Overview
Joubert syndrome is a rare autosomal recessive ciliopathy defined by the pathognomonic 'molar tooth sign' on brain MRI (cerebellar vermis hypoplasia with elongated superior cerebellar peduncles), hypotonia, developmental delay, and oculomotor apraxia. Retinal dystrophy (Leber congenital amaurosis-like) occurs in ~30% of patients and is a major cause of visual impairment. Over 40 causative genes have been identified, all encoding proteins of the primary cilium or basal body.
Genetics
Genetically heterogeneous with 40+ causative genes. CEP290 is the most common gene associated with retinal involvement. All inheritance is autosomal recessive.
| Gene | Locus | Inheritance | Notes |
|---|---|---|---|
| CEP290 | 12q21.32 | AR | Most common gene with retinal involvement; also causes LCA10 |
| TMEM67 | 8q22.1 | AR | Meckelin; associated with liver/kidney involvement |
| CC2D2A | 4p15.32 | AR | Coiled-coil and C2 domain-containing protein 2A |
| AHI1 | 6q23.3 | AR | Abelson helper integration site 1; cerebellar vermis hypoplasia |
| INPP5E | 9q34.3 | AR | Inositol polyphosphate-5-phosphatase E |
Clinical Presentation
Neonatal/Infancy
- Hypotonia
- Oculomotor apraxia
- Episodic hyperpnea/apnea
Childhood
- Developmental delay and intellectual disability
- Ataxia
- Retinal dystrophy in ~30%
Variable
- Renal disease (nephronophthisis) in some
- Liver fibrosis in some
- Polydactyly in some
Diagnosis
- Brain MRI: Molar tooth sign — pathognomonic
- ERG: Cone-rod or rod-cone dystrophy if retinal involvement
- Genetic testing: Comprehensive ciliopathy gene panel
- Renal ultrasound: Nephronophthisis screening
- Developmental assessment: Cognitive and motor evaluation
Current Research & Treatment
No disease-modifying treatments approved. CEP290-targeted antisense oligonucleotide therapy (sepofarsen) for the LCA10 mutation is relevant for patients with CEP290-JBTS retinal involvement. Ciliopathy research is advancing rapidly with multiple gene therapy programs in development.
Active Clinical Trials
The following active clinical trials are investigating treatments for Joubert Syndrome. Trial status and enrollment may change; always verify directly on ClinicalTrials.gov.