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L1 Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1997, 1998, 2005, 2012

NORD is very grateful to Joseph Kim, NORD Editorial Intern from the University of Notre Dame, and Connie TRM Schrander-Stumpel, MD, PhD, Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), MaastrichtUMC+, Maastricht, the Netherlands, for assistance in the preparation of this report.

Synonyms of L1 Syndrome

Disorder Subdivisions

General Discussion

L1 syndrome is an inherited, X-linked disorder occurring in males that primarily affects the nervous system. The disease is mainly characterized by hydrocephalus (increased fluid in the center of the brain), spasticity of the lower limbs (muscle stiffness), adducted thumbs (clasped towards the palm), aphasia (difficulty with speaking), seizures, and agenesis of the corpus callosum (underdeveloped or absent connecting tissue between the left and right hemispheres of the brain). Affected individuals have intellectual disability in the mild to moderate range. L1 syndrome is caused by abnormalities (mutations) in the L1CAM gene, which affects about 1 in 30,000 males.

The acronym CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus) syndrome was originally proposed in 1995 by Dr. Erik Fransen to describe L1 syndrome but is no longer used.


The variable types of L1 syndrome were once thought to be different diseases, but all of the following conditions are now known to be 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 intellectual disability.

MASA syndrome (mental retardation, aphasia, spastic paraplegia adducted thumbs) is characterized by mild to moderate intellectual disability, 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 intellectual disability and more or less normal findings on MRI of the brain.

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


L1 syndrome is an X-linked genetic disorder that occurs primarily in males. L1 syndrome is caused by mutations in the L1CAM gene located on the X chromosome at Xq28.

Chromosomes are present in the nucleus of the human cells and contain an individual’s genetic information. Normal individuals contain 23 pairs of chromosomes for a total of 46. There are 22 autosomes (chromosomes that are not sex chromosomes) numbered 1-22, and sex chromosomes labeled X and Y. Normal males have one X and one Y chromosome while normal females have two X chromosomes. Each chromosome has two arms; a short arm labeled "p" and a long arm labeled "q". These chromosomes are even further divided into numbered bands. For example, "chromosome Xq28" refers to band 28 on the long arm of the X chromosome. These bands are specific locations for the thousands of genes located on individual chromosomes.

An abnormal gene on the X chromosome causes X-linked disorders, such as L1 syndrome. Normal females have two X chromosomes, in which one is activated chromosome and the other is inactivated. The majority of female carriers for L1 syndrome do not show symptoms because the X chromosome containing the disease gene is usually the inactivated chromosome. Males have only one X chromosome and will develop L1 syndrome if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters, but will only pass their normal Y chromosome to their sons. Therefore, all of the daughters of an affected male will be carriers for the disease while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease while daughters have a 50 percent chance of becoming carriers.

Affected Populations

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.

Related Disorders

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

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain and spinal cord. Symptoms develop due to lack of the fatty covering (myelin sheath) of nerve cell fibers. Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, brain stem and spinal cord. Signs may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, and late onset loss of motor abilities and progressive deterioration of intellectual function. The neurologic signs of PMD are usually slowly progressive. PMD is associated with abnormalities (mutations) in the PLP1 gene. Several forms of the disorder have been identified including classic PMD; connatal PMD; transitional PMD; and PLP1 null syndrome. Forms of complicated spastic paraparesis and pure spastic paraparesis (designated SPG2) are also caused by the PLP1 gene. (For more information about Pelizaeus-Merzbacher disease, search for this term in the Rare Disease Database.)

Standard Therapies

Neuropathology and neuroimaging are used to reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius, corpus callosum agenesis/hypogenesis, cerebellar hypoplasia, small brain stem, and agenesis of the pyramids.

MRI or autopsy that reveals bilateral absence of the pyramids is a characteristic finding of L1 syndrome, which is a confirmed diagnosis of the disease.

Molecular genetic testing for the L1CAM gene is available to confirm the diagnosis. Carrier testing for at-risk relatives, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) can be performed, but requires prior information on any disease-causing mutations in the family.

Clinical Testing and Work-Up
Patients with L1 syndrome should be closely monitored by a team of specialists and physicians. Early intervention and monitoring are very important to help the affected individual in development.

The treatment of L1 syndrome is directed toward the specific symptoms that are apparent in each individual. The best management involves the collaboration of a multidisciplinary team, which includes expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics.

Surgical treatment may need to be performed for hydrocephalus. Shunting of cerebrospinal fluid (CSF) can reduce intracranial pressure from the brain.

Although surgical intervention is not usually necessary, tendon transfer may help thumb function for patients with adducted thumbs. Splints may also help reduce the severity of adduction.

Intellectual disability is highly variable and developmental progress should be monitored and counseling provided.

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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

Contact for additional information about L1 syndrome:

Connie TRM Stumpel, MD, PhD
Clinical Geneticist
Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW)
MaastrichtUMC+, Maastricht, the Netherlands
(043) 3875778

L1 Syndrome Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., mental retardation, aphasia, hydrocephalus, etc.].)

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:


Weller S, and Gartner J. Genetic and clinical aspects of X-linked hydrocephalus (l1 disease): mutations in the L1CAM gene. Hum Mutat. 2001;18:1-12.

Finckh U, Schroder J, Ressler, B, et al. Spectrum and detection rate of the L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. Am J Med Genet. 2000;92:40-6.

Schrander-Stumpel CT, Krijne-Kubat B, Vandevijver N, et al. Studies of congenital hydrocephalus with special emphasis on the X-linked type: the need for a protocol. Proceedings of the Greenwood Genetic Center. 2000;19:74.

Fransen E, Van Camp G, D'Hooge R, et al. Genotype-phenotype correlation in L1 associated diseases. J Med Gent. 1998:35:399-404.

Schrander-Stumpel C, Fryns JP. Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counseling. Eur J Pediatr. 1998;157:355-62.

Fransen E, Lemmon V, Van Camp G, et al. CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1. Eur J Hum Genet. 1995;3:273-84.

Bianchine JW, Lewis RC Jr. The MASA syndrome: a new heritable mental retardation syndrome. Clin Genet. 1974;5:298-306.

Schrander-Stumpel C, Vos YJ. (Updated December 23, 2010). L1 Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed July 18, 2012.

L1 Syndrome . Genetics Home Reference. http://ghr.nlm.nih.gov/condition/l1-syndrome Reviewed March 2008. Accessed July 18, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. MASA Syndrome. Entry No: 303350. Last Edited April 7, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 18, 2012.

Report last updated: 2012/08/02 00:00:00 GMT+0