Information on the following diseases can be found in the Related Disorders section of this report:

• X-linked Hydrocephalus
• Complicated X-linked Spastic Paraplegia
• Uncomplicated X-linked Spastic Paraplegia
• X-linked Mental Retardation Renpenning Type (Renpenning Syndrome)

The variable types of L1 syndrome were once thought to be different diseases, but all of the following conditions are caused by mutations in the L1CAM gene:

X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS) is characterized by severe hydrocephalus that often begins prenatally, adducted thumbs, spasticity and severe mental retardation.

MASA syndrome (mental retardation, aphasia, spastic paraplegia adducted thumbs) is characterized by mild to moderate mental retardation, aphasia (delayed speech), hypotonia that progresses to spasticity, adducted (clasped) thumbs, and variable widening of the third ventricle in the brain.

X-linked complicated hereditary spastic paraplegia type 1 is characterized by spastic paraplegia (shuffling gait), mild to moderate mental retardation and normal findings on MRI of the brain.

X-linked complicated corpus callosum agenesis is characterized by variable spastic paraplegia, mild to moderate mental retardation and abnormalities in the corpus callosum of the brain.

L1 syndrome is caused by an abnormality in L1CAM gene located on the X chromosome at Xq28. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq28" refers to band 28 on the long arm of the X chromosome . The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

L1 syndrome is inherited as an X-linked recessive genetic trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off’ and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

L1 syndrome is a genetic condition that occurs almost exclusively in males. The birth prevalence of the HSAS type of L1 syndrome is approximately 1 in 30,000 births. The frequency of all types of L1 syndrome is not known. Approximately 5% of female carriers of an L1CAM gene mutation have some symptoms that are usually mild.

Symptoms of the following disorders may be similar to those of L1 syndrome. Comparisons may be useful for a differential diagnosis:

PLP1-related disorders are a group of disorders that are variable in severity and caused by mutations in the PLP1 gene. Pelizaeus-Merzbacher disease is a PLP1-related disorder in which symptoms begin in infancy and include nystagmus (rapid eye movements), hypotonia (low muscle tone) and mild mental retardation and progress to severe spasticity and ataxia (uncoordinated movements). Spastic paraplegia 2 (SPG2) is a milder type of PLP1 disorder characterized by late onset, exaggerated reflexes (hyperreflexia), and an awkward (spastic) gait. Some individuals with SPG2 may also have nystagmus, gradual deterioration of the nerves of the eyes (optic atrophy), mild intellectual disability, and/or impaired ability to coordinate voluntary movements of the arms. PLP1-related disorders are inherited as X-linked recessive genetic traits. (For more information about Pelizaeus-Merzbacher disease, search for this term in the Rare Disease Database.)

Diagnosis
The diagnosis of L1 syndrome is based on a thorough clinical evaluation, detailed patient history, identification of characteristic physical findings, and advanced imaging techniques. Advanced imaging studies (e.g., CT or MRI scanning) may reveal or confirm the presence of certain brain abnormalities (e.g., hydrocephalus, enlargement of ventricles, aqueductal stenosis, agenesis of corpus callosum). Molecular genetic testing for mutations in the L1CAM gene can be used to confirm the diagnosis. Prenatal diagnosis and carrier testing are possible if an L1CAM gene mutation has been identified in an affected family member.

Treatment
The treatment of L1 syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat disorders of the nervous system (neurologists), specialists who diagnose and treat skeletal abnormalities (orthopedists), speech pathologists, physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Surgery for hydrocephalus may be indicated to insert tubes (shunts) to drain excess cerebrospinal fluid away from the brain and relieve pressure. Surgery is not usually necessary to treat adducted thumbs.

Early intervention is important to ensure that children with L1 syndrome reach their potential. Special services that may be beneficial to affected children may include special education, special social support, physical therapy, and/or other medical, social, and/or vocational services.

Genetic counseling may be beneficial for family members of affected individuals.

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