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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ABO Incompatibility

Many babies become 'jaundiced' after birth, primarily, as the result of ABO incompatibility. The reader below had a baby who developed severe complications with the same - fortunately a rare event - but gives us reason to discuss this condition as it is now the most common cause of hemolytic disease of the newborn (HDN)....

• At Tue Sep 30, 09:21:00 PM 2008, Zoe said…

Dear Dr,

Blood tests taken at the time of the birth of my first baby showed an ABO incompatibility - our pediatrician informed us that my body had released antibodies that had attacked our baby's immune system. As a result he had jaundice for almost 12 weeks and many many tests. I am O+ and my son is A+.

I am currently pregnant with our second child and am concerned after reading articles that state the severity of the condition is greater with subsequent pregnancies, and can result in serious conditions or even fetal death.
Should we be concerned? Are there tests that can be done during the pregnancy to determine if the baby is at risk?
Many many thanks for your help.

• At Wed Oct 08, 10:37:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Zoe:

All people who have O blood types make antibodies against both the A and the B blood group antigens. These antibodies develop very early in life, usually during the first year after birth, probably as the results of similar antigens carried on certain foods and bacteria that normally colonize the gut. Usually these antibodies are of the class of IgM antibodies that are too large to cross the placenta, so that even if you have a baby with A or B blood, the antibodies won't be able to get on the baby's side of the placenta and cause destruction of the baby's red blood cells. You are someone who has antibodies against these blood groups of the IgG class. IgG antibodies readily cross the placenta to the baby, are actively concentrated from your blood to the baby’s side and, indeed, are a major source of protection against many of the things in the environment that could hurt the baby during the first 3-6 months of life before its own immune system has matured.

Unfortunately, the placenta cannot differentiate which IgG antibodies are there to protect the baby and which might hurt, as is also the case in Rh-disease. Your IgG anti-A antibodies can cross the placenta, attach to the baby’s red blood cells, and then mediate destruction of the baby's red blood cells by the baby's own immune system. Not only can that cause fetal anemia (more common in Rh-isoimmunization than with ABO incompatibility) but it can also release large quantities of hemoglobin from the baby’s blood cells. One of the breakdown products of hemoglobin is bilirubin. Bilirubin is metabolized by the liver, but the fetal liver is not efficient at that until after the baby is born. Indeed, high levels of bilirubin can accumulate in the baby before or, more commonly, after birth and if these are not quickly reduced by phototherapy, exchange transfusion, and simple maturation of the liver’s metabolic pathways, this can accumulate in the baby’s brain and cause brain damage (kernicterus).

ABO incompatibility occurs in approximately 15% of all pregnancies. Indeed, since we implemented prophylactic therapy for Rh-disease, ABO incompatibility has become the major cause of hemolytic disease of the newborn (HDN). Fortunately, less than 5% of ABO incompatibility pregnancies result in babies that develop HDN (less than 1% of all pregnancies) and usually the primary manifestation is hyperbilirubinemia rather than anemia. ABO incompatibity can occur in first pregnancies but severity is not necessarily worse in subsequent pregnancies (unlike the situation with Rh-isoimmunization). Black babies are more likely to have severe complications than Caucasians.

The hyperbilirubinemia can often be recognized by a yellow-orange appearance of the baby’s skin and eyes (jaundice). Usually simple phototherapy (bili lights) during the first few days after delivery is sufficient to manage increased bilirubin levels until the baby’s liver adjusts to life outside the womb. Some babies can have a more severe and prolonged course because of the concentration of the antibodies throughout their bodies. However, exchange transfusion is necessary in only about 0.1% of HMD pregnancies related to ABO incompatibility.

If you have another baby with an A blood type, this could happen again, but the recurrence rate is much lower and the outcome much less predictable with ABO incompatibity than with Rh-isoimmunization. You did not tell me whether your baby’s complications were from severe anemia or from hyperbilirubinemia (or both). However, tests that you could consider having done before and during another pregnancy are the following:

1) Check your husband’s blood type to see if he has one (heterozygote) or two (homozygote) doses of the A gene. If he has two, then all your babies with him MUST end up having the A blood type. If he has only one, then half your babies could have O blood types just like you and not be affected by the antibodies at all

2) If your husband is homozygous, then there would be no sense in testing another baby to find out what its blood type is during the pregnancy since it would have to have an A blood type and would therefore be ‘at risk’. But, if he is heterozygous, that testing could be done (by amniocentesis or direct testing of the baby’s blood by percutaneous umbilical cord blood sampling – PUBS) and if the baby has O blood, then you could rest assured and relax the rest of the pregnancy

3) If fetal anemia is a concern, the degree of fetal anemia caused by the antibodies can be monitored by a noninvasive ultrasound procedure called Doppler flow velocimetry (DFV). Using DFV we can measure the velocity of blood (peak systolic velocity – PSV) in a vessel called the middle cerebral artery in the baby's brain. If that blood flow velocity is higher than expected at a given gestational age, this might indicate the baby is developing severe anemia. PUBS could then be done, the degree of anemia determined precisely (as well as the bilirubin levels), and the baby could be transfused with O blood directly by injection in the umbilical vein

4) For your next pregnancy, if you choose to have one, you should get a consultation with a specialist in Maternal-Fetal Medicine. In fact, you might even want to do that BEFORE you think seriously about getting pregnant again.

Hope this helps. Best wishes! Dr T

Labels: ABO incompatibility, Rh-isoimmunization

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Medicaid Funding Cuts

I work in the State of South Carolina. Yesterday was a bleak day for me (and should be an embarrassment to the state) and speaks to the short-sightedness of people who sit in positions of power with regard to their understanding of the economics of providing sensible health care in the U.S. today. A few weeks ago we were informed by the State Medicaid office that due to budget shortfalls, reimbursement for Medicaid patients was going to be cut across the board by about 3%. To make that blow a little more palatable, we were also told that the cuts would be “equitably distributed.” Yesterday those cuts took effect. They were not equitably distributed – $200.00 in reimbursement was cut from every delivery (16.7%).

The silent response to the announcement has been deafening, proving once again that women, children, and providers of services to those who need it most can be counted upon to offer little resistance to legislative decisions that affect the most critical stages of human development – at least in states like South Carolina. Of course, the legislature conveniently timed the move to just as they closed session for the year and the cuts have barely been publicized in the press or newscasts. Again, it is amazing to me how tacitly this irresponsible legislative decision has been received. However, as I found out yesterday, not many providers are even aware of the cuts and/or the impact of the same on their practices. And yet, more than 50% of the prenatal care delivered in the State of South Carolina is covered by Medicaid.

Let me explain why my ranting and raving is justified. The State of South Carolina has one of the highest rates for premature delivery, teen pregnancy, sexually transmitted infections (including HIV), obesity in teens and young adults, and pregnancy complications related to all of the above. The proposed cuts will impact access to care in the patient population in which it has been proven repeatedly that every dollar spent can save the health care system 2- to 3-fold the investment. No thought was given to the nature or the impact of the cuts. The cuts are not value driven or based on needs assessment, they are simply ‘across the board’

Currently, my department is the largest obstetrical Medicaid provider in the state – almost 3000 deliveries per year. Multiply $200.00 times 3000 deliveries and you will see the immediate impact on my department ($600,000). Counted among those patients are a large number of unfunded “self pay” patients (approximately 850 per year) to whom we also provide care, mostly for free, until the time of delivery when we can submit a claim for “emergency Medicaid” for the delivery fee alone (none of the prenatal care). Many of these unfunded (mostly Hispanic) patients receive the same high level of prenatal care as do patients who qualify for Medicaid throughout their pregnancies on the front end. However, they require high levels of resource utilization in terms of provider and staff time/effort and the added expense of interpreters. This is an extremely high-risk group for maternal, fetal, and neonatal complications. If we limit their access to care in our clinic (which may be our only solution to the budget cuts for us at this point), the cost to the State of South Carolina will also bury any perceived savings.

Community providers may also use these reductions as a reason to abandon the care of Medicaid patients completely. This was a lesson learned the hard way by the state several years ago. Obstetrical providers, particularly in rural communities, do not receive sufficient reimbursement to cover the expense to their practices for OB patients (the many office visits and phone calls, the hours spent with the patient in labor, the same reimbursement regardless of time spent and mode of delivery, not to mention LIABILITY insurance premium for OB providers). In the absence of prenatal care, these patients will still end up on our doorstep with increased morbidity, hospital costs, and lengths of stay. They will utilize already over-burdened and expensive emergency room facilities for their ”prenatal care.” Indeed, any perceived ‘savings’ to the state will be readily negated by the effects of reduced access to care. In addition, it does not take many extremely premature babies, admitted to the neonatal intensive care units as the result of these short-sighted and irresponsible measures, to incur expenses many times this amount, initially, with the risk of these children being a long-term burden to the health care system at multiples of the initial expense.

Perhaps the most compelling reason for reversing the decision to cut state funding for Medicaid is the loss of federal matching funds. Currently, the government provides a match of about $3.00 for every dollar spent by the state – in other words, by cutting $28.5 million in state funding, the total loss of health care dollars to the State of South Carolina is about $90,000,000.00! Including the state cuts, the total LOSS for prenatal, peripartum, and child care is then $120,000,000!!! The public needs to be informed and understand these issues as well because in the end we will all will incur the financial burden of these short-sighted actions.

Legal challenges to such cuts are possible, but in the end, sensible legislative action will be the only solution. Legislators must be appraised of the issues detailed above and educated to understand that money spent in prenatal care and women’s and children’s services is an investment and not a burden to health care cost containment. For too long, we have spent a disproportionate share of health care dollars caring for the problems later in life that might have been prevented by adequate education, nutrition, physical education, and health care funding prenatally and early in life.

Labels: medicaid, prenatal care

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