NORD gratefully acknowledges Joseph Kim, NORD Editorial Intern from the University of Notre Dame, and Connie Stumpel, MD, PhD, Department of Clinical Genetics, and School for Oncology & Developmental Biology (GROW), Maastricht University Medical (MUMC+), Maastricht, The Netherlands, for assistance in the preparation of this report.
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 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.
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.
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.
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.
The diagnosis is sometimes made in a male with a nonspecific developmental delay using exome sequencing. When this is the case, a good clinical workup is needed to look for other signs of the syndrome in the affected male and in his family members.
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 is recommended for family members of affected individuals.
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: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about L1 syndrome:
Connie TRM Stumpel, MD, PhD
Prof. of Clinical Genetics
Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW)
MaastrichtUMC+, Maastricht, the Netherlands
L1 Syndrome Resources
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.].)
Otter M, Wevers M, Pisters M, et al. A novel mutation in L1CAM causes a mild form of L1 syndrome: a case report. Clinical Case Reports 2017;5(8):1213-1217.
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.
Stumpel C, Vos YJ. L1 Syndrome. 2004 Apr 28 [Updated 2015 Mar 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1484/ Accessed April 12, 2018.
L1 Syndrome . Genetics Home Reference. http://ghr.nlm.nih.gov/condition/l1-syndrome Reviewed April 2017. Accessed April 12, 2018.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. MASA Syndrome. Entry No: 303350. Last Edited 10/12/2015. Available at: http://omim.org/entry/303350 Accessed April 12, 2018.
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