Ocular and renal features often seen in conjunction with Joubert syndrome together constitute the cerebellooculorenal syndromes (CORSs). Cerebellooculorenal syndromes are a group of autosomal recessive syndromes characterized by the variable association of brain, eye, and kidney abnormalities, plus occasional malformations in other organs such as the liver.
The molecular basis for the cerebellar anomalies seen in Joubert syndrome patients is unknown and is likely genetically distinct from classical Joubert syndrome. Mutations in genes that regulate early specification and development of domains of the cerebellum may be responsible for the brain abnormalities observed in Joubert syndrome. The early specification of cerebellar territory in vertebrates is regulated via the expression of homeotic genes. These homeotic genes are homologous to the segment-polarity genes in Drosophila, which encode transcription factors known as "paired-box," or Pax genes. Their transcripts influence the expression of vertebrate homologues of engrailed (en), a Drosophila gene encoding a transcription factor containing a homeobox domain. The expression of en genes is further regulated by wnt1, a homologue of the Drosophila wingless gene. The wnt1 gene is primarily expressed during early neuronal development. Disruption of wnt1 results in agenesis of cerebellar structures. Recently, the wnt1 gene has been excluded as being causative for Joubert syndrome.
Keeler et al. (2003) performed a genome scan in a consanguineous (first cousins) family from the United Arab Emirates with cerebellooculorenal syndrome 2. The mother had six pregnancies with two affected female children. The 15-year-old affected child had hydrocephalus at birth, requiring a ventriculoperitoneal shunt. Facial dysmorphic features included a depressed nasal bridge with hypertelorism, high-arched palate, and low-set ears. There were no abnormal eye movements or panting respirations in the neonatal period, although she displayed severe hypotonia and developmental delay. Brain MRI showed the MTI, absence of the cerebellar vermis, and abnormal kinked corpus callosum. The occipital cortex appeared malformed, with possible polymicrogyria. Ophthalmological examination showed double contoured coloboma of the retina and choroid below the optic disk, as well as optic atrophy and impaired vision. The 5-year-old affected child had an enlarged head circumference at birth and required a ventriculoperitoneal shunt for hydrocephalus at age 14 months. She had similar facial dysmorphisms, as well as panting respirations, jerky eye movements, hypotonia, and mental retardation. Brain MRI showed the MTI, thin corpus callosum, and possibly malformed occipital cortex. Ophthalmological examination showed bilateral coloboma of the optic-nerve head. Abdominal ultrasound in both affected children showed normal-sized liver and kidneys. Karyotype in both children was normal. However, linkage analysis defined a novel locus on chromosome 11p12-q13.3, with a maximum two-point LOD score of Z=5.2 at the marker D11S1915. This finding, lead Keeler et al. (2003) to propose that the cerebellooculorenal form of Joubert syndrome is a distinct genetic entity from the Joubert syndrome 1 locus at chromosome 9, in which there is minimal involvement of retina or kidney
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