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.
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.
The L1CAM gene is located close to the end of the long arm of the X chromosome, in the band referred to as Xq28. Since the L1CAM gene is on the X chromosome, usually only males are affected. This is because females have two X chromosomes , while males have only one. In a female, if one X chromosome has an L1CAM mutation on it, the non-mutated L1CAM gene on the other X chromosome can usually provide enough good L1CAM protein to support normal brain development. Males, on the other hand, having only one X chromosome, cannot compensate for an X-linked gene mutation .
The inheritance pattern for L1CAM spectrum disorders follows the typical X-linked inheritance pattern. Males are usually the only ones affected, and most females who carry L1CAM mutations are unaffected. There may be several affected brothers in a single family. In addition, in a family where the L1CAM mutation has been passed through several generations, the normally developed mothers of affected males may have affected brothers, or the normally developed sisters of affected males may have affected sons. If a female carries a mutation in L1CAM, she has a 50% chance of passing the mutation to each of her children. Therefore, approximately half her sons will be affected, and approximately half her daughters will be carriers. There is no known case in which an affected male has reproduced.
L1CAM mutations exhibit 100% penetrance, meaning that any male who has the L1CAM mutation will be affected, albeit with varying degrees of severity. This contrasts with some other disorders, in which some family members are unaffected, despite having the same gene mutation that has been seen in other affected family members.
The incidence of hydrocephaly from all causes is approximately 1 in 2,000 live births in the general population. The X-linked form is thought to account for approximately 5% of the total cases of hydrocephaly, or approximately 1 in 25,000 to 50,000 males. In very rare cases a female may be affected, usually mildly. There are no systematic data comparing the incidence of L1CAM spectrum disorders in different races.
Signs and symptoms
Most patients with mutations in L1CAM exhibit mental retardation (MR), the degree of which can vary from mild to severe. The vast majority also exhibit hydrocephaly, which can be mild and not require any medical intervention, or severe enough to be life-threatening. The most severe cases of hydrocephaly are associated with stenosis (narrowing or pinching closed) of the aqueduct of Sylvius. The aqueduct of Sylvius (also called the cerebral aqueduct) is a narrow channel connecting the third ventricle, located deep in the midbrain, to the fourth ventricle, located underneath the cerebellum in the posterior part of the brain. The brain's cerebrospinal fluid (CSF) is made by cells lining the first two ventricles, called the lateral ventricles, which are located in the forebrain. The CSF normally flows from the first two ventricles, through the third ventricle, then into the fourth ventricle, before flowing out of the brain. Stenosis of the aqueduct of Sylvius stops the outflow of CSF, and causes an accumulation of fluid, and pressure, primarily in the first two ventricles. Since there is no mechanism to stop CSF production in the lateral ventricles, this form of hydrocephaly is progressive. The pressure can become so great that it stretches the developing skull bones, which are still not fully hardened, resulting in the child having a head that is visibly enlarged (macrocephaly). In the process, the brain tissue is pressed against the skull, with predictably devastating effects on brain function. Many of the more severely hydrocephalic patients are either still-born or die within one year of birth.
Approximately 80% of patients with L1CAM mutations exhibit adducted thumbs (clasped across the palm). A smaller percentage exhibit aphasia (lack of speech), or problems with leg control that range from walking with a shuffling gait to spastic paraplegia that leaves them unable to walk at all.
The most common finding in brain imaging studies is the absence (agenesis) or underdevelopment (hypoplasia) of the corpus callosum. The corpus callosum is a large fiber tract that projects between the left and right hemispheres of the brain and enables information to be transferred from one hemisphere to the other. It is uncertain whether the abnormalities in the corpus callosum are an important cause of these patients' MR. It is most likely that the pressure exerted on the developing brain tissue by the hydrocephaly is a more consistent and important cause of the MR seen in these patients. Another brain structure seen to be underdeveloped in some patients with L1CAM mutations is the corticospinal tract. The corticospinal tract begins in the motor control region of the cerebral cortex and runs downward to connect with the spinal cord neurons that control the legs. Abnormal development of the corticospinal tract is probably the cause of the shuffling gait/spastic paraplegia seen in some patients with L1CAM mutations.
In the more severely hydrocephalic patients, hydrocephaly can be seen by ultrasound at 20 weeks gestation, or approximately half-way through the fetal period. For less severely affected patients, some degree of hydrocephaly is usually noted within a year after birth, along with a general developmental delay. These babies do not roll over, sit up, or reach for objects as early as babies typically do. In rarer cases, some mildly affected patients are not diagnosed until an age at which speech problems or problems with their walking gait can be observed. Adducted thumbs, when present, are noticeable from birth or are sometimes even visible upon ultrasound analysis.
Genetic testing involves a search for mutations in the L1CAM gene in patients with L1CAM spectrum disorders. The sequence of the L1CAM gene from the affected patient is compared to the normal L1CAM sequence. DNA is usually obtained from a blood sample for postnatal diagnosis. For prenatal diagnosis, DNA can be extracted from amniotic fluid cells obtained by amniocentesis , or from chorionic villus sampling.
Treatment and management
In the most severely hydrocephalic cases, the baby must be delivered by Cesarian section, because the head has grown too large by the end of the pregnancy for the baby to be delivered through the vagina. For the more severely affected patients, a ventriculoperitoneal shunt can be used to reduce the pressure inside the brain. The shunt is a tube inserted into the lateral ventricles that allows the CSF to drain into the peritoneum, or abdominal cavity. This provides a means for the CSF to flow out of the brain in cases of HSAS, in which the aqueduct of Sylvius has been closed and the CSF can not flow out of the brain by the usual channel. Shunting markedly reduces the pressure on the brain, and has saved many patients' lives. However, shunting will not prevent these patients from having MR or other L1CAM spectrum features.
Other methods for managing cases of L1CAM spectrum disorders are focused on the specific features the individual patient exhibits. Special education is almost always necessary, with the specific program designed to accommodate the degree of cognitive disability seen in the individual patient. Physical therapy and mechanical aids such as walkers can be used to help patients with milder degrees of spastic paraplegia. Speech therapy has also benefited some of the less severely aphasic patients. There is generally little improvement when these therapies are applied to more severely affected patients.
The prognosis for patients with L1CAM mutations is highly variable. The most severe cases of L1CAM mutations involve fetal demise, presumably because of the pressure exerted on the developing brain by the hydrocephaly. However, in less severe cases, the lifespan is determined primarily by general health and care factors. A number of patients with less severe L1CAM spectrum disorders have lived at least into their 50s.
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Guardians of Hydrocephalus Research Foundation. 2618 Avenue Z, Brooklyn, NY 11235-2023. (718) 743-4473 or (800) 458-865. Fax: (718) 743-1171. guardians1 @juno.com.
Hydrocephalus Support Group, Inc. PO Box 4236, Chesterfield, MO 63006-4236. (314) 532-8228. hydrobuff @postnet.com.
National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424. <http://www.ninds.nih.gov>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
L1 Mutation Web Page. <http://dnalab-www.uia.ac.be/dnalab/l1/>.
Ron C. Michaelis, PhD, FACMG