LIS1 knockout homozygous null mice die during embryogenesis and heterozygous mice survive with delayed neuronal migration confirmed by in vitro and in vivo cell migration assays. Most lissencephaly cases are associated with deletions of mutations of the LIS1 gene and the results are usually more severe in the posterior brain regions.One study showed that of an isolated group of patients with lissencephaly, 40% resulted from an LIS1 deletion and another 25% resulted from an intragenic mutation of the gene. Patients with missense mutations tend to have less severe symptoms, pachygyria, and rare cases of subcortical band heterotopia. Truncated (shortened) mutations of LIS1 tend to cause severe lissencephaly. Doublecortin
Doublecortin (DCX or XLIS) mutations are responsible for X-linked disorders. While LIS1 mutations tend to cause severe malformations in the posterior brain, DCX mutations focus much of their destruction on anterior malformations and are linked to lissencephaly in males and subcortical band heterotopias in females. Women with DCX mutations tend to have an anteriorly-predominant subcortical band heterotopia and pachygyria. DCX was the first known gene causing X-linked lissencephaly and subcortical band heterotopia. It is found on chromosome Xq22.3-q23 and has nine exons that code for 360 proteins. DCX is expressed exclusively in the fetal brain.Spastic cerebral palsy is by far the most common type, occurring in 70% to 80% of all cases. Moreover, spastic CP accompanies one of the other types in 30% of all cases.
Some children with quadriplegia also have hemiparetic tremors, an uncontrollable shaking that affects the limbs on one side of the body and impairs normal movement. Occasionally, terms such as monoplegia, paraplegia, triplegia, and pentaplegia may also be used to refer to specific manifestations of the spasticity. Pathogenesis
Pachygyria, lissencephaly (smooth brain), and polymicrogyria (multiple small gyri) are all the results of abnormal cell migration. The abnormal migration is typically associated with a disorganized cellular architecture, failure to form six layers of cortical neurons (a four-layer cortex is common), and functional problems. The abnormal formation of the brain may be associated with seizures, developmental delay, and mental dysfunctions.Normally, the brain cells begin to develop in the periventricular region (germinal matrix) and then migrate from medial to lateral, to form the cerebral cortex. Diagnosis
Different imaging modalities are commonly used for diagnosis. While computed tomography (CT) provides higher spatial resolution imaging of the brain, cerebral cortex malformations are more easily visualized in vivo and classified using magnetic resonance imaging (MRI) which provides higher contrast imaging and better delineation of white and gray matter.Diffuse pachygyria (a mild form of lissencephaly) can be seen on an MRI as thickened cerebral cortices with few and large gyri and incomplete development of the Sylvian fissures. severe epilepsy
reduced longevity
varying degrees of mental retardation
intractable epilepsy
spasticityCognitive ability correlates with the thickness of any subcortical band present and the degree of pachygyria.