Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies.

Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.

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SUMMARYWe studied the clinical, neuropsychological, neurophysiologic, and genetic features of an Italian family with familial cortical myoclonic tremor with epilepsy (FCMTE). Clinically affected members of the family had limb and voice tremor, seizures, and myoclonus involving the eyelids during blinking. Neuropsychological testing disclosed visuospatial impairment, possibly due to temporal lobe dysfunction. Neurophysiologic findings suggested increased primary motor cortex excitability with normal sensorimotor integration. Linkage analysis excluded the 8q24 locus, where patients shared a common haplotype spanning 14.5 Mb in the pericentromeric region of chromosome 2.

Joubert Syndrome Related Disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the "molar tooth sign" (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and MeckelGruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in two out of 16 families with cerebello-renal presentation (~12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (<2%).

The GAG deletion in the DYT1 gene usually causes a typical form of primary torsion dystonia (PTD) with early onset in a limb, rapid generalization, and sparing of cranial-cervical muscles, but atypical phenotypes have often been reported. Here, we describe a large DYT1 Italian family with phenotypically heterogeneous PTD that recapitulates all the atypical features associated with the DYT1 mutation, including late age at onset, focal or segmental phenotypes, onset or spreading of dystonia to the cranial-cervical muscles. Of 38 healthy family members, 15 also carried the DYT1 mutation, with an estimated penetrance of 21%. A literature review of atypical familial cases of DYT1-PTD showed that late onset, cervical involvement, and limited progression of dystonia are features frequently seen in DYT1 families. However, nearly all of these atypical patients fall within at least one of the clinical categories that best predict the DYT1 carrier status, namely, early onset, onset in a limb, and family history positive for early-onset dystonia.

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X-linked hydrocephalus (XLH) is a genetic disorder leading to a syndrome characterized by mental retardation, bilateral adducted thumbs, and spasticity of upper and lower limbs. In most cases, X-linked mutation leads to a defective activity of the neuronal cell adhesion molecule L1CAM (L1 cell adhesion molecule, OMIM 308840). Depending on mutations of L1CAM, four X-linked neurological syndromes have been described. These syndromes are very different albeit each one possesses marked variability. In the present study, we describe a novel L1CAM mutation in a 33-year-old woman reporting two voluntary terminations of pregnancy due to fetal hydrocephalus. The genetic analysis identified the potential splicing variant c.1267+5delG. When analyzed in vitro, this mutation produces the skipping of exon 10. The same mutation was confirmed in analyzing DNA from amniocytes from the second pregnancy, and ultrasound scan and autopsy confirmed the occurrence of a severe L1 syndrome. These data describe a novel L1 mutation which improves our understanding on genotype-phenotype correlation while confirming the importance of prenatal screening for L1CAM mutations.