L1 syndrome describes a group of conditions that primarily affect the nervous system and occur almost exclusively in males. These conditions vary in severity and include, from most severe to least, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis.

HSAS is an acronym for the characteristic features of the condition: a buildup of fluid in the brain (hydrocephalus) that is often present from before birth, muscle stiffness (spasticity), thumbs that are permanently bent toward the palms (adducted thumbs), and narrowing (stenosis) of a passageway in the brain called the aqueduct of Sylvius. In individuals with HSAS, stenosis of the aqueduct of Sylvius causes hydrocephalus by impeding the flow of cerebrospinal fluid (CSF) out of fluid-filled cavities called ventricles. Individuals with HSAS often have severe intellectual disability and may have seizures.

MASA syndrome is also named for the characteristic features of the condition, which are intellectual disability (mental retardation) that can range from mild to moderate, delayed speech (aphasia), spasticity, and adducted thumbs. Individuals with MASA syndrome may have mild enlargement of the ventricles.

Spastic paraplegia type 1 is characterized by progressive muscle stiffness (spasticity) and the development of paralysis of the limbs (paraplegia). Affected individuals also have mild to moderate intellectual disability. People with spastic paraplegia type 1 do not usually have major abnormalities in structures of the brain.

X-linked complicated corpus callosum agenesis is defined by underdevelopment (hypoplasia) or absence (agenesis) of the tissue that connects the left and right halves of the brain (the corpus callosum). People with this condition can have spastic paraplegia and mild to moderate intellectual disability.

The life expectancy of individuals with L1 syndrome varies depending on the severity of the signs and symptoms. Severely affected individuals may survive only a short time after birth, while those with mild features live into adulthood.

The conditions that make up L1 syndrome were once thought to be distinct disorders, but since they were found to share a genetic cause, they are now considered to be part of the same syndrome. Family members with L1 syndrome caused by the same mutation may have different forms of the condition.

L1 syndrome is caused by mutations in the L1CAM gene. The L1CAM gene provides instructions for producing the L1 cell adhesion molecule protein (shortened to L1 protein), which is found throughout the nervous system. This protein is present on the surface of nerve cells (neurons), where it attaches (binds) to proteins on neighboring neurons to help the cells stick to one another (cell-cell adhesion). The L1 protein plays a role in numerous functions of neurons that contribute to brain development, thinking ability, memory, and movement.

L1CAM gene mutations that cause L1 syndrome lead to an L1 protein that cannot facilitate cell-cell adhesion or participate in various neuronal functions. Disruption of these functions likely impedes the growth and development of the brain, leading to the signs and symptoms of L1 syndrome.

Some L1CAM gene mutations result in the production of a protein that is abnormally short and nonfunctional or result in a complete absence of the protein. These mutations typically lead to severe cases of L1 syndrome, often HSAS. Other mutations change the structure of the protein, impairing the protein's ability to interact with other proteins at the cell surface or preventing the protein from reaching the cell surface where it is needed. These mutations typically lead to less severe cases of L1 syndrome, usually MASA syndrome or the other milder forms of this condition. While a mutation's effect on the L1 protein can sometimes provide a clue to the severity of the condition, individuals with the same or similar mutations can have very different signs and symptoms.

Normal Function

The L1CAM gene provides instructions for producing the L1 cell adhesion molecule protein (shortened to L1 protein), which is found on the surface of nerve cells (neurons) throughout the nervous system. The L1 protein spans the cell membrane, with one end of the protein inside the cell and the other end projecting from the outer surface of the cell. This positioning allows the L1 protein to attach (bind) to other proteins, including other L1 proteins, on neighboring neurons to help these cells stick to one another (cell-cell adhesion).

The L1 protein plays a role in the movement (migration) and organization of neurons and the outgrowth of axons, which are specialized extensions of neurons that transmit nerve impulses. The protein also plays a role in the formation of the protective sheath (myelin) that surrounds certain neurons and the formation of junctions between nerve cells (synapses), where cell-to-cell communication occurs. These neuronal functions contribute to brain development, thinking ability, memory, and movement.

Health Conditions Related to Genetic Changes

L1 syndrome

More than 350 mutations in the L1CAM gene have been found to cause L1 syndrome. L1 syndrome describes a group of conditions that vary in severity, primarily affect the nervous system, and occur almost exclusively in males. People with L1 syndrome often have brain abnormalities, intellectual disability, and movement problems. The L1CAM gene mutations that cause this condition lead to an L1 protein that cannot facilitate cell-cell adhesion or participate in various neuronal functions. Disruption of these functions likely impedes the growth and development of the brain, leading to the signs and symptoms of L1 syndrome.

Some L1CAM gene mutations result in the production of a protein that is abnormally short and nonfunctional or result in a complete absence of protein. These mutations typically lead to severe cases of L1 syndrome. Other mutations change single protein building blocks (amino acids) in the L1 protein, impairing the protein's ability to interact with other proteins at the cell surface or preventing the protein from reaching the cell surface where it is needed. These mutations typically lead to the milder forms of L1 syndrome. While a gene mutation's effect on the L1 protein can sometimes provide a clue to the severity of the condition, individuals with the same or similar mutations often have very different signs and symptoms.

Other disorders

Rarely, mutations in the L1CAM gene have also been found in individuals with both a buildup of fluid in the brain (hydrocephalus) and Hirschsprung disease. Hirschsprung disease is an intestinal disorder characterized by the absence of nerves in parts of the intestine. It is unclear whether this set of features should be classified as part of the L1 syndrome group of disorders (described above) or as a separate condition. It is likely that the L1CAM gene mutations that cause these features contribute to disruption of the normal migration and function of nerve cells in the brain and intestine, leading to hydrocephalus and Hirschsprung disease.

Other Names for This Gene

• antigen identified by monoclonal antibody R1
• CAML1
• CD171
• L1CAM_HUMAN
• MIC5
• N-CAML1
• neural cell adhesion molecule L1

Genomic Location

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

The prevalence of L1 syndrome overall is unknown; however, HSAS is estimated to affect 1 in 30,000 males.