X-linked hydrocephaly Health Article

Definition

Hydrocephaly refers to the accumulation of cerebrospinal fluid (CSF) in the fluid-filled cavities, called ventricles, that are located deep in the core of the brain. The designation X-linked indicates that this form of hydrocephaly results from a mutation in a gene that is located on the X chromosome, in this case the L1 cell adhesion molecule (L1CAM) gene.

Description

Cell adhesion molecules (CAMs) provide the traffic signals that guide the cells of developing organs to migrate to their proper places and make the appropriate connections with the cells with which they interact. The L1CAM protein is embedded in the membrane of nerve cell axons. Axons are projections from the nerve cell body that carry impulses to sometimes distant targets. As a developing axon grows toward its target, its leading end is capped by a growth cone similar in function to that of a plant root. The growth cone of a developing axon is rich in L1CAM. The L1CAM protein has a large, complex extracellular domain (portion of the protein outside the nerve cell), a transmembrane domain within the nerve cell membrane, and a small intracellular domain (portion inside the nerve cell). The extracellular domain acts as a feeler, and binds to CAMs that are either on the surface of other cells or floating in the extracellular fluid. The binding of the L1CAM protein to various CAMs in its environment sends signals into the nerve cell that direct the projecting axon to grow to the appropriate length, follow the course required for it to reach its target, and stop when appropriate.

The L1CAM protein is critical for proper development of several long fiber tracts in the forebrain. These include the corpus callosum, which is a thick fiber bridge that connects the left and right cerebral hemispheres, and the corticospinal tract, which extends from the motor control region of the cerebral cortex down to the spinal cord.

The developing axon often extends many cell diameters away from the cell body, and must interact with CAMs from many different sources to insure that it follows the correct route to its target. The complex extracellular domain of the L1CAM protein interacts with a variety of CAMs in the environment to serve several important functions. Because of the many functions L1CAM serves, the specific brain changes and functional handicaps that are seen in any individual patient with an L1CAM mutation depend on which of L1CAM's functions are lost and which are spared by the specific mutation that occurs in the L1CAM gene. Most families have their own unique L1CAM mutation. Some mutations abolish all of L1CAM's functions, while others change only a small piece of the L1CAM protein. Therefore, there is marked variability between patients in terms of which brain structures are most affected and what the primary physical and behavioral symptoms will be. Because of this variability, patients with different L1CAM mutations have been given diagnoses such as X-linked hydrocephaly (XLH), X-linked spastic paraplegia type 1 (SPG1), hydrocephaly with stenosis of the aqueduct of Sylvius (HSAS), X-linked agenesis of the corpus callosum (XLACC), and MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs). Because these patients all presented with such different combinations of brain changes and functional handicaps, it was originally thought that these were all distinct disorders, with different biological causes. As of 2001, an effort is being made to unite these disorders under the general heading L1CAM spectrum, to reflect the fact that these are not distinct disorders, but merely alternative possible consequences of L1CAM mutations.