Object: Mutations in the gene that codes for the human neural cell adhesion molecule L1 (L1CAM), are known to cause a wide variety of anomalies, now understood as phenotypic expressions of L1 syndrome. The correlations between genotype and phenotype, however, are not fully established. The authors report the results of a nationwide investigation of L1CAM gene mutations that was performed to improve the understanding of L1-mediated molecular mechanisms of X-linked hydrocephalus and to establish neurorimaging criteria for this severe form of L1 syndrome.
Methods: Ninety-six genomic DNA samples from members of 57 families were obtained from the Congenital Hydrocephalus Research Committee. By using polymerase chain reaction and direct DNA sequencing, the authors identified 25 different L1CAM gene mutations, 20 of them novel, in 26 families with X-linked hydrocephalus. All the mutations were L1CAM loss-of-function mutations, and all the patients had severe hydrocephalus and severe mental retardation. In all cases, specific abnormalities were visible on neuroimaging: a rippled ventricular wall after shunt placement, an enlarged quadrigeminal plate, a large massa intermedia, and hypoplasia of the cerebellar vermis (anterior or total). The patients also had adducted thumbs, spastic paraplegia, and hypoplasia of the corpus callosum, which are characteristic of L1 syndrome.
Conclusions: The L1CAM loss-of-function mutations cause a severe form of L1 syndrome, unlike the milder form produced by mutations in the L1CAM cytoplasmic domain. We also identified neurorimaging criteria for this severe form of L1 syndrome. These criteria can be used to predict loss-of-function mutations in patients with X-linked hydrocephalus and to help in diagnosing this syndrome.