L1-associated diseases: clinical geneticists divide, molecular geneticists unite

Abstract

The neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is essential in the development of the nervous system. It is mainly expressed on neurons and Schwann cells, and plays a key role in axon outgrowth and pathfinding through interactions with various extracellular ligands and intracellular second messenger systems. Mutations in L1 are responsible for a wide spectrum of neurologic abnormalities and mental retardation. This spectrum includes X-linked hydrocephalus, MASA syndrome, X-linked complicated spastic paraplegia type 1 and X-linked agenesis of the corpus callosum. These four diseases were initially described as distinct clinical entities with an overlapping clinical spectrum, but can now be lumped into one syndrome caused by mutations in the L1 gene. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus, which has led to the acronym CRASH syndrome.