Finding Our Way with L1CAM

x chromosomeThe causes of hydrocephalus are varied and in many cases result from a combination of genetic susceptibility, environmental factors, and injury. One example with a clear genetic linkage is X-linked hydrocephalus, a rare genetic disorder that occurs in about 1 of 30,000 births (Edwards 1961). X-linked hydrocephalus is characterized by stenosis, or narrowing, of the aqueduct of Sylvius and severe ventriculomegaly. It is part of a group of conditions linked by mutations in the L1CAM gene. Collectively the conditions are called L1 syndrome, whose symptoms can vary greatly in severity, and include: MASA (mental retardation, adducted thumbs, shuffling gait and aphasia) syndrome, certain forms of X-linked spastic paraplegia (SPG1), and X-linked agenesis of the corpus callosum (ACC).

The vast majority (99%) of symptomatic individuals are male. L1CAM mutations can occur in a person through a spontaneous, new (de novo) mutation or by inheriting the mutation from his or her mother. There are no reported cases of inheritance through the father. L1CAM mutations are inherited through the maternal line because L1CAM is located on the X chromosome (X-linked inheritance). During reproduction, an individual acquires two sex chromosomes, one from each parent. Females have two X chromosomes (XX) while males have an X chromosome from the mother and a Y chromosome from the father (XY).

Females with one affected X chromosome are called ‘carriers’ and have less than a 5% chance of showing clinical symptoms. This is because females have a second, intact copy, of the L1CAM gene which is inherited from the father.  A female carrier has a 50% chance of transmitting the affected gene to each child. Males with an affected X chromosome have L1 syndrome because the Y chromosome does not contain the L1CAM gene. Therefore, in males, all of the gene products are produced from the one affected L1CAM gene. The severity and type of symptoms are dependent on where and what genetic mutation is present.


During brain development, the L1CAM gene produces the L1 cell adhesion molecule (L1). L1 is primarily present in developing neurons and plays a critical role in guiding new neurons into the correct positions and helping axons grow and make connections with other neurons. Disruptions caused by mutations in the L1CAM gene impair these critical function and alter brain development.

One theory suggests that inactive L1 results in slow neural migration and axon growth. As a result, neurons in the developing brain are both miss-positioned and fail to make the correct connections to other neurons throughout the brain and spinal cord. These factors could account for clinical symptoms such as adducted thumbs and developmental challenges. An additional question is why disruptions in L1CAM cause hydrocephalus. Two theories have been posed. One suggests that L1CAM mutations decrease the brain elasticity, through alterations in white matter, which in turn makes the brain more susceptible to changes in intracranial pressure. Another theory suggests that maldevelopment of the brain leads to aqueductal stenosis and subsequent hydrocephalus.

More research is needed to test these theories and others, but by uncovering and understanding how L1 functions, it may be possible to develop targeted therapies to stop disease progression and improve quality of life. The ultimate goal, of course, is to repair or replace inactive L1 before any harm can be done.

Here are some Research 101 blogs by Dr. Jenna Koschnitzy, our Research Programs Director, that provide good background reading to better understand this blog:

Neurons – a brain superhighway!

What’s the Matter?