X-Linked Hydrocephalus - 3 - The Role of L1CAM Mutations

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 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

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X-Linked Hydrocephalus - 2 - HSAS/MASA Spectrum of Disease

Yesterday we began a discussion of “X-linked hydrocephalus.” As we pointed out, this is not a single disease entity, but a spectrum of overlapping syndromes that are characterized by variable expression of Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, sometimes referred to as CRASH. All are the result of a variety of mutations in the cell adhesion molecule L1 (L1CAM) gene, located on the X-chromosome at Xq28 and have variable penetrance even within families. The two most common ‘syndromes’ are often considered together as the HSAS/MASA spectrum.

HSAS stands for Hydrocephalus as result of Stenosis of the Acqueduct of Sylvius. The characteristic picture of acqueductal stenosis was described in the case presented in our last post. The baby developed symmetrical enlargement of the lateral ventricles, as well as the 3rd ventricle which sits beneath the lateral ventricles and in the midline between the thalami. Under normal circumstances, the cerebrospinal fluid (CSF) drains from the lateral ventricles into the 3rd ventricle and then must pass along a very narrow canal, the Acqueduct of Sylvius, into the 4th ventricle, sitting directly in front of the cerebellum, before emptying into the large space at the back of the brain (the cisterna magna) and then the spinal canal. When the Acqueduct of Sylvius becomes obstructed (for any number of different reasons), the plumbing backs up with enlargement of both the lateral ventricles and, eventually, the 3rd ventricle. This obstruction is termed acqueductal stenosis.

Interestingly, in HSAS, acqueductal stenosis might actually be a secondary effect of the condition and not the primary cause of the ventricular enlargement, although there can be no doubt that when it occurs, the stenosis contributes to the ventriculomegaly. X-linked inheritance is thought to account for about 7 to 27% of hydrocephalus of unknown etiology in males; and, among males with acqueductal stenosis, 25% have an X-linked condition. In HSAS, the hydrocephalus can occur anytime during pregnancy, but usually will not be seen before midtrimester. Hydrocephalus may also not develop until early infancy and in some cases, not at all. Indeed, about 50% of babies do not survive the first year of life, but among those who do, 50% will have minimal or no hydrocephalus.

Central nervous system findings frequently accompanying HSAS include agenesis of corpus callosum, agenesis of the cavum septum pellucidum, fusion of thalami, and hypoplasia of the pyramids and corticospinal tracts. About 90% of cases will also have flexed adducted thumbs. Mental retardation commonly occurs and is often severe to profound, but there are instances in which the children have normal intelligence. In hydrocephalus accompanied by acqueductal stenosis from other causes, insertion of a shunt to drain the ventricles may improve developmental outcome, but this is not necessarily the case in HSAS. In other words, in HSAS, the effect of the condition on the central nervous system is more global and not simply the consequence of acqueductal stenosis when it is present.

In the MASA complex, Mental handicap occurs in 100%, Aphasia (absent speech associated with severe cognitive defect) occurs in 90%, Shuffling gait in 90%, and Adducted thumbs in 90%. Agenesis of the corpus callosum is often present as well, but the spectrum of ventricular enlargement and enlargement of the head overall is much more variable than in HSAS. Indeed, affected males may have normal head circumference and ventriculomegaly or increased head circumference and no ventriculomegaly, or typical hydrocephalus with enlargement of both.

As in many X-linked conditions, female carriers are usually asymptomatic, but concern has been raised that there they may be at risk with regard to the HSAS/MASA spectrum of conditions. Halliday and colleagues (J Med Genet 1986;23:23-31) reported not only that “the intellectual outcome was notably poorer in the X linked cases” of males compared to males with acqueductal stenosis from non-heritable conditions, but “poor school performance was also described in five of 19 mothers of X linked cases” compared to “only one of 64 mothers of the remaining cases.” Indeed, one of the developmentally delayed female carriers also had ventriculomegaly.

In another study, Kaepernick and colleagues (Clin Genet 1994;45:181-5), studied a family with 22 known affected males with the MASA syndrome. There findings not only point to the overlapping spectrum of HSAS and MASA, but also to the probable cause of some carrier females being affected: “Clinical findings varied widely amongst the affected family members, with some appearing initially to have the MASA syndrome and others to have X-linked hydrocephalus (HSAS). Important findings included the presence of adducted thumbs in two obligate carriers, learning problems or mild mental retardation in three females, two of whom were obligate carriers, and hydrocephalus with neonatal death in three females born to obligate carriers. X-inactivation analysis in lymphocytes from the two women with adducted thumbs revealed preferential inactivation of one X chromosome, suggesting that nonrandom X-inactivation may be responsible for clinical expression in females.”

In our next post on this subject, we will discuss the importance of mutations in the L1CAM gene that lead to the variety and variability of conditions accompanying the HSAS/MASA spectrum of diseases...

Labels: a, acqueductal stenosis, agenesis of the corpus callosusm, HSAS, L1CAM, MASA, X-linked hydrocephalus

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X-Linked Hydrocephalus - 1 - Introduction

Within the past year, we had the pleasure of seeing a young woman who was referred to us in early pregnancy with a strong family history of “X-linked hydrocephalus.” Indeed, she was known to be a carrier of a mutation in the cell adhesion molecule L1 (L1CAM) gene, located on the X-chromosome at Xq28, which is commonly the culprit. As in other X-linked conditions, such as hemophilia, this meant that any male child she conceives has a 50% chance of getting the X-chromosome that carries the mutation and therefore of being affected by the condition. In most instances, female babies are not affected by X-linked conditions because they have the benefit of one normal X-chromosome and, indeed, our patient had already had two perfectly normal little girls.

At the time of her first visit at 12 weeks, there were no abnormalities seen in her baby, but we did suspect that the baby was male. We also knew that the condition may not manifest itself until midtrimester or even later, so follow-up was arranged. When she was seen at 19 weeks, no abnormalities were seen again and the baby was confirmed to be male. We also confirmed that a structure called the cavum septum pellucidum was present in the baby’s brain, a finding that often rules out agenesis of the corpus callosum that frequently accompanies L1CAM-associated, X-linked hydrocephalus syndromes. With these reassuring findings, we were all beginning to feel more optimistic about the pregnancy. To be on the prudent side, however, she was scheduled to return again.

At 25 weeks, the sonographer informed me that everything still looked fine, but she admitted the head had not been well-visualized because of its position in the pelvis. So I took my turn at looking. After a few minutes, I managed to elevate the fetal head, the head suddenly turned, and my sonographer took an audible deep breath as it was very apparent to both of us the baby had developed severe hydrocephalus in the 6 weeks between visits. Both lateral ventricles were symmetrically enlarged, as well as the third ventricle situated between the thalami, findings consistent with acqueductal stenosis typically associated with X-linked hydrocephalus. We all had tears in our eyes as we told our patient that her only son was affected by the condition…

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“X-linked hydrocephalus” is associated with diverse mutations in the L1CAM gene and the locations and the types of the mutations play a significant role on the expression and severity of the syndromes associated with them. Indeed, at least four phenotypes accompany mutations in the L1CAM gene:

X-linked hydrocephalus (HSAS)
MASA syndrome
Complicated spastic paraplegia type 1 (SPG1)
X-linked agenesis of the corpus callosum

The main clinical features of these have been given the acronym CRASH and this has the following components:

Corpus callosum hypoplasia
Retardation
Adducted thumbs
Spastic paraplegia
Hydrocephalus

Expression of these varies both between and within families, so even if a specific mutation is identified, there may be variable expression of the same.

In our next post, we will elaborate on HSAS/MASA syndromes and provide a little more information about the significance of L1CAM mutations in the pathogenesis of these conditions…

Labels: acqueductal stenosis, agenesis of the corpus callosusm, HSAS, L1CAM, MASA, X-linked hydrocephalus

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