Genetic origins of Autism; when is autism, not autism? Fragile X and Rett Syndrome

48:365 World Autism Awareness Day

Image by mattbeckwith via Flickr

Please note, this post is just the result of personally driven research over the past couple of days. It is not the informed opinion of someone who works with or lives with children who have either Fragile X or Rett syndrome. I am very open to being corrected if I have made any factual errors. I saw researching, writing and sharing this post as an educational opportunity. Please feel free to accordingly further my education.

The criteria for identifying autism spectrum disorder (ASD), refer to symptoms rather than cause. So there are a variety of causes (some known, many unknown), that will lead to an ASD diagnosis. With the looming changes to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR to DSM-5), there has been increased awareness and discussion of how known genetic causes – such as Fragile X syndrome and Rett syndrome – affect the accuracy of an ASD diagnosis.

The proposals in DSM-5, recommend the removal of Retts from the diagnostic manual, and therefore, out of its current position as one of the five pervasive developmental disorders (PDDs) that form the “autism spectrum.” However, Fragile X, which is the leading known genetic cause of autism, would not be excluded from the spectrum in the DSM-5. Understanding why these two genetic conditions which lead to autism, will be treated differently in regards to autism in the DSM-5, sheds some light on the broader relationship between genetic causes of autism, and autism as a symptom-defined condition.

Like ASD, Rett syndrome can be diagnosed purely on symptom criteria. Unlike autism (in the broadest sense; the spectrum as a whole), the specific genetic mutation causing the symptoms of Retts, is known and can be identified in the individual. The rationale for the removal of Retts from the DSM-5 turns not strictly on the fact that the cause of the autism is known (otherwise, Fragile X and other genetic causes would also exclude an autism diagnosis). The rationale includes the fact that Rett patients often only have autistic symptoms for a brief period in early in childhood, so inclusion in the autism spectrum is not appropriate for most of these patients. The diagnosis of autism is usually highly stable, with only 7% falling off the spectrum on follow-up. (As a side point, it is interesting to note too that Retts almost exclusively affects girls, whereas autism is usually found in a male to female ratio of 4:1.)

Fragile X syndrome is not so closely tied to the symptoms that match autism, as Retts is. Whereas Retts syndrome is considered part of the autism spectrum, many people with Fragile X syndrome are not autistic, can exhibit other and distinct (sometimes severe) outcomes of the syndrome, and can be carriers (not exhibiting symptoms at all). About a third of children with Fragile X syndrome meet the criteria for ASD (though only between 2% and 6% of autistic children have Fragile X syndrome).

The proposed DSM-5 recommends clearly identifying if there is a known genetic cause of a person’s autism; explicitly including Fragile X as an example of such a cause. There are good reasons for this. Not just because the family and extended family need to know they might be carriers and how this can affect future children. But also because particular treatments and therapies better suit children with Fragile X (or other conditions), than the wider autistic population. There is ongoing research also specifically directed at Fragile X, which could specifically benefit those people whose autism is caused by it (it’s worth noting too that breakthroughs in such research may indeed also end up benefitting those with autism not caused by Fragile X).

So Fragile X and autism are separate diagnoses, which may also occur together. In the same way that a vast variety of other conditions can make it more likely a child exhibits autistic behaviours, yet falls short of meeting the criteria for autism.

Other than Rett syndrome, there are no other genetic conditions that automatically and explicitly fall under the autism spectrum umbrella in the DSM-IV. That is to say, there is no single and known genetic (or as yet, environmental) cause for the other categories; CDD, PDD-NOS, Aspergers, and (classic) autism.

(Those four remaining categories of autism spectrum disorder, would be essentially folded into the single reference term of “autism spectrum disorder” rather than “PDD” as they are currently know in the DSM-IV-TR. The criteria for that new all-encompassing category will be changed to accommodate and clarify what falls under its umbrella, and what does not. The exact details of that are far wider ranging that what I am covering in this post, though I have previously shared my personal opinion on the matter if you’re interested.)

As autism and its range of causes become better understood, it will be interesting to see what goes the way of Rett (as a separate, genetic condition that often presents differently from the majority of people on the spectrum), and what goes the way of Fragile X (an underlying condition that mostly does not present itself as autism). There are going to be (and already are) a raft of conditions that fall between and beyond those two genetic examples, but they are instructive in trying to get your head around the ongoing discourse about the relevance of autism causes, and about the future of the autism diagnostic category more generally.

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34 Responses to Genetic origins of Autism; when is autism, not autism? Fragile X and Rett Syndrome

  1. Sharon says:

    Thanks for this. I have been wondering lately how Fragile X is differentiated. BY this I mean how is it some come to be tested for Fragile X and others not, if the symptoms are ASD like. Why dont all children diagnosed with ASD get tested for Fragile X, or are there further symptoms beyond the ASD ones that mark Fragile X apart? Any ideas?

    • From my own reading, it is actually advised that any child with autism, be tested for Fragile X. Here’s a link to one of the charities that shares this view: http://www.nfxf.org/html/autism_and_fragile_x_syndrome.htm

      When we got my son’s diagnosis, they then ordered a blood test; one of the things they were looking for was Fragile X.

      There are also some ways in which children who have Fragile X syndrome and autism, differ from children who just have autism (such as various common physical features of those with Fragile X: http://www.fragilex.org.nz/about_fragile_x . Incidentally, that is another chraity which says autistic children should be tested for Fragile X). But I don’t think the differences are marked or distinct enough to suggest by themselves (without a blood test) that a child does or doesn’t have Fragile X. I might look further into this though, good question.

  2. Kitty Kay says:

    Fragile x is the most common form of inherited mental retardation (sorry but that’s still the medical term). Autism itself is not MR therefore if your child does not show any signs of MR there would be no reason to test for fragile x. But at the same time it is a very interesting disorder as while signs may be there as a child sometimes they do not show up until after puberty so how do you decide who should be tested?. Many of the behavioral symptoms are similar if not the same as autism. Besides being a form of MR fragile x has some physical symptoms which include:
    Physical signs may include:

    *Flat feet
    * Flexible joins and low muscle tone
    Large body size
    * Large forehead or ears with a prominent jaw
    * Long face
    * Soft skin
    I may be wrong on this but I do not believe autism has any physical signs.
    http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002633/

    • That completely turns on two things you have assumed: (1) That autism is not classified as a form of mental retardation or intellectual disability anyway, and (2) that the difference (if there is one) between mental retardation and autism, can be always clearly identified. It is not at all clear that either of those statements is true.

      And there is absolutely no reason to apologise for using the medical term mental retardation. Even highly politically correct people aren’t arguing about wiping out that usage.

      As for the claim that autism doesn’t have any phsyical signs, that is a rather confused claim in this context, because of the very thing I directly discussed in the post: There are a wide variety of openly acknowledged causes of autism. It is defined by its symptoms. Therefore, just because you can point to differing physical characteristics of a sub-group of autistic people, you cannnot conclude that those people do not have autism. By that reasoning, you’ll also have to deny that any Downs children ever can have autism, which is clearly false. You’ve got the reasoning backwards; it’s not that having physical signs excludes you from an autism diagnosis, which is how you’ve presented the claim. The true claim is that autism doesn’t have to be accompanied by physical signs (such as abnormalities, large heads etc), that is not the same as saying having physical signs excludes a diagnosis.

      I should also add for the sake of completeness, that not all people with Fragile X display the physical symptoms you’ve listed, so they can not be used to idependently identify nor exclude a Fragile X (or of course, autsim) diagnosis.

      • Kitty Kay says:

        I have always been told by my sons doctors that Autism is not MR, that does not mean that someone who has MR can not have autism lots of things coexist with each other. That’s where I got that from. I know that not all people with fragile x will have the physical symptoms. When reading the information on it they seem to be the only difference between autism and fragile x , but since the neurological symptoms are very similar I’m not sure how it could differentiate between the two besides a genetic test which would show fragile x but still not rule out autism. I didn’t mean that if you have physical signs of something else that autism is off the table. I think it is a very interesting disorder in that someone could have it and never know. That it can be in families for generations before someone shows signs of it. Autism can be with any disorder and did not mean you have to have one or another. That would be like saying just because your diabetic you have to be obese. I may have confused my writing as it sounded right in my head but did not come across right. (happens all the time to me)

      • Kitty Kay says:

        Sorry forgot something MR is based on IQ tests only. If a IQ is in a certain range than the person is classified as MR. For something to be a form a MR one of the symptoms has to be MR in a majority if not all cases.

  3. Kitty Kay says:

    sorry again i was wrong MR is not solely based on IQ but it is a major factor in the dx.

  4. Not all people with Fragile X are MR. It is a spectrum disorder with the full-mutation presenting in a wide variety of ways. Not all people with Fragile X have the physical characteristics. Not all people with Fragile X have autism. All that being said, it is recommended that all persons with an autism diagnosis be tested for Fragile X. It is an incorrect assumption to say that “my autistic child is not diagnosed MR so therefore they can’t have Fragile X”. While Fragile X has been said to be the “leading inherited cause of mental retardation”, it does not always cause mental retardation. I have three children with Fragile X. Two of my children (both of the boys) meet the DSM diagnostic criteria for autism. They both also test as MR. My daughter has the full-mutation, has a diagnosis of Asperger’s and is adjunct faculty at a community college (teaching English, she has her Master’s degree). It’s pretty obvious that she isn’t MR, and testing confirms this. My opinion is that we will find many causes of what we now label “autism” and we will find that there may in fact be many distinct types, in spite of the DSM current move towards consolidation of the diagnosis. Bottom line, if someone has autism they should be tested for Fragile X. The reasoning is not just for “family planning” purposes. Did you know that if you are a carrier of Fragile X you are at significantly increased risk for a number of other health issues ranging from depression/anxiety to infertility (premature ovarian failure POF) to a movement disorder (frequently misdiagnosed as Parkinson’s) called FXTAS (Fragile X Tremor/Ataxia Syndrome) to dementia (sometimes occurring as a manifestation of FXTAS) For the most accurate and detailed information on Fragile X, please visit http://www.fragilex.org.

  5. MJ says:

    “The proposed DSM-5 recommends clearly identifying if there is a known genetic cause of a person’s autism; explicitly including Fragile X as an example of such a cause. ”

    Do you have link to where the DSM V says that? I don’t remember seeing that on the DSM V autism page.

    • Sure MJ:

      You can see them discussing and suggesting the idea here, in the paragraph that begins “The eight panel addressed..”: http://www.dsm5.org/research/pages/autismandotherpervasivedevelopmentaldisordersconference%28february3-5,2008%29.aspx:

      “Regarding how to incorporate subgroups of ASDs with an identifiable etiology (e.g., Fragile X, tuberous sclerosis) into the diagnostic framework, options include listing the medical condition on Axis III, including a subtyping scheme on Axis I (e.g., autism, Fragile X type), or excluding it from the diagnosis altogether, as is now done with Rett’s syndrome.”

      And you can see explicit mention of it under the rationale of removing Rett’s. They state:

      “Like other disorders in the DSM, Autism Spectrum Disorder (ASD) is defined by specific sets of behaviors and not by etiology (at present) so inclusion of a specific etiologic entity, such as Rett’s Disorder is inappropriate. To ensure that etiology is indicated, where known, clinicians will be encouraged to utilize the specifier: “Associated with Known Medical Disorder or Genetic Condition.” In this way, it will be possible to indicate that a child with ASD has Fragile X syndrome, Tuberous Sclerosis, 22q deletion, etc.”

      Link for that statement: http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=95#

      That was a good question by the way, thank you for asking it so I could provide the links for others too.

  6. Bonnie says:

    I just found this blog and am happy to see the discussion involving Fragile X and autism and even more happy to see that most of what is said seems correct, with the latest information that I’ve read. I will be a new follower! I have twin sons with Fragile X and am a carrier (obviously), as is my dad and was his mother. We have no idea how long this might have passed through our ancestors before showing up in my sons.

    • A heart-felt “welcome to my blog” Bonnie.

      I love your own blog title (and blog presentation) by the way, and look forward to having a good wander around your posts and learning more about Fragile X.

  7. Zoe says:

    I have previously read elsewhere that fragile X many be what is termed a phenotypical autism, meaning that the behaviours and symptoms will often place a person into a diagnosis of autism using the current scales, but that it is not caused by the same mechanism that is responsible for stereotypical autism (whatever the ’cause’). Other genetic conditions may have their own phenotypical traits and appear to be autistic in nature; while the behaviour may be similar to that of a person with stereotypical autism, the reason for the behaviour may be different (such as the reasons for avoiding or limiting eye contact). It is therefore very important to correctly idenify whether the autism is stereotypical or phenotypical as many therapies designed to support people with stereotypical autism will not help, and may even hinder, those whose autistic traits are caused by something specific, such as fragile X syndrome. When talking about our son in layman’s terms we describe him as having ‘a form of autism’ to help people understand him, in truth he has fragile X syndrome and a few of its phenotypical autistic traits.

    • Hi Zoe.

      I think what you’re saying is very important, but of course, without an understanding of what causes (and evidence so far suggests it is a wide range of things that can do so) “sterotypical autism” as you term it, it’s hard to make a meaningful separation or proceed accordingly in the way you suggest. So the separaton between phenotypical and sterotypcial autism, doesn’t get us very far at this point in our knowledge and understanding of autism.

      I think the best approach we have available at this point is to react to the causes we can and do know, rather than think of the large remaining pool as all caused by potentially the same thing (or even type of thing). And I think the attitudes reflected in the DSM-5 towards Retts and Fragile X, reflects that approach.

      Thanks for your thought-provoking comment.

  8. amanda says:

    was just wondering the benefit of testing for fragile x? my 2 year old son has autism diagnosis. he currently has early intervention and building blocks ( extension service of ei) his neurologist is requesting a fragile x blood test from him. i wanted to but found out our insurance doesnt cover it and it costs a couple grand. if fragile x is similar to autism, what different services will he get when he goes to school that differs from autism if he gets fragile x diagnosis? she said he will get different services, but i am still not sure what services? and would it be worth it to save up for test? whether or not i have more children i know if he has autism or fragile x i still eithor way have about a 20% chance of another one. i am mostly wondering about schoolwise, what is the difference?

    • Hi amanda,

      I am so sorry to hear it would cost that much! It was free for us here in New Zealand, so I hadn’t considered the cost question before.

      Knowing it’s Fragile X (or not) does matter, particularly because it means you and other family members might be carriers. Fragile X doesn’t just lead to autism, it can lead to other (sometimes very serious) problems too. I’m not clear on the specifics of how therapies and interventions might differ if it is Fragile X, though I have been told there is a difference. Your specialsits should have explained those differences to you, I’d suggest going back to them / contacting them for an explanation of how it might make the diffrerence. Your 20% figure as to whether your child has Fragile X or not, re possible future autism, is incorrect according to what I’ve been told by a family who are Fragile X carriers, and from my own research. The figure is more like 50% chance of future children having autism if you are a carrier. The 20% figure re having future children with autism, is also a highly variable one, depending on whether you know the cause of the first child’s autism (some causes are known), and I’ve heard the figure more generally varies from 1 in 12 to 1 in 5 (that last figure being 20% of course). It sounds to me like these are serious issues that you need to see a professional genetic counsellor about, particularly considering the amount of money involved for you.

      I sincerely wish you the best, I hope you find the answers you need to get your child the best help possible. Take care.

  9. Bonnie says:

    If your son has Fragile X, your chances of having another child with Fragile X is 50%. I’d fight back with your insurance company. If your neurologist thinks the test is important, who is your insurance agent to argue with the doctor?

    The therapies for autism and Fragile X can be very similar, but it would be important to note the subtle differences between Fragile X and autism. As one Fragile X mom explained, take the lack of eye contact, for example. In autism, often the lack of eye contact is due to the child’s inability to recognize that eye contact is something we expect in order to communicate. They just don’t get the nonverbal communication that is passed between eyes so they don’t bother with looking at people who are speaking to them. In Fragile X however, often the lack of eye contact is due to extreme anxiety. Forcing that child to make eye contact can increase the anxiety and in turn increase the negative behaviors.

    Get the test. Make your insurance company pay for it. Don’t take no for an answer.

  10. amanda says:

    thanks. do you think there is still a chance of having it if my mother got genetic testing? my mom had unknown neuropathy in her legs and they did a very expensive test on her and found “heriditary spastic parapledgia”. my mom never mentioned fragile x however. it seems like all the mental impairments are on my moms side such as manic depression and anxiety ocd and i am positive her brother has autism eventhough undiagnosed. it seems like she would have that gene? i had my husband call the insurance company. one person said they will need to talk to the provider. the next sent him and the neurologist a 84 page email about what they cover, never mentioning autism/fragile x. the dr said she is also working with 100 other families trying to deal with this as well. she said many insurance companies wont cover genetic testing even if they seem to cover mostly everything. we have a good plan…. blue cross blue shield HMO. i hope she can figure it out because i would like to find out even for myself. i had major emotional problems with depression/anxiety/ocd and social problems. i also have eye contact problems too sometimes. but my problem i always tried to hide. i think it was more mild than my sons problem. but i look at him and hope that he wont have to go throught he same crap i did.

    • MJ says:

      Amanda,

      Just a couple of thoughts, for whatever they are worth.

      Even if you mother had some level of genetic testing done, the tests would have had to look for the fragile x mutation specifically to find it. I don’t know whether that would be a standard test included for adults unless there was a specific reason to go looking for it. And, as I understand it, the tests for fragile x have only come into widespread use during the past 10-15 years. So if she were tested even as late as 1995 it might not have been included even if it were a standard.

      One other thing to keep in mind is that the mutation can be inherited from other family members who don’t show any outward signs of having fragile x. So just because one side of the family might have been cleared doesn’t mean that the other side isn’t a carrier.

      As for whether the test is important to do or not, the short (and long) answer is it depends. There are some different approaches that can be used when dealing with fragile x compared to autism that might be more effective. There are also more drugs under active development that can help correct the specific problems of fragile x while there are very few that target the core symptoms of autism.

      However, on the flip side, it has been my experience that there are better services available with an autism diagnosis rather than fragile-x. Although the availability of services is going to depend on exactly where you live.

      For what it is worth, I believe that it is standard practice (at least in parts of the US) to rule out fragile-x when making an autism diagnosis. When my children were diagnosed, the doctor making the diagnosis ordered an entire battery of genetic testing to rule out various other conditions and I know that fragile x was one of those conditions. My insurance paid for all of those tests but I don’t know whether that is standard.

      If you have a case manager through early intervention you may want to talk them about what is normal in your area. They might also be able to connect you to an advocate who will work with you to help you deal with the insurance carrier. Or at least these services are available in my area.

      Some states (assuming you are in the US) also have supplemental insurance available at low or no cost to children with an autism diagnosis and this insurance will (again sometimes) pick up charges that your primary insurance won’t. Your case manager should be able to help you there as well.

  11. Bonnie says:

    Unless they specifically tested your mom for the Fragile X gene, her genetic test would not have told her anything about it. Fragile X testing is specific — that might be why it’s more expensive.

    Everything you said here just amplifies why you, your son, and your mom should all get tested. Because carriers of the FX gene (which, if your son has FX, you and possibly your mom would be carriers ) have a MUCH higher incidence of OCD, anxiety, depression — all the stuff you listed above that you and your mom have dealt with. You mention you think your mom’s brother might have had autism – that’s another huge red flag. Any possibility it might have been Fragile X? A whole lot of us who have children with Fragile X discover someone else in our family trees who either has or could have had it, and was just never diagnosed properly.

    Perhaps a genetic counselor who knows more about Fragile X and how it affects families could convince your insurance to pay for testing. http://www.fragilex.org is a good place to check for information about all the health issues and symptoms. Amanda, email me privately if you would like to talk more about this…. bkkorman@aol.com

  12. amanda says:

    the test for fragile x costs 2 grand about. they didnt know what was wrong with my mom. after MRI’s, scans and ruling out pretty much everything they still had no idea. the test cost the insurance 10 thousand dollars!!! i assumed they looked at everything for that amount of money. i know they where looking at x chromosome abnormalities. i am not positive they did a fragile x test, but it seems like it was so expensive, they must have looked for everything. she just got the test done this year. but i also understand that they may not have saw that still and also it could have come from someone else. i assume its not from my sons genetic father because he was the sperm donor and i have 12 of my sons siblings on facebook. none of them have any problem like that. people are mentioning that if i have more kids it is with a different father because i am married now. but i am positive it came from my family whatever my son has.
    i am happy to hear there is secondary insurance that may cover it. i wish i knew where to look for it. I mentioned to the woman from EI that my insurance wont cover it and she didnt have much advise. it seems she didnt even know they usually do that testing. i’m kind of discouraged because i took my son to a neurologist at one of the top rated hospitals….boston childrens. so they should be correct on what they are telling me i should think. also, does insurance cover genetic counsiling? not sure they would seeing where they dont cover genetic testing. thanks bonnie. i can email you, but still wanted to share what i was saying to other people too

    • MJ says:

      Amanda,

      The best I can suggest is to try and talk to other parents in your area who also have children on the spectrum. They will better be able to tell you what services and supports are available in your area and how to access them.

      If you don’t know any other parents, I would suggest looking for a local resource to talk to on sites such as Autism Link (http://autismlink.com/) or contact your local chapter of Autism Speaks. Or sometime there is a yahoo group for autism parents in your area (http://groups.yahoo.com/). A quick search turned up at least two that look to be for autism parents in Massachusetts.

  13. amanda says:

    Lars finally is going to get his bloodwork! what a battle!

  14. Kammy says:

    Is there a connection between fragile x and rett syndrome? If you were to be tested for one would the other one show up?

  15. Veronica says:

    Great research. Rett Syndrome, along with Landau Kleffner (what some say Jenny McCarthy’s son really has), Fragile X and certain metabolic disorders are often misdiagnosed as autism.

  16. Veronica says:

    It never hurts to ask doctor to test for other things when you are dealing with something as complex as an autism diagnosis. It’s important to get an accurate picture of what’s going on.

  17. Leona Byrne says:

    Thanks for this post and the discussion on FX. I am very pleased to read several of you have children with fx and the amount of information those of you who do not, have. I wanted to clear up one point which was touched on a couple of times. If a woman carries the fx gene, either in the full or pre mutations, every single pregnancy has a 50% chance of the fx gene being passed on to the child. This is because a woman has 2 X genes, one will be affected by fx. If that x is passed on to the child, they will have either full or pre mutation guaranteed. if however the mothers good “x” gene is passed on, the child will not have the fx gene at all. Equally so, if a man has the fx gene in either a pre or full mutation, every single one of their daughter will get the gene…. but none of their sons (as they will get the fathers Y gene). I have 3 children, 2 are full mutations, one male one female, and the third is now a carrier as they have lowered the number of repeats for premutation down to 40-45 up to 200. He has a repeat count of 41. Also, both my fx children also have an ASD diagnosis, however my daughter is very much more Autistic than fx, and my son is very much more fx than ASD. There are definitely traits that are very specific to fx and to ASD. As for the MR comment, both of my children with fx have a lower than 70 IQ score, hence MR, however my daughter reads fluently, can do basic maths and is succeeding academically at school… and will do so until the learning becomes abstract, then I am afraid her deficiencies in that area will make learning very difficult for her. Thanks for the blog.

  18. Pingback: Infertility Genetic Cause Of Autism | Secret Pregnancy Blog

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