Genes shown to cause lissencephaly include both autosomal and X-linked genes. Below, the mutations of LIS1 or DCX genes are discussed as they are most commonly linked to neuronal migration disorders including lissencephaly-pachygyria and subcortical band heterotopia. LIS1
LIS1 is responsible for the autosomal form of lissencephaly. Mutations of the LIS1 gene are associated with about 80% of those affected with lissencephaly. LIS1 was the first human neuronal migration gene to be cloned. It is responsible for encoding the alpha subunit of the intracellular Ib isoform of platelet-activating factor acetylhydrolase. It is located on chromosome 17p13.3 and has 11 exons with a coding region of 1233bp. LIS1 protein appears to interact with tubulin to suppress microtubule dynamics. The protein is highly conserved and studies have shown that it participates in cytoplasmic dynein-mediated nucleokinesis, somal translocation, cell motility, mitosis, and chromosome segregation. LIS1 encodes for a 45kDa protein called PAFAH1B1 that contains seven WD40 repeats required for proper neuronal migration. The LIS1 gene encodes for a protein similar to the β subunit of G proteins responsible for degrading bioactive lipid platelet-activating factor (PAF). This leads to theories that LIS1 might exert its effect on migration through microtubules. Specific concentrations of PAF may be necessary for optimal neuronal migration by influencing cell morphology adhesion properties. Studies have shown that addition of PAF or inhibition of platelet-activating factor acetylhydrolase (PAF-AH) decreases cerebellar granule cell migration in vitro. Addition of PAF to hippocampal cells have shown growth cone collapse and neurite retraction.
Classifications
The degree of cerebral cortex malformation caused by genetic mutations is classified by the degree of malposition and the extent of faulty grey matter differentiation.Neuronal migration disorders are generally classified into three groups:

lissencephaly/subcortical band heterotopia
cobblestone
‘other’ heterotopias The ‘other’ types are associated with corpus callosum agenesis or cerebellar hypoplasia while the cobblestone lissencephalies are associated with eye and muscle disorders.Classical lissencephaly, also known as type I or generalized agyria-pachygyria, is a severe brain malformation of a smooth cerebral surface, abnormally thick (10-20mm) cortex with four layers, widespread neuronal heterotopia, enlarged ventricles, and agenesis or malformation of the corpus callosum. Classical lissencephaly can range from agyria to regional pachygyria and is usually present along with subcortical band heterotopia (known as ‘double cortex’ to describe the circumferential bands of heterotopic neurons located beneath the cortex). Subcortical band heterotopia is a malformation slightly different from lissencephaly that is now classified under the agyria-pachygyria-band spectrum because it consists of a gyral pattern consistent with broad convolutions and an increased cortical thickness. The established classification scheme for lissencephaly is based on the severity (grades 1-6) and the gradient. Grade 1: generalized agyria
Grade 2: variable degree of agyria
Grade 3: variable degree of pachygyria
Grade 4: generalized pachygyria
Grade 5: mixed pachygyria and subcortical band heterotopia
Grade 6: subcortical band heterotopia alone
Gradient ‘a’: from posterior to anterior gradient
Gradient ‘b’: from anterior to posterior gradient Grade 1 and Grade 4 are very rare. Grade 2 is observed in children with Miller–Dieker syndrome (a combination of lissencephaly with dysmorphic facial features, visceral abnormalities, and polydactyly).