L1CAM – X-linked Hydrocephalus with Stenosis of the Aqueduct of Sylvius

X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (XLH, HSAS) is a congenital neurodevelopmental disorder caused by hemizygous mutations in the neuronal cell adhesion molecule gene L1CAM. Affected males present with prenatal‐onset ventriculomegaly, adducted thumbs, spasticity and agenesis of the corpus callosum, while carrier females are typically asymptomatic. Inheritance is X-linked recessive, consistent with segregation of pathogenic alleles in multiple pedigrees across generations.

Genetic evidence for L1CAM in XLH is definitive: over 100 unrelated affected males have been reported with segregating L1CAM mutations across >50 families (PMID:7920659). Segregation analysis demonstrates affected male relatives in at least 19 sibships, and obligate carrier testing confirms X-linked transmission. Case series and linkage studies first implicated L1CAM in HSAS, and subsequent reports have described numerous private and recurrent alleles confirming causality.

The variant spectrum is dominated by loss-of-function alleles—nonsense, frameshift, and splice-site mutations leading to truncation or absence of L1CAM—alongside pathogenic missense and silent splice-altering changes. Deep-intronic and hypomorphic variants have also been described. For example, the recurrent hemizygous nonsense mutation c.1672C>T (p.Arg558Ter) illustrates the prototypical truncating mechanism in HSAS (PMID:19641926).

Functional studies support a loss-of-function mechanism. Pathogenic missense mutations impair L1CAM homophilic and heterophilic binding, disrupt cell surface expression and neurite outgrowth in NIH-3T3‐based assays (PMID:12442287). Knock-out and knock-in animal models recapitulate ventriculomegaly and neural migratory defects, and rescue experiments confirm allele-specific effects on neuronal adhesion and axonal guidance.

No high‐quality reports refute the L1CAM–XLH association; all identified variants co-segregate with disease, and functional data uniformly demonstrate concordance with human phenotypes. No alternative loci have been consistently implicated in isolated X-linked hydrocephalus.

Key Take-home

L1CAM harbors definitive evidence for causing X-linked hydrocephalus via loss-of-function alleles; genetic testing enables accurate diagnosis, family counseling and prenatal intervention.

References

• Nature genetics • 1994 • X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. PMID:7920659
• Pediatric surgery international • 2009 • L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung's disease. PMID:19641926
• Human Mutation • 2002 • Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons. PMID:12442287

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