LIS1 and DCX1 and Classical Lissencephaly

Abstract

Abstract Classical lissencephaly (LIS) is either a sporadic autosomal disorder or an X-linked dominant disorder that affects approximately 1:40,000 individuals. It is characterized by the presence of a severely thickened cerebral cortical gray matter with widely spaced gyri and sulci. Diagnosis of LIS is made by the characteristic magnetic resonance imaging (MRI) appearance of the brain. Associated clinical features include significant mental retardation, intractable epilepsy, and shortened life expectancy. Syndromes related to LIS include the double cortex syndrome, a less severe genocopy syndrome; lissencephaly with cerebellar hypoplasia; polymicrogyria; and cobblestone (or type II lissencephaly) with associated congenital muscular dystrophy and eye disease. Positional cloning identified the LIS1 (lissencephaly-1) gene on chromosome 17p13.3 and the doublecortin (DCX) gene on chromosome Xq22.3–23 as independently responsible for cases of LIS. The two genes encode for microtubule-associated proteins and are critical for neuronal migration. Although their exact role in migration remains unclear, they appear to function with dynein, the main minus end–directed microtubule motor, to both leading process stabilization and nuclear translocation. Submicroscopic deletions or intragenic LIS1 mutations are associated with LIS, whereas larger deletions are associated with Miller–Dieker syndrome (MDS). Most DCX mutations are single-base mutations leading to amino acid substitutions or frameshift mutations. Genetic counseling depends largely on the results of mutation analysis, and prenatal diagnosis is available. Treatment consists of supportive measures and seizure prevention, with a focus on quality of life.