Variable clinical phenotype in two siblings with Aicardi-Goutières syndrome type 6 and a novel mutation in the ADAR gene.

Aicardi-Goutières syndrome (AGS) is a hereditary inflammatory encephalopathy resulting in severe neurological damage in the majority of cases. We report on two siblings with AGS6 due to compound heterozygosity for a known and a novel mutation in the ADAR gene and a strikingly variable phenotype. The first sibling presented at 12 months of age with a subacute encephalopathy following a mild respiratory infection. The child developed a spastic tetraparesis, generalized dystonia and dysarthria. In contrast, the younger sibling presented with an acute episode of neurological impairment in his third year of life, from which he recovered without sequelae within a few weeks. These findings illustrate a striking intrafamilial phenotypic variability in patients with AGS6 and describe the first case of a full recovery from an acute encephalopathy in an AGS patient. Our findings also suggest that AGS should be considered as an important differential diagnosis of an infection-triggered encephalopathy in infancy despite the absence of typical neuroimaging findings.

Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.

Uveal melanoma (UM) is both the most common and fatal intraocular cancer among adults worldwide. As with all types of neoplasia, changes in Ca(2+) channel regulation can contribute to the onset and progression of this pathological condition. Transient receptor potential channels (TRPs) and cannabinoid receptor type 1 (CB1) are two different types of Ca(2+) permeation pathways that can be dysregulated during neoplasia. We determined in malignant human UM and healthy uvea and four different UM cell lines whether there is gene and functional expression of TRP subtypes and CB1 since they could serve as drug targets to either prevent or inhibit initiation and progression of UM. RT-PCR, Ca(2+) transients, immunohistochemistry and planar patch-clamp analysis probed for their gene expression and functional activity, respectively. In UM cells, TRPV1 and TRPM8 gene expression was identified. Capsaicin (CAP), menthol or icilin induced Ca(2+) transients as well as changes in ion current behavior characteristic of TRPV1 and TRPM8 expression. Such effects were blocked with either La(3+), capsazepine (CPZ) or BCTC. TRPA1 and CB1 are highly expressed in human uvea, but TRPA1 is not expressed in all UM cell lines. In UM cells, the CB1 agonist, WIN 55,212-2, induced Ca(2+) transients, which were suppressed by La(3+) and CPZ whereas CAP-induced Ca(2+) transients could also be suppressed by CB1 activation. Identification of functional TRPV1, TRPM8, TRPA1 and CB1 expression in these tissues may provide novel drug targets for treatment of this aggressive neoplastic disease.