Detailed classification of brain malformations such as lissencephaly has led to the positional cloning of genes required for normal neuronal migration and the identification of unique molecular pathways governing brain structure. While classical magnetic resonance imaging (MRI) patterns of lissencephaly involve primarily the cerebral cortex, malformations in this spectrum can be associated with significant cerebellar underdevelopment and have recently been referred to as lissencephaly with cerebellar hypoplasia (LCH). The phenotypic features of 34 children were found to define 6 subtypes of LCH. Two of these (LCHa and LCHb) were associated with mutation in the LIS1, DCX and RELN genes, respectively. Gene mutations that exemplify four additional classes (LCHc, d, e and f) remained to be determined. Phenotypic features included small head circumference, cortical malformation ranging from agyria to simplification of the gyral pattern and from near normal cortical thickness to marked thickening of the cortical gray matter. Cerebellar manifestations ranged from midline hypoplasia to diffuse volume reduction and disturbed foliation. We conclude that LCH is within the spectrum of DCX and LIS1 mutations, that LCH associated with RELN mutation is distinguished by the severity of cerebellar and hippocampal involvement, and that several distinctive patterns indicate additional genetic mutations that can produce LCH.
- Brain malformation
- Genetic classification