The CRASH spectrum of overlapping syndromes that are characterized by variable expression of Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, are all the result of a variety of mutations in the cell adhesion molecule L1 (L1CAM) gene, located on the X-chromosome at Xq28. L1CAM is a transmembrane glycoprotein belonging to immunoglobulin superfamily of cell adhesion molecules. Its expression appears to be essential during embryonic development of the central nervous system and, based on the findings in the HSAS/MSAS spectrum of presentations, it must also be involved in the development of pathways for cognitive function and memory.
As mentioned in previous posts, there are a variety of L1CAM mutations with familial inheritance patterns that have been identified. MacFarlane and colleagues (Hum Mutat 1997;9:512-18) reported that most of the mutations identified have been point mutations – missense, nonsense, and splice site. In rarer instances, larger chromosomal rearrangements and deletions of variable length have also been found. Several authors have demonstrated that the severity and phenotypic expression of HSAS/MASA syndromes depend to a large extent on the site of the mutation.
Michaelis and colleagues (J Med Genet 1998;35:901-4) hypothesized that disease severity might be correlated with mutations at the sites of the key amino acid residues responsible for maintaining immunoglobulin-type C-like structure of L1CAM and fibronectin type III-like domains (which with the L1CAM product interacts). Indeed, they found that key mutations in either of these were more likely to produce severe hydrocephalus, adducted thumbs, and survival less than one year. Mutations in the fibronectin domains alone were more likely to cause severe hydrocephalus and decreased survival, but were less likely to be associated with adducted thumbs. Similarly, Kanemura and colleagues (J Neurosurg 2006;1055( suppl):403-12) studied 96 DNA samples from members of 57 families with HSAS/MASA by polymerase chain reaction and direct DNA-sequencing and concluded that L1CAM “loss of function mutations” resulted in most severe manifestations of hydrocephalus, retardation, adducted thumbs, spastic paraplegia and hypoplasia of corpus callosum.
So, the question remains, how does malfunction or nonfunction of L1CAM contribute to the abnormalities associated with X-linked HSAS/MASA syndromes? Thelen and colleagues (J Neurosci 2002;22:4918-31) reported that L1CAM under normal circumstances “potentiates integrin-dependent neuronal cell migration to extracellular matrix proteins through ?1-integrins and intracellular signaling to mitogen-activated protein (MAP) kinase.” This migration of neural cells is necessary for axon growth, fasciculation, and neural migration. In other words, malfunction of L1CAM can contribute to decreased growth of and connections between neuronal cells throughout the central nervous system. This most certainly accounts for the ‘global’ problems associated with HSAS/MASA syndromes that cannot be explained by the degree of hydrocephalus alone or that may be present in the absence of hydrocephalus.
The mechanism by which L1CAM effects its action on neuronal cell migration appears to be through its potentiation of interactions between the neuronal cells and the ‘cytoskeleton’ – the highway along which the cells must travel to reach their various destinations. As pointed out by Buhusi and colleagues (J Neurosci 2008;28:177-88), “Dynamic modulation of adhesion provided by anchorage of axonal receptors with the cytoskeleton contributes to attractant or repellent responses that guide axons to topographic targets in the brain. The neural cell adhesion molecule L1 engages the spectrin-actin cytoskeleton through reversible linkage of its cytoplasmic domain to ankyrin.” In their elegant study in a mouse model in which an L1 point mutation was identified that abolishes ankyrin binding and is associated with vision impairment, they found “striking mistargeting of mutant ganglion cell axons from the ventral retina…to abnormally lateral sites in the contralateral superior colliculus, where they formed multiple ectopic arborizations.” In other words, the neurons did not migrate to where they were supposed to go and furthermore they formed abnormal connections with other neurons. More recent studies (e.g. Law, et al., Development 2008;135(14):2361-71 and Wang, et al., J Cell Biol 2008 Jan 14;180:233-46) are dissecting this mechanism in much greater detail than I am capable of exploring herein!
The only other point I wanted to mention before closing this series is the following: Because of the extensive research that has been done on HSAS/MASA X-linked conditions, individuals from affected families can have carrier status determined and counseling provided prior to conception. Furthermore, for individuals with the desire and the resources, the possibility of in vitro fertilization preceded by preimplantation genetic diagnosis (PGD) exists and can be used to identify both affected males and carrier females prior to embryonic transfer (Gigarel, et al., Hum Genet 2004;114:298-305). This provides the extraordinary possibility of eventually eliminating the mutation and the risk associated with these devastating conditions from affected families.