Involvement of the midbrain and hindbrain (MHB) in the various groups of lissencephalies was examined in an MRI study of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) studied at University of California San Francisco, and centers in France, Belgium, and Turkey. The three major groups of lissencephaly (cLIS or LIS type 1; vLIS or variant LIS; and CBSC, cobblestone complex or LIS type 2) showed significant differences in the appearance and severity of associated MHB malformations; the least severe MHB malformations occurred with cLIS and the most severe with CBSC lissencephaly. The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (P= 0.0029). Based on the data obtained here and that in the literature, a new classification of lissencephalies is proposed: Classic LIS (LIS1, LIS1 mossaicism, DCX (XLIS); Variant LIS (ARX, RELN, VLDLR, ND1, ND2, ND3, TL-LIS; Cobblestone complex (FCMD-Fukuyama type, WWS, MEB; and related MD syndromes (CMD merosin deficiency). [1]

COMMENT. Lissencephaly or smooth brain is characterized by a paucity of gyri, ranging from complete agyria to localized pachygyria. It is usually classified in 2 groups, classic (cLIS or lissencephaly type 1), and cobblestone complex (CBSC, lissencephaly type 2). Five genes are identified as causing cLIS, and numerous genes are associated with CBSC, also called dystroglycanopathies. Most patients with CBSC have congenital muscular dystrophies with CNS involvement, including Fukuyama CMD, and Walker-Warburg syndrome. Relatively few investigators had stressed the importance of mesencephalic and rhrombencephalic involvement in association with cerebral cortical dysgenesis until the work of Sarnat, colleagues and others in the 1990s. A classification of cerebral malformations proposed by Sarnat et al in 2004 also stressed the inclusion of thalamic, brainstem and cerebellar malformations in association with lissencephaly and holoprosencephaly. In an editorial, Dr Sarnat reviews the progress of our understanding of the genetic programming of neural tube development and the need for research on a genetic mechanism for the association of forebrain and hindbrain malformations in the lissencephalies. [2]