This article includes discussion of Joubert-Boltshauser syndrome, agenesis of cerebellar vermis, and vermian agenesis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Joubert syndrome is a malformation syndrome affecting brainstem and cerebellum, resulting in early hypotonia, subsequent truncal ataxia, delayed milestones, and, finally, cognitive impairment of varying degrees. Although a rare condition, its pathogenetic understanding is likely to contribute significantly to the organization and function of the hindbrain. Molar tooth sign is the diagnostic neuroimaging finding on axial cuts through the midbrain/hindbrain region. In this article, the author gives an update of the diagnostic workup, refers to other cerebello-oculo-renal syndromes, and summarizes the actual knowledge about molecular genetics. The genetic situation is complex in view of marked genetic heterogeneity and modifier genes. More than 38 different associated genes have been reported; however, in about 30% of affected individuals, a pathogenic mutation is still unknown; increasing use of whole-exome sequencing will lower this percentage. All genes are related to the primary (nonmotile) ciliary-basal body apparatus. Joubert syndrome can be grouped among the ciliopathies. Joubert syndrome is now the best-studied hindbrain malformation.
Historical note and terminology
In 1969, Marie Joubert and colleagues reported a previously undescribed syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation associated with agenesis of the cerebellar vermis (Joubert et al 1999). They observed this condition in 4 siblings of a family; there was remote consanguinity of the parents. Boltshauser and Isler added 3 cases and suggested the designation “Joubert syndrome” (Boltshauser and Isler 1977). Friede and Boltshauser published the first detailed postmortem report in 1978 (Friede and Boltshauser 1978). Maria and colleagues drew attention to characteristic MRI findings (molar tooth appearance of midbrain) and gave detailed neuro-ophthalmologic findings (Maria et al 1997). So far, larger series reported are from Maria and colleagues and Boltshauser and colleagues (Maria et al 1997; Steinlin et al 1997; Gitten et al 1998). Studies of larger American patient series were particularly supported by a patient organization called the Joubert Syndrome Foundation, later named Joubert Syndrome and Related Disorders Foundation. Diagnostic criteria were discussed on October 16, 1998, in Montreal at a satellite symposium of the Child Neurology Society Meeting; this symposium was devoted to Joubert syndrome.
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