Development of the cerebral cortex: II. Lissencephaly.

Lissencephaly refers to diso rders of brain form ation in wh ich the surface of the cerebral cortex appears smooth. In affected individuals the layers of cells in the cerebral cortex are abnormal. Scientists believe that this is due to disruption of the early migration pattern of neurons. The two most common forms of lissencephaly are isolated lissencephaly and Mill er-Dicker syndrome (MDS). Pati ent s with MDS have congenital abnormalit ies affecting the heart , kidneys, and other organ systems in addition to the abnormalities that are seen within the eNS in both variants . As was d iscussed in the last Devel opment and Neurobiology column (see January issue of the j ournal ), the normal cerebral cortex is d ivided into six d istin ct cellular layers (Fig. 1). The brains of pat ient s with lissenceph aly have onl y four. As might be expected with such d isturbances of brain maturation, these patients are profoundly retarded from birth and often develop seizure disorders. In 1993, a gene on chromosome 17 was isolated and was named LIS1. Unrelated patients with lissencephaly were found to be missing one copy of this gene because of a microdelerion, a mutation that results in the loss of stretches of DNA on a chromosome. Depending on the size of the deletion, the protein that is encoded by that gene will be either truncated or enti rely missing. In pat ients with isolated lissencephaly. the delet ions are small and are contained within the boundaries of the LIS1 gene. In patients with the more severe MDS, the deletio ns are larger and they extend beyond the boundaries of the LISI gene. These results suggested that in MDS, the dele-