Finding Our Way with L1CAM

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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?

7 Comments for : Finding Our Way with L1CAM
    • Alysha
    • May 28, 2019

    My son is 8, he has the L1cam and i was wondering, if there are many families out the there that doesn’t have other people/medial professional that understand the children, can they do any more research on the gene to help out people, i am willing to work with people so more people understand the gene

    • Kitty Brockmeier
    • April 23, 2016

    In our family, we have had 4 females born with hydrocephalus. I had two babies, one who lived and one who died a week before birth from hydrocephaly. My first cousin (George) and his wife had a two boys with different neurological problems and a girl with hyrdrocephalus. The hydrocephalic daughter gave birth to a daughter with hydrocephalus. (This daughter has several children male and female without hydrocephalus. I tried to discuss this with the March of Dimes organization in Topeka, but it was never followed up on. Perhaps this group would be interested in researching why so many girls were born with this birth defect since 1969. I had several miscarriages before Angie’s birth – I have always believed it was Nature’s way of handling an abnormal fetus. Would someone care to contact me about this rare (as far as I know) circumstance? I’d be happy to discuss it and give you the names and phone numbers of my cousin and his daughter and grandchild.

      • Liliana Madrigal
      • September 5, 2018

      Hello my name is lily and i have a son who was recently born with hydrocephalus due to the X chromosome and i was told the same thing and well i just want more info. I can go more into detail and his journey so far by email and so on. I would much appreciate a response. Thank you.

        • Natalia
        • October 3, 2018

        Hi Liliana, I encourage you to reach out to our support staff if you have specific questions about your son’s hydrocephalus diagnosis. The email address is:

        • Amrin
        • November 12, 2018

        What you do for you son ? Plz inform me I have similar problem

        • Amrin
        • November 12, 2018

        What treatment you do for you son ? Plz inform me I have similar problem

    • Bernadette
    • March 28, 2016

    Four months ago, my husband recently went through two surgeries in one day (bleeding from the residual tumor caused a second emergency surgery), to remove a pituitary macroadenoma which resulted in a communicating hydrocephalus. Subsequently, the lumbar puncture, lumbar drain and VP shunt procedure each gave him the ability close his mouth and to speak normally and with cognition for ONE day but this ability to speak left him within 2-3 days, each time after the procedures. A medium pressure shunt was placed and the ventricles have not decreased in size in 30 days since implantation. The day he returned from the OR with the shunt, he could close his mouth, open his eyes widely and speak for that day and again lost the ability to do those things within 3 days. Has anyone ever heard of a case such as this? I am begging the surgeons to replace the shunt with a programmable version or a low pressure valve because the medium pressure valve is not enabling him to speak or maintain a closed mouth or move his limbs as he was able to do in the first 12 hours following all of the foregoing procedures. My husband will die without intervention. He has been in hospital for 4.5 months and has survived 5 pneumonias, G tube infection, bladder infection and sepsis. Time is of the essence. Anyone heard of a similar case\/

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