The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders

Abstract

A group of disorders with disparate symptomatology, including congenital cerebellar ataxia, retinal blindness, liver fibrosis, polycystic kidney disease, and polydactyly, have recently been united under a single disease mechanism called 'ciliopathies'. The ciliopathies are due to defects of the cellular antenna known as the primary cilium, a microtubule-based extension of cellular membranes found in nearly all cell types. Key among these ciliopathies is Joubert syndrome, displaying ataxia, oculomotor apraxia, and mental retardation* with a pathognomonic 'molar tooth sign' on brain magnetic resonance imaging. The importance of ciliary function in neuronal development has been appreciated only in the last decade with the classification of Joubert syndrome as a ciliopathy. This, together with the identification of many of the clinical features of ciliopathies in individuals with Joubert syndrome and the localization of Joubert syndrome's causative gene products at or near the primary cilium, have defined a new class of neurological disease. Cilia are involved in diverse cellular processes including protein trafficking, photoreception, embryonic axis patterning, and cell cycle regulation. Ciliary dysfunction can affect a single tissue or manifest as multi-organ involvement. Ciliary defects have been described in retinopathies such as retinitis pigmentosa and Leber congenital amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes with nephronophthisis and cystic dysplastic kidneys, and liver conditions such as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the ciliopathies and screening strategies following diagnosis is an important part of the treatment plan of children with cilia-related disorders.

Figure 1

Genotype–phenotype correlates in Joubert syndrome (JS) and Joubert syndrome and related disorders. CORS, cerebellar-ocular-renal syndrome; SLS, Senior-Løken syndrome; LCA, Leber congenital amaurosis; NPHP, nephronophthisis. Genes with major effect are in bold, other genes contributing to each phenotype are listed as well.

Figure 2

Magnetic resonance imaging showing a normal cerebellar vermis and superior cerebellar peduncles on (a) axial and (b) sagittal images. (c) and (d) show cerebellar vermis hypoplasia and thickened superior cerebellar peduncles perpendicular to the brainstem (arrow), consistent with the molar tooth sign.

Figure 3

(a) Example of duplication of the great toes (preaxial polydactytly). (b) Notched upper lip seen in orofacial digital syndrome type VI. (Images courtesy of Dr. Maha Zaki, Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.)

Figure 4

Lingual hamartoma and tongue tumors (arrows) seen in orofacial digital syndrome type VI.