摘要：

Joubert syndrome (JS) is a rare autosomal recessive syndrome characterised by agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations (OMIM: 213300). There is a distinctive (but not unique) MRI appearance in the posterior fossa of the brain termed the molar-tooth-sign, and the diagnosis of JS is usually made when this MRI finding is documented in an infant in combination with hypotonia, episodic hyperpnea or apnea, abnormal eye movements, with a variety of facial and other dysmorphisms. Later, developmental delay and cerebellar ataxia develop. In some JS patients a retinal dystrophy, coloboma and renal abnormalities manifest. It is apparent that JS is a clinically heterogeneous entity and that both intrafamilial and interfamilial variation exists. Overlap with other vermal hypoplasias and rare cerebellar-retinal-renal disorders exists, but whether such disorders are allelic to forms of JS awaits gene isolation and molecular clarification. Recently the first JS locus was found on chromosome 9q34 by homozygosity mapping in a consanguineous family of Omani origin. A second consanguineous family of similar ethnicity demonstrated haplotype segregation consistent with linkage to this 9q34 locus. Linkage to the 9q34 region was excluded in two additional consanguineous families, establishing genetic heterogeneity in the Joubert syndrome. Haplotype analyses in an additional 26 Joubert pedigrees including three with consanguinity, showed no evidence of homozygosity within this interval. These data suggest that the major JS genetic loci are yet to be discovered. Genes crucial to cerebellar and brainstem development are functional candidates, particularly homeotic genes specifying the vermal domain. We have excluded several strong functional candidate genes such as WNT1, EN1, EN2 and FGF8, by mutation analysis and direct DNA sequencing. To characterize the underlying molecular mechanism of the JS, it may be necessary to further define the syndrome. By careful examination, the JS can be distinguished from the related but genetically distinct syndromes, COACH, Senior-Loken and Arima.

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