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L1 Syndrome.


Stumpel C1, Vos YJ2.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2004 Apr 28 [updated 2015 Mar 5].

Author information

Department of Clinical Genetics, Academic Hospital Maastricht and School for Oncology & Developmental Biology (GROW), Maastricht University and University Hospital Maastricht (MUMC+), Maastricht, The Netherlands
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands



The phenotypic spectrum of L1 syndrome includes: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS); MASA syndrome (mental retardation, aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs); SPG1 (X-linked complicated hereditary spastic paraplegia type 1); and X-linked complicated corpus callosum agenesis. Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50).


The diagnosis of L1 syndrome can be established in males with characteristic clinical and neuropathologic findings and a family history consistent with X-linked inheritance. Of note, bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding. Detection of a hemizygous pathogenic variant in L1CAM confirms the diagnosis of L1 syndrome.


Treatment of manifestations: It is best to involve a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Shunting of the cerebrospinal fluid (CSF) should be performed as needed to reduce intracranial pressure. Surgery for adducted thumbs is not indicated; in some milder cases, tendon transfer and/or splint may improve thumb function. Surveillance: Monitoring of developmental progress and neurologic findings.


L1 syndrome is inherited in an X-linked manner. Women who are carriers have a 50% chance of transmitting the L1CAM pathogenic variant in each pregnancy. Sons who inherit the L1CAM pathogenic variant will be affected; daughters who inherit the pathogenic variant will be carriers. Affected males do not reproduce. Carrier testing of at-risk female relatives and prenatal testing are possible if the L1CAM pathogenic variant has been identified in an affected family member.

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