Resumo

Idiopathic Basal Ganglia Calcification (IBGC), also known as “Fahr’s Disease” (FD), is a neuropsychiatric condition characterized by brain calcinosis, which is inherited in an autosomal dominant manner. Neuroimaging techniques, such as computerized tomography (CT) may identify calcifications in basal ganglia, thalamus, cerebral white matter, cerebellum and internal capsule, associated with normal biochemical and endocrine screening. Linkage analysis of familial idiopathic basal ganglia calcification to a 13.3-cM critical region on chromosome 14 (IBGC1 locus), was described for a large American multigenerational family (FY1 family). Another small kindred, from Spain, has also been reported as possibly linked to this locus, however other families from China, Canada and Germany have been excluded from the chromosome 14 region, suggesting that this condition would be genetically heterogeneous. Our group identified a heterozygous non-synonymous single nucleotide polymorphism (C>G) at the exon 20 of the MGEA6/cTAGE5 gene, shared by the affected and not present in the controls at the FY1 family. This missense substitution (Pro521Ala) in a region where proline is highly conserved, was considered a rare variation, with a minor allele frequency (MAF) of 0.0058. The populational frequency of a given variation is an indirect indicative of potential pathogenicity. Aiming to advance the understanding of its biological role, we performed the sequencing of control samples from Brazilian population for the (Pro521Ala) variation together with members of two nuclear families with FD, adding an imaging genetics analysis where the tridimensional reconstruction of the calcification is compared between relatives and across generations. All subjects in two families were normal for the main metabolic tests. The DNA was extracted from peripheral blood of patients and 100 controls samples from Brazil. The DNA was amplified by PCR and sequenced in a Mega Bace 1000. The tridimensional reconstructions of CT images were analyzed with the 3D-Doctor software to determine location, shape and volume for calcium deposits. Sequencing analysis did not show the Pro521Ala polymorphism at the 100 populational controls neither at the family’s members, suggesting again genetic heterogeneity for familial IBGC. Totting up this result with previous Pro521Ala populational analysis we define a new MAF of 0,0036, reinforcing the rarity of this variation. The neuroimaging analysis showed a strikingly similar pattern of calcification in the basal ganglia, white matter and cerebellum in one of the families, with asymptomatic twins. The second family present similar pattern calcification in cerebellum and basal ganglia over three generations, including also two asymptomatic subjects. These results suggest a certain level of heritability for the anatomical distribution of calcification depositions and this may be associated with particular disease related loci. Our group is now searching for new approaches to identify the specific gene for this new family with IBGC.