3.2.3. PAFAH1B1-Associated Lissencephaly/Subcortical Band Heterotopia

*PAFAH1B1*-associated lissencephaly/subcortical band heterotopia, also referred to as *LIS1*-associated lissencephaly/subcortical band heterotopia, encompasses Miller–Dieker syndrome (MDS), isolated lissencephaly sequence (ILS) and, infrequently, subcortical band heterotopia (SBH) [120]. MRI findings for lissencephaly are the absence or the abnormal broadening of cerebral gyri, and the aberrant thickness of the cerebral cortex. Less frequently, it may be possible to observe an enlargement of the lateral ventricles, mild hypoplasia of the corpus callosum and of the cerebellar vermis. In *PAFAH1B1*-associated SBH, just beneath the cortex of the parietal and occipital lobes there are subcortical bands of heterotopic gray matter separated from the superficial cerebral cortex by a thin layer of white matter. Histologically, the cerebral cortex in LIS1-associated lissencephaly consists of four layers: a poorly defined marginal zone, which, however, has a very high cell density; a superficial neuronal layer with diffusely scattered neurons; a deeper neuronal layer with relatively sparse neurons; and a deepest neuronal layer with neurons arranged in columns.

The architectural alterations of the human cerebral cortex and hippocampus can be somewhat recapitulated in genetically engineered mice. For example, the overexpression of *pafah1b1* disturbed neuronal migration and layer formation in the developing cerebral cortex [121], whereas *lis1* deficiency in homozygous mice resulted in early embryonic death and in heterozygous mice led to a derangement of the normal hippocampal organization with ectopy of the granule cells [122]. Of note, Lis1, the protein encoded by *Pafah1b*, is part of the Pafah1b complex and binds, downstream of the Vldlr receptor, to Dab1 that becomes phosphorylated in response to Reln [123].
