Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia

Joubert syndrome (JS) is an autosomal recessive ciliopathy characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability. The brain is malformed, with severe vermian hypoplasia, fourth ventriculomegaly, and molar tooth appearance of the cerebral and superior cerebellar peduncles visible as consistent features on neuroimaging. Neuropathological studies, though few, suggest that several other brain and spinal cord structures, such as the dorsal cervicomedullary junction, may also be affected in at least some patients. Genetically, JS is heterogeneous, with mutations in 13 genes accounting for approximately 50% of patients. Here, we compare neuropathologic findings in five subjects with JS, including four with defined mutations in OFD1 (2 siblings), RPGRIP1L, or TCTN2. Characteristic findings in all JS genotypes included vermian hypoplasia, fragmented dentate and spinal trigeminal nuclei, hypoplastic pontine and inferior olivary nuclei, and nondecussation of corticospinal tracts. Other common findings, seen in multiple genotypes but not all subjects, were dorsal cervicomedullary heterotopia, nondecussation of superior cerebellar peduncles, enlarged arcuate nuclei, hypoplastic reticular formation, hypoplastic medial lemnisci, and dorsal spinal cord disorganization. Thus, while JS exhibits significant neuropathologic as well as genetic heterogeneity, no genotype-phenotype correlations are apparent as yet. Our findings suggest that primary cilia are important for neural patterning, progenitor proliferation, cell migration, and axon guidance in the developing human brain and spinal cord.