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Polymicrogyria (PMG) is characterized by an excessive number of small and prominent brain gyri, separated by shallow sulci. Bilateral perisylvian polymicrogyria (BPP) is the most common form of PMG. Clinical signs include pseudobulbar paresis, mental retardation, and epilepsy. Familial forms of BPP have been described and a candidate locus was previously mapped to chromosome Xq28, distal do marker DXS8103. The objective of this study was to perform linkage analysis in one family segregating BPP. A total of 15 individuals, including 8 affected patients with BPP were evaluated. Family members were examined by a neurologist and subjected to magnetic resonance imaging scans. Individuals were genotyped for 18 microsatellite markers, flanking a 42.3 cM interval on ch Xq27-q28. Two-point and multipoint linkage analysis was performed using the LINKAGE package and haplotype reconstruction was performed by GENEHUNTER software. Our results showed a wide spectrum of clinical manifestations in affected individuals with BPP, ranging from normal to mild neurological abnormalities. Two-point linkage analysis yield a Zmax = 2.06 at theta = 0.00 for markers DXS1205 and DXS1227. Multipoint lod-scores indicate a candidate interval of 13 cM between markers DSXS1205 and DXS8043, on ch Xq27.2-Xq27.3. These results point to a new locus for BPP in a more centromeric location than previously reported.

We describe the clinical and molecular evaluation of two patients, mother and daughter (proband), with bilateral periventricular nodular heterotopia (BPNH). The clinical evaluation revealed a more severe phenotype in the proband, with mental retardation and seizures. Imaging studies showed bilateral periventricular nodules in both patients. We identified a novel mutation, c.987G-->C mutation in exon 6 of the Filamin A (FLNA) gene in the genomic DNA of both patients. Complementary DNA (cDNA) sequencing revealed the maintenance of intron 6 in the mutated allele. Bioinformatics analysis indicates that the mutation identified in both patients probably destroyed the intron 6 donor-splicing site, which is likely to introduce a premature stop codon resulting in a truncated FLNA protein. In addition, X-chromosome inactivation studies in DNA of blood cells revealed a skewed pattern in the proband, and real time quantitative polymerase chain reaction (PCR) showed a higher expression of the mutated allele in the proband compared to that of the mother. This variation in expression of the mutated allele may be responsible for the differences in the clinical manifestations observed in both patients.

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