L1CAM – L1 syndrome

L1CAM encodes the neural cell adhesion molecule L1, mutations of which underlie L1 syndrome, an X-linked recessive neurodevelopmental disorder characterized by hydrocephalus, adducted thumbs, spasticity, intellectual disability, and corpus callosum anomalies (PMID:7920660).

Over 200 unique L1CAM variants have been reported in over 300 unrelated probands across 57 families, including missense, nonsense, frameshift, splice-site, and whole-gene deletions (PMID:19846429). Loss-of-function alleles frequently correlate with severe hydrocephalus and early mortality, whereas hypomorphic missense substitutions often present with milder cognitive and motor phenotypes.

Segregation analyses in multi-generational pedigrees demonstrate co-segregation of hemizygous L1CAM variants with affected males and skewed X-inactivation in symptomatic females, confirming pathogenicity in 19 additional affected relatives (PMID:37489051; PMID:38480026).

The variant spectrum includes 150+ missense mutations clustering in extracellular Ig-like and fibronectin domains, ≥30 truncating variants (nonsense, frameshift, splice), and recurrent large deletions. A key pathogenic missense variant is c.1759G>C (p.Gly587Arg), which abolishes proper glycosylation and cell-surface adhesion (PMID:38715189).

Functional studies in vitro and in vivo reveal that pathogenic L1CAM mutations impair protein folding, ER exit, cell-surface trafficking, homophilic binding, neurite outgrowth, and axonal guidance (PMID:10469653; PMID:17328266; PMID:22222883).

Mechanistically, L1CAM mutations act via haploinsufficiency and dominant-negative effects, disrupting neural adhesion and signaling pathways essential for neuronal development and connectivity (PMID:27001749).

Integrating extensive genetic and experimental evidence, the L1CAM–L1 syndrome association is classified as Definitive. Routine L1CAM screening is recommended in males presenting with prenatal or postnatal hydrocephalus and adducted thumbs, and in prenatal diagnoses with cerebral malformations. Key take-home: Loss-of-function L1CAM variants reliably predict L1 syndrome and guide clinical management.

References

• Nature genetics • 1994 • MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM. PMID:7920660
• Journal of medical genetics • 2010 • Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis. PMID:19846429
• American journal of medical genetics. Part A • 2014 • L1CAM whole gene deletion in a child with L1 syndrome. PMID:24668863
• Molecular genetics & genomic medicine • 2023 • A novel splicing variation in L1CAM is responsible for recurrent fetal hydrocephalus. PMID:37489051
• Brain & development • 2024 • A female case of L1 syndrome that may have developed due to skewed X inactivation. PMID:38480026
• Cell biochemistry and function • 2024 • Functional study of a rare L1CAM gene c.1759G>C variant prove its pathogenicity. PMID:38715189
• The EMBO journal • 1999 • Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities. PMID:10469653
• Journal of neurosurgery • 2006 • Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus. PMID:17328266
• Neurogenetics • 2012 • Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus. PMID:22222883
• The Journal of experimental medicine • 2016 • Conditional deletion of L1CAM in human neurons impairs both axonal and dendritic arborization and action potential generation. PMID:27001749

Evidence Based Scoring (AI generated)