial Transplant. 2001;16(12):2412-5.
  18. 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.
  19. Poretti A, Christen HJ, Elton LE, et al. Horizontal head titubation in infants with Joubert syndrome: a new finding. Dev Med Child Neurol. 2014;56(10):1016-20. doi: 10.1111/dmcn.12489.

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Updated on June 5, 2024
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