X-Linked Hydrocephalus - 3 - The Role of L1CAM Mutations
Thursday, October 16, 2008
Kenneth F. Trofatter, Jr., MD, PhD
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 β1-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.
Labels: acqueductal stenosis, agenesis of the corpus callosusm, HSAS, L1CAM, MASA, X-linked hydrocephalus
6 Comments:
At Wed Oct 22, 02:26:00 PM 2008,
Anonymous said…
Dear Dr Trotaffer,
I dont know how to post a question so I apologize in advance. I really like the blog and I want to ask a question which you may or may not be able to answer. I am 35 and I got pregnant accidentally though I am very happy. I was extended nursing my other child through the night and I guess once I stopped the night nursing, I ovulated but I never had a period. Its scary to become pregnant this way but I assume if my hormones weren't normal it wouldn't have happened. I have decided not to get an amnio because I dont want even a small risk of harming the baby and it wouldnt change my choice of what to do anyway. But I am going through all the other tests. I had the triple screen and they told me this reduced my risk to 1 in 5000 (combined with ultrasound). But i guess there is still something as too information. I was told my PAAP-A and beta hcg are high. One is 90th percentile and one is 80th (I cant remember which is which). I happen to know that 95th percentile for beta hcg is a marker for downs and so naturally I worry anyway. Finding out I have a high beta hcg (though perhaps not abnormal) explains why in the second trimester Im still quite queasy (whereas in my last pregnancy I was totally fine after 12 weeks). The genetic counselor (probably overkill but they recommend this for women who dont do amnio) told me there are no adverse effects she knows of from high beta hcg (within a range) and high paap-a. Im a worry wart. This pregnancy is so different. At 16 weeks I look so much more pregnant than I did in my previous pregnancy and I havent gained any extra weight above whats recommended. Can you explain what accounts for variations in beta hcg and paap-a? would be much much obliged. thanks in advance.
At Tue Oct 28, 10:27:00 AM 2008,
proud papa said…
Dr. Trotaffer,
IS there a section where we can send you questions? I didn't see a section on your blog.
My wife and I recently received the news that we are expecting our third child. The first two pregnancies were without complications and my two girls are healthy. My wife is 34 and had some blood work done that included the BUN test. The bun came back indicating a high risk for Downs so an amnio has been set for two weeks along with a second ultrasound. The first Ultrasound came back normal, which the nurse said was a good sign. What in the bun test indicates that the baby may have downs? What do they look for and how accurate is it? Is the ultrasound more accurate than the bun test? along these lines how accurate will the amnio and second ultrasound be? How worried should we be that the buns results are correct given the fact that the prior pregnancies were ok and that our kids are healthy. There is also no history of downs in either of our immediate familiy histories or extended families going back several generations. Any information or stats you can provide would be greatly appreciated.
At Fri Oct 31, 05:12:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 22: Since both are elevated. It probably just represents a largere than average placenta and perhaps a larger than average baby in the end! Both are made by the placenta. The important thing is that your COMPOSITE risk based on all the factors is only 1 in 5000. The overwhelming odds are that everything is fine. Best wishes and relax. Let us know how things turn out. Dr T
At Wed Dec 17, 06:58:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To proud papa: I apologize for the delay in my response but there have been some problems with the 'blogger' and I just received your question this week. I am sure you are mistaken about the test that was done on your wife. BUN (blood urea nitrogen) is not a screening test for Down syndrome. You report that she was told she is at "high risk" for Down syndrome, but what was the actual risk result she was given. A completely normal ultrasound reduces that risk by AT LEAST 50% and in the hands of an expert, at least 60-80%. The amniocentesis can tell you with relative certainty (close to 100%) whether or not the baby has Down syndrome or any other chromosomal abnormality. A negative family history for Down syndrome does not alter your wife's age alone risks. ANYONE at ANY AGE can have a baby with a chromosomal abnormality. Best wishes and I hope everything turns out well for you. Dr T
At Tue Jun 30, 09:29:00 PM 2009,
Shrinkologist said…
cytoskeleton refers to the internal scaffolding of a cell. The scaffolding or "highway" that is located outside the cell is the extracellular matrix.
At Mon Jul 13, 06:53:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To shrinkologist - You're right. Don't know how I slipped on that one!
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