L1 Syndrome

National Organization for Rare Disorders, Inc.

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It is possible that the main title of the report L1 Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


  • L1 spectrum
  • L1 disease
  • MASA syndrome
  • SPG1 (X-linked complicated hereditary spastic paraplegia type 1)
  • X-linked corpus callosum agenesis
  • X-linked hydrocephalus with stenosis of the aqueduct of sylvius
  • HSAS, aqueductal stenosis, X-linked

Disorder Subdivisions

  • None

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.

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




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.


National Hydrocephalus Foundation

12413 Centralia Rd.

Lakewood, CA 90715-1653


Tel: (562)924-6666

Fax: (562)924-6666

Tel: (888)857-3434

Email: nhf@earthlink.net

Internet: http://www.nhfonline.org

Hydrocephalus Association

4340 East West Highway Ste 950

Bethesda, MD 20814


Tel: (301)202-3811

Fax: (301)202-3813

Tel: (888)598-3789

Email: info@hydroassoc.org

Internet: http://www.hydroassoc.org

National Aphasia Association

350 Seventh Avenue

Suite 902

New York, NY 10007


Tel: (212)267-2814

Fax: (212)267-2812

Tel: (800)922-4622

Email: responsecenter@aphasia.org

Internet: http://www.aphasia.org

NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/

NIH/National Institute on Deafness and Other Communication Disorders

31 Center Drive, MSC 2320

Communication Avenue

Bethesda, MD 20892-3456

Tel: (301)402-0900

Fax: (301)907-8830

Tel: (800)241-1044

TDD: (800)241-1105

Email: nidcdinfo@nidcd.nih.gov

Internet: http://www.nidcd.nih.gov

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/

For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.