Single cell lineage analysis in human focal cortical dysplasia

Focal cortical dysplasia (FCD) is a developmental malformation of the human cerebral cortex that is closely associated with epilepsy. Dysplastic, 'balloon' and heterotopic neurons that comprise FCD are heterogeneous cell populations that exhibit abnormal morphologies. A pivotal unanswered question is how these cell types are generated during cortical development. As a strategy to define the lineage relationships between cells in FCD, the size of a heterozygous trinucleotide (CAG) repeat sequence within the X-chromosome encoded androgen receptor (XAR) mRNA was determined by RT-PCR and direct sequencing in single, microdissected cells from six female patients with FCD compared with control cortex. As a consequence of X-chromosome inactivation, only one of the two XAR alleles is expressed in all somatic cells, and cell types derived from distinct progenitors will express XAR CAG repeat lengths of differing size. Disparate XAR CAG repeat lengths were detected with equal frequency in single dysplastic, 'balloon' and heterotopic neurons in FCD whereas the XAR CAG repeats lengths in control cortex were identical in 70-80% of closely apposed neurons. These results support a random X-inactivation pattern in FCD. We propose that dysplastic, 'balloon' and heterotopic neurons in FCD derive from a population of progenitor cells or post-mitotic neurons during cortical development.