Doctor's In-Depth: Detecting Fragile X at Birth

A pediatric neurologist at Rush University Medical Center in Chicago, Ill., talks about a new blood test to diagnose newborns with fragile X syndrome.

Here is Elizabeth Berry-Kravis, M.D., Ph.D. 

What is fragile X?

Dr. Berry-Kravis: Fragile X is a single gene disorder located on the X chromosome. Women have two X chromosomes and men have one X chromosome. Fragile X syndrome involves the silencing of that gene by a mutation so the gene doesn't make its normal product, which is called fragile X mental retardation protein, or FMRP. That protein is important for brain cells to connect with each other the way that they should, and therefore when the gene is not making its protein and is silenced we get fragile X syndrome, which is a disorder of learning, and there are lots of behavior problems -- problems like anxiety -- and attention problems, hyperactivity. Many of the individuals with fragile X syndrome also have autistic symptoms, so we think the fragile X gene may be a clue as to some of the pathways that are involved in autistic disorders.

Is Fragile X is a cause of autism, or is it just related to it?

Dr. Berry-Kravis: Fragile X is one cause of autism. Autism is probably has many, many causes; maybe even in the hundreds or thousands. These involve probably gene, and maybe environmental interactions, but the Fragile X gene is one gene that can produce a condition that would fall under the autistic spectrum.

Fragile X condition has been known for years. How come we don't hear about it often?

Dr. Berry-Kravis: 1969 was when the Fragile X chromosome was first identified in a family that had mental retardation that was being passed on in an X-linked fashion to the boys and the men in the family. The chromosome test wasn't put into regular use until around 1980, even though it was  discovered in 1969. The chromosome test looked for this Fragile X site. It looked like the tip of the X chromosome was sort of breaking off. In 1991, when the gene was found, we learned the reason the chromosome looked that way was that there was a big expansion of DNA in the Fragile X gene, which is called FMR1, standing for Fragile X Mental Retardation 1. The big expansion of CGGs, which are a kind of DNA, would make the chromosome look as though it was breaking, because it was unstable in that area. That CGG expansion mutation -- is what causes the gene to be inactivated as well.

Tell us what's going on with this blood test.

Dr. Berry-Kravis: Fragile X syndrome, since 1991 when the gene was found, has been identified with a gene test, where we can take the DNA from someone's blood and look at it and see if that expanded CGG mutation is there or not; but that's a fairly involved procedure. It's a test that costs on the order of $400 to $500 to do, and it involves lots of man hours of time in the lab, so thus far no one has been able to think about screening, about screening for Fragile X with a large population, because the test was so time intensive. Recently, Dr. Flora Tassone at the University of California, Davis developed a test that can do a high throughput screen. It involves two PCR reactions and then you run it through sequencing machines and it pulls out whether the mutation is there or not. She can do that test on a much smaller sample. Typically we would require around three milliliters of blood, but she can do that test on 1/100^th of a newborn screening blood spot, like what they collect from babies in every state to screen for genetic and metabolic diseases. Also the test is much, much cheaper than the standard DNA tests, so she can run that test for just a couple dollars, for a very small fraction of what it would cost to run the standard test. When we run that test, and if we get a positive, then we can run the typical test to confirm it -- to make sure all of the diagnoses are correct; but this test could be applied, for instance, to screening large numbers of newborns, and even every newborn in the state.

In this study, how many children do you hope to screen?

Dr. Berry-Kravis: Our hope is to screen every baby that's born here at Rush University Medical Center. Because the project is still a research project -- it's a pilot project -- we get consent from the parents that they want to have the test done, so we won't get consent from every parent, but we're hoping to get consent from a good proportion of the parents, and there are about 2,500 births per year here at Rush and we're going to run the project for five years, so it's about 12,000 samples that we'll be hopefully screening. This will help us identify what the population frequency of Fragile X mutations are, which we haven't got a good handle on here in the United States, and it will allow us to look at multiple ethnic populations, because here at Rush we have a good mix of all different ethnic populations that we can look at the gene frequency in, and get kind of an overall gene frequency in the United States. Plus it will identify anyone who is born with a Fragile X mutation, and then we can follow up on that, retest the child, and anyone who is identified as positive will come in for an extensive battery of testing and very careful developmental follow-up. We will get people enrolled in an appropriate developmental programs and really try to get working with them right from early on so that we can attack any kind of developmental problems as early as possible.

Currently, when do parents typically discover their child has fragile X?

Dr. Berry-Kravis: That varies a little bit. Ten years ago the average age of diagnosis was maybe seven or nine. It's been coming down and most recently it was more like two or three, and that's because people are more aware of fragile X syndrome as the years have gone on. You cannot tell a newborn baby has fragile X. Often the motor milestones are pretty normal. The child may be a little bit delayed at walking, but not really so much that it's obvious to the family or the pediatrician that something's clearly wrong. Sometimes the family knows that the baby just isn't right, and keeps trying to tell people this, but because there's no really obvious sign of it, often testing isn't done right away. Doctors kind of wait to see if things will catch up, but the most obvious sign of fragile X initially is that the child doesn't learn to talk at the right time, The child may have unusual behavioral features and look somewhat autistic, and so usually around two or three it becomes clear that language and communication are delayed. Then often many tests are done, including the Fragile X test, and sometimes not including the Fragile X test, but often the child has to go through EEGs and MRIs and lots of expensive testing to find out that the diagnosis is fragile X. So having a way of screening for babies ahead of time would prevent all that unnecessary testing most children go through before they come up with their diagnosis of fragile X. We are interested in what happens when you tell a family that a child has fragile X right from birth. There are concerns that will get in the way of maternal bonding. There are many concerns about that, so that is one of the reasons this is a pilot program. No one would ever just mandate that the whole world have Fragile X screening at birth, but we think it's very important to run this program, to see what happens with the families, to find out if the families feel it was useful to have the test results early, and if the families feel that they derived a benefit by being able to get into developmental follow-up, and early intervention right away. We, of course, would like to maximize the opportunities for every child diagnosed with fragile X, and we're hoping that having that intervention and support early on will result in better adaptability and better functioning.

How important is early intervention in helping children with fragile X?

Dr. Berry-Kravis: There are no studies that definitively tell us that early intervention makes the child more intelligent or have a higher IQ, but what we do see is that kids who are in early intervention from early on, the families have many more strategies for dealing with their behaviors. For example, if they can't communicate, early intervention gives them strategies for being able to communicate, and so the child is more functional and happier. Even if they're not more intelligent, they're more adapted to their environment and they seem to be able to do more. Plus the families are equipped with many more strategies to deal with the child's behavior, and the child does not get into difficult behavioral patterns as much. One example of that is if a family doesn't know that their family has Fragile X and is just kind of dealing with developmental issues, and doesn't really have the support of early intervention, they may allow the child to continue with a behavior that's maladaptive or disruptive. The child may get in the pattern of thinking that they can do that behavior all the time, and it can be very difficult to get rid of that behavior later when the child is older and when the behavior may be more disruptive because the child is bigger; but if the child is in early intervention and people recognize this is a maladaptive behavior and this is how we deal with it, then often the families have strategies to reverse that behavior early on before it becomes a set behavior pattern. Then when the child is older, they no longer engage in that behavior and as a result they can be more functional. They can be, for instance, in a regular education classroom. They can be with normally developing peers because they don't have these behaviors that prevent them from interacting.

How important is this blood test for the medical community?

Dr. Berry-Kravis: We feel like it's important because it's going to identify people who are going to have problems developmentally, and it's going to identify some people with the smaller fragile X mutation called the premutation, which can cause things like premature ovarian failure in women, or a later onset degenerative problem that is somewhat like Parkinson's, but involves problems with tremors and walking. It will identify those people as well, so they won't wind up going on asearching mission for what's wrong with them. There may be many other subtle effects of the smaller mutation in families that we haven't been able to dissect out yet, but having a population study like this will allow us to know what all the effects of the fragile X mutation are. Relative to other things that are screened for, the fragile X mutation is probably a little bit more frequent than some of the things we screen for by state testing in Illinois and other states. We'll identify more people with the Fragile X mutation than some of the other screening tests identify, but we have less of a direct treatment. Some of those diseases have a specific diet or a specific treatment that patients need to go on, and so therefore it's absolutely crucial for them to be diagnosed; but there is research in the fragile X field which seems to be going down the path to leading to disease-specific treatments that actually treat the underlying biology of fragile X, to sort of compensate for the lack of the fragile X protein and improve the brain connections and wiring. If those treatments work out, then it's going to be crucial to do newborn screening because it will be important to get babies on those kinds of treatments early on to maximize their learning, as well as their early intervention. We're hoping that the process of figuring out how to do newborn screening and how to disseminate the information to the families when they get a positive result -- and that's going to take some years -- actually dovetails with the research that we're doing on how to treat the underlying disorder in fragile X, so that when we're ready to have a treatment, we're also ready to find the patients that need the treatment.

Do you think having this early intervention and making more parents aware of this condition will spur the research a little farther, or maybe develop earlier interventions for newborns?

Dr. Berry-Kravis: Yes. I think we have very little information on whether you can do something with a baby that will help with the baby's development. Why is that? Because no one is diagnosed when they're a baby except for if you have an older sibling or a cousin with fragile X, and you happen to find out while one child in the family is still a baby, then sometimes we'll have a baby that's diagnosed with fragile X, but that's very unusual. Most of the time people are toddlers, or even up into preschool or elementary years, before they're diagnosed. There may be some interventions that one could implement for babies that would be more helpful than intervening later on. Of course, that's a topic of important research -- how to best approach these babies, but we also feel the new treatments that will likely be developed over the next 10 years are going to be important, and of course those treatments will be used in older people first and then eventually be moved on into the infancy period if they're successful; but again, with all of these treatments we need to know which babies to do treatment with.

What is the occurrence of fragile X in the general population?

Dr. Berry-Kravis: Fragile X has been quoted to be one in 4,000 males and one in 4000- 6,000 females. Those incidences are based on one large French Canadian study. We actually think that the population incidence is more likely higher here in the U.S. There may be some data here in the U.S. to suggest it's likely one in 1,000 or one in 2,000 babies here. The current quoted figures for someone to be a carrier of fragile X syndrome are one in 250 for women and one in 800 for men. We think that frequency may be as high as one in 100 for women and one in 250 for men in the U.S., but we don't know until we have some kind of true population study to confirm that, and that's one of the things that the newborn screening study can accomplish as well.

What's the difference in how quickly results can been received between the older test and the new one?

Dr. Berry-Kravis: The chromosome test from the 1980's costs about $600. The blood test that was the DNA test that was discovered in 1991 started out at about $250, and now it's about $400 or $450 for the most part. You can get it done in a week if it's urgent. For instance if you have a prenatal result that you have to get done, but it probably takes on average about three to four weeks for people to get their results back from that test. For this test, we're running the samples all in big batches, but you can get the result faster, even in a couple days.

Does fragile X affect girls differently than boys?

Dr. Berry-Kravis: Because the gene is on the X chromosome and girls have an X chromosome with a normal gene that compensates, they're generally less involved, so they tend to be a little less autistic, and they're higher functioning. They usually fall sort of at the low end of normal, or in a learning disability, or very mild mental impairment range, whereas boys usually fall in the moderate range of intellectual disability, with some being severe and some being more mild.

Boys can be just learning disabled and, of course, those are the kind of boys that would be picked up in newborn screening, but you wouldn't find because their pediatrician and their psychologist and the people that are taking care of them would never think they have fragile X because they would think they're too mildly affected for fragile X. I think, again, we're not picking up all of the most mildly affected individuals with fragile X.

Is it a better possibility a child with fragile X who gets early intervention will grow up and be on their own than someone who had a later intervention?

Dr. Berry-Kravis: We'd like to think the individuals with the earlier intervention will be more functional. In other words, because they had a good approach to their behavior right from the beginning, they'll be able to go in the community and have a job and live more independently. Will they live totally independently? For the majority of fragile X patients, probably not, because they'll need support for issues that are cognitive, like managing finances and things like that; but if we could treat the brain connectivity, too, then we would hopefully be able to significantly increase their independence.

Is the difference between Brian and the twins, Elizabeth and Brett's, abilities because Brian was diagnosed at a later age?

Dr. Berry-Kravis: There is a range of intellectual ability in fragile X, and so intellectually Brian is somewhat higher functioning than Brett. Of course, Lizzy is higher functioning than either of the boys because she's a girl; but Brett, because he had the early intervention, is more manageable behaviorally and more adaptable, has been able to seemingly learn to do more things despite the fact that his natural cognitive ability isn't perhaps as high as Brian's. I think the difference is that Brett, who had the early intervention from right when he was one or so, seems to be able to apply what he has and use it in the world better than what Brian can do. 

Elizabeth Berry-Kravis, MD, PhD

 Rush University Medical Center

Chicago, IL

(312) 942-4036

http://www.rush.edu