Abnormal development of the human cerebral cortex

Abstract

This review presents an overview of human cortical malformation based on the insights gained from examination of human fetal brains. Examination at early stages of fetal brain development allows the identification of the specific pathways which are disrupted in human cortical malformation. Detailed examination of human fetal brains in parallel with studies of genetics and animal models is leading to new concepts of cortical malformations. Here we review a range of human cortical malformations based on a simple classification according to the developmental process thought to be disrupted: neuroblast proliferation, undermigration, overmigration, cortical maturation and destructive lesions. A single case example of a dated intrauterine injury illustrates the spectrum of malformations which may result at a single period in development. The recommended methods of examination of human fetal brain are described together with some of their pitfalls. Detailed neuropathological observations indicate the need for caution in the classification of malformations; radiological findings and pathology of the mature brain do not reflect the specific disruptive pathways of cortical malformations. While many insults may lead to the same pattern of malformation, a single insult can lead to multiple patterns of malformation. Our detailed studies of the human fetal brain suggest that the interface between the meninges and the radial glial end feet may be an intriguing new focus of interest in understanding cortical development.

Patterns and pathways of calcification in the developing brain

“…The pattern of vascular calcification seen in one case with BLC‐PMG was similar to that in one case of ring chromosome X and three cases of Sturge–Weber syndrome (SWS) (Figs and ).…”

“…Dystrophic calcification is described in tumours, tuberous sclerosis, and vascular and cortical malformations . While cell membrane integrity and calcium homeostasis may be impaired in these conditions, we suggest that ischaemic insults in early fetal life may also cause malformation, the calcification being residual evidence of the primary pathology …”

Whole‐exome sequencing identifies compound heterozygous mutations in WDR62 in siblings with recurrent polymicrogyria

“…The latter cortical regions are especially important to neurogenesis [Lim and Alvarez-Buylla, 1999]. Proper cortical development depends on the coordinated processes of neuronal proliferation and differentiation, and defects can result in a number of brain malformations [Squier and Jansen, 2010]. …”

Renewed focus on the developing human neocortex

“…It is also clear, however, that external events can interfere with the timetable of development leading to brain malformation. Waney Squier and Anne Jansen have investigated how stroke and brain injury in utero, during sensitive periods of development, as well as genetic malformations, lead to epilepsy caused by the erroneous migration of inhibitory interneurons (Hannan et al 1999;Squier et al 2003;Squier & Jansen, 2010 in this issue). Alcohol, radiation, diet and infection could all have an impact on cortical development.…”