Isolated lissencephaly sequence and double-cortex syndrome in a German family with a novel doublecortin mutation

Isolated Lissencephaly Sequence (ILS) and Double-Cortex Syndrome (DC) are n euronal heterotopias caused by developmental defects in neuronal precursor cell migration. We report on the clinical and genetic assessment of a Germa n pedigree with DC/ILS. Affected males showed clinical symptoms typical of lissencephaly, i.e. seizures, severe mental retardation and extensive physi cal disability starting in the early postnatal period. Females, however, di splayed a milder phenotype with epileptic seizures being the only clinical symptom of note. The MR imaging of a male ILS patient showed a smooth corte x with pachy-gyria, hydrocephalus and a diffuse, broad distribution of grey matter throughout the brain. In the affected female, a double cortex syndr ome in the form of a subcortical bilateral band of grey matter was evident by MR imaging. The molecular and genetic basis of DC/ILS is associated with mutations in t he X-linked doublecortin gene (DCX). The genetic assessment of the family r evealed a novel missense mutation 211 G-->T in DCX exon 2 in affected famil y members. This mutation cosegregated with the clinical symptoms and result ed in a non-conservative amino acid substitution A71S. DCX is a microtubule -associated phosphoprotein and mutations in DCX might affect cytoskeletal d ynamics and the regulation of cell migration.