Lissencephaly, Genetics of


The term lissencephaly (literally ‘smooth brain’) covers rare malformations of the brain characterised by a paucity of normal gyri and sulci with absent (agyria) or abnormally wide gyri (pachygyria) associated with an abnormal cortical layering. Different forms of lissencephalies have been described: classical lissencephalies (also called type I) and their variants, and cobblestone lissencephalies (also called type II). Classical lissencephalies include lissencephalies with mutations in LIS1, DCX, ARX or TUBA1 genes, isolated lissencephalies without any identified genetic defect, lissencephalies with severe microcephaly (microlissencephaly) and lissencephalies associated with syndromes including multiple malformations. The cobblestone lissencephaly is observed in three related syndromes characterised by an overmigration of neurons and glial cells into the arachnoid space: Walker–Warburg, Fukuyama and muscle–eye–brain (MEB) syndromes, caused by mutations in genes involved in O‐glycosylation of α‐dystroglycan.

Key Concepts

  • Lissencephaly is defined by a ‘smooth brain’ with absent (agyria) or abnormal wide gyri (pachygyria).
  • Lissencephaly is caused by abnormal neuronal migration during corticogenesis.
  • Neuropathological analysis distinguishes several types of lissencephalies: classical lissencephalies and cobblestone lissencephalies.
  • Classical lissencephalies are caused by mutations in LIS1, DCX, ARX and Tubulin genes.
  • Cobblestone lissencephalies are caused by defects in O‐glycosylation of α‐dystroglycan.
  • Microlissencephalies are caused by dysfunctions of centrosomal‐dependent neuronal progenitor proliferation and of neuronal migration.

Keywords: neuronal migration; LIS1; DCX; tubulinopathies; alpha‐dystroglycanopathies

Figure 1. Classical lissencephaly (LIS1 gene mutation). (a) Axial brain section showing agyria–pachygyria with anterior–posterior gradient (anterior being more severe) and the classical figure‐eight appearance of shallow Sylvian fissures. (b) Coronal brain section showing the preserved cerebellum.
Figure 2. Cobblestone lissencephaly. (a) Axial brain section showing pachygyry and polymicrogyry with anterior–posterior gradient, and hydrocephalus. (b) Sagittal brain section showing brain stem and cerebellar hypoplasia.


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Passemard, Sandrine, Chalard, François, Verloes, Alain, and Gressens, Pierre(Feb 2018) Lissencephaly, Genetics of. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020224.pub2]