OBJECTIVES: Malformations of cerebral cortex (MCC) are an important cause of epilepsy. Our main goals were: to search for mutations in genes responsible for MCC (FLN1, LIS1, DCX and EMX2), to map the locus for familial perisylvian polymicrogyria and to investigate the molecular mechanisms of the mutations identified. Methods: Mutation screening was performed by PCR, DHPLC and sequencing. HUMARA and Real Time PCR were performed to study the molecular mechanisms of mutations. Linkage analysis was carried out by PCR, Fragment profiler® and MLINK® software. RESULTS: Deleterious mutations were identified in 3/108 patients. We found a G987C splicing mutation in the FLN1 in two related patients with periventricular nodular heterotopia. Skewed X-chromosome inactivation was detected as the possible mechanism responsible for clinical differences observed in the two patients. An A1385C transversion (H277P) in LIS1 was identified in one patient with lisencephaly. Only neutral variants were identified in DCX and EMX2. Linkage analysis has detected a locus in Xq27.2-Xq27.3 for familial polymicrogyria. CONCLUSION: We believe that the low frequency of mutations identified may be due to mosaicism, mutations in non-coding regions, deletions and patients with atypical neuroimaging findings. Deleterious mutations in EMX2 were not found in patients with schizencephaly and polymicrogyria. We found a locus for familial perisylvian polymicrogyria in Xq27.2-Xq27.3.
Central Nervous System; development; cortical malformations; genetics