L1 Syndrome

What Causes L1 Syndrome?

L1 syndrome is caused by abnormal changes (mutations) in a gene called the L1CAM gene. This gene is responsible for the production of a protein that is vital in normal nerve cell functioning. The L1CAM mutations that cause L1 syndrome to interfere with the production of the L1 protein, so the nerve cells that depend on it cannot grow and function normally, leading to the syndrome’s symptoms.

Is L1 Syndrome Hereditary?

L1 syndrome is an inherited disorder that is passed from parents to their children. The L1CAM gene is located on the X chromosome, meaning that it is an X-linked disorder. Females have two copies of the X chromosome, one inherited from each parent, but males have only one copy of the chromosome. Therefore, females are likely to have only one copy of the mutated gene, so they typically have mild or no symptoms at all. However, males who inherit a mutated L1CAM gene have no normal copy of the gene to compensate, so they develop more severe symptoms.

X-linked disorders have a unique pattern of inheritance:

• Males with the mutation will always pass the mutation to their daughters.
• Males cannot pass the mutation to their sons.
• Daughters of males with the mutation will be carriers of the mutated gene.
• Females with the mutation will pass the disorder to their sons half the time.
• Daughters of females with the mutation will be carriers half the time.

How Is L1 Syndrome Detected?

L1 syndrome can sometimes be diagnosed before birth. Mothers who are known carriers or have a family history of the disorder may be advised to undergo screening exams to detect the syndrome during pregnancy. Chorionic villus sampling or amniocentesis can identify the disorder-causing gene mutations, and ultrasound imaging after the twentieth week of pregnancy may detect hydrocephalus, which is often a characteristic of the disorder.

How Is L1 Syndrome Diagnosed?

L1 syndrome may be diagnosed when a child presents symptoms of the disorder, brain malformations commonly associated with L1 syndrome, and the genetic mutations that cause the disorder. The diagnostic process usually includes:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Imaging scans such as MRI or CT to look for hydrocephalus, stenosis of the aqueduct of Sylvius, or brain malformations such as agenesis of the corpus callosum or a small brain stem
• Genetic testing to look for disorder-causing L1CAM mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is L1 Syndrome Treated?

L1 syndrome has no cure, and treatment will not reverse the effects of its symptoms. Treatments and therapies aim instead to lessen the impact of symptoms and prevent complications. Common treatments and therapies include:

• Surgery to install a thin plastic tube (called a shunt) to drain excess fluid from the brain in the case of hydrocephalus
• Physical therapy
• Speech therapy
• Special education

How Does L1 Syndrome Progress?

The long-term outlook for children with L1 syndrome varies depending on the severity of the symptoms. The effects of the disorder vary widely from case to case, and even people with the same disorder-causing gene mutations may show very different symptoms. In some cases, the symptoms are so severe that the child does not survive long after birth. In patients with less severe symptoms, survival to adulthood is common.

Long-term effects of L1 syndrome can include:

• Speech impairments
• Mobility problems associated with rigid muscles
• Seizures
• Fluid accumulation in the brain (hydrocephalus) that causes neurological symptoms
• Intellectual disability

How Is L1 Syndrome Prevented?

There is no known way to prevent L1 syndrome when the disorder-causing gene mutations are present. Parents with a family history of the disorder or who have had another child with L1 syndrome are advised to consult a genetic counselor to assess their risk if they plan to have another child. Parents trying to have a child via in vitro fertilization may have fertilized embryos screened for the mutations before implantation.

L1 Syndrome Caregiver Tips

• The different forms of L1 syndrome and the wide variation of symptoms even within the disorder’s subtypes mean that your child’s experience is different from that of every other child with the condition. Learn as much as you can about the disorder’s unique effects on your child so you can best support them.
• Remember that you’re not alone. Online support groups can be significant sources of information and can link you with families also living with L1 syndrome.

L1 Syndrome Brain Science

The L1CAM gene carries instructions for making a protein called the L1 cell adhesion molecule protein. This protein is essential to nerve cells in the central nervous system, where it lies on the surface of the cells and sticks to proteins on the surface of other cells. The process allows the nerve cells to cling to one another, which is vital to their proper functioning.

Some L1CAM mutations that cause L1 syndrome result in a non-functional L1 protein or a complete absence of the protein. These mutations usually produce the more severe forms of L1 syndrome, such as HSAS. Other mutations produce an altered L1 protein that doesn’t function normally. These mutations typically cause less severe forms of the disorder, such as MASA syndrome.

L1 Syndrome Research

Title: Brain Development Research Program

Stage: Recruiting

Principal investigator: Elliott H Sherr, MD, PhD

University of California, San Francisco

San Francisco, CA

Dr. Elliott Sherr and his collaborators at the University of California, San Francisco (UCSF) are studying the genetic causes of disorders of cognition and epilepsy, in particular disorders of brain development that affect the corpus callosum, such as Aicardi syndrome, as well as two additional brain malformations, polymicrogyria and Dandy-Walker malformation. The investigators’ research aims to better understand the underlying genetic causes as a foundation to develop better treatments for these groups of patients.

Researchers are studying both the genetics and clinical features of these disorders. We hope to understand the problems faced by individuals with these disorders as well as their causes. In the future, we hope to develop therapies that are geared specifically for individuals based on the underlying biology. To participate in the study, participants will be asked to provide a copy of the magnetic resonance imaging (MRI) documenting Agenesis Corpus Callosum (ACC), Polymicrogyria (PMG), or Dandy-Walker malformation (DWM), clinical information, and saliva or blood samples from the affected individual and the parents. Please see contact information and our webpage:  https://brain.ucsf.edu/elliott-sherr-md-phd

Title: Efficacy Study of Hydrocephalus Surgery by Methods of Neuroelectrophysiology

Stage: Recruiting

Contact: Jian Wang

Nicolet EEG

Pleasanton, CA

The symptoms of hydrocephalus in some patients will be relieved after the cerebrospinal fluid release test is carried out. Neuroelectrophysiology in patients with disorders of consciousness of post-traumatic hydrocephalus (PTH) can establish the association with consciousness and muscle tone to a certain extent and predict the shunt effect of PTH with disorders of consciousness.

Title: Genetic and Physical Study of Childhood Nerve and Muscle Disorders

Stage: Recruiting

Contact: Carsten G. Bonnemann, MD

National Institute of Neurological Disorders and Stroke (NINDS)

Bethesda, MD

Objective: To diagnose and elucidate the underlying disease mechanism in patients with neuromuscular and neurogenetic disorders with congenital or pediatric-onset (phase 1 of the protocol) and to study the natural history and mechanism of disease in neuromuscular and neurogenetic disorders of childhood (phase 2 of the protocol).

Study population: Patients with childhood-onset neuromuscular and neurogenetic disorders, their affected and unaffected family members, and healthy volunteers. Patients with later onset of disorders known to typically have childhood-onset will be included.

Design: Diagnostic and prospective longitudinal natural history study.

Outcome Measures: Diagnose and characterize patients with neuromuscular and neurogenetic disorders with congenital or pediatric-onset and study the natural history and underlying disease mechanism. In the characterized patient population, identify and develop effective outcome measures for use in future clinical trials, including applicable motor scales, quality of life scales, biomarkers from blood and urine, imaging studies, and pulmonary function tests.