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Alberto Ruggieri
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Fragile X symptoms don’t add up to autism, studies suggest

by  /  8 May 2014

Fragile X syndrome is an inherited form of intellectual disability often linked to autism: About one-third of people with fragile X syndrome also have an autism diagnosis.

Several studies in the past few months, however, suggest that the set of autism-like symptoms seen in people with fragile X syndrome only superficially resemble those of the classic definition of autism1, 2.

Fragile X syndrome results from mutations in a single gene, FMR1. The fragile X protein also influences the expression of several autism-linked genes. With this known entry point, research into treatments for the syndrome has surged ahead.

In contrast, autism is genetically complex, and as a result is diagnosed based primarily on behavioral symptoms. Many children with well-characterized genetic disorders, fragile X syndrome included, show some of the symptoms associated with autism, and often merit a diagnosis of the disorder — some researchers have begun referring to these subtypes of the disorder as “autisms.”

But what is labeled as autism in these individuals may in fact be a distinct condition.

This has implications for treatments. Some treatments being developed for fragile X syndrome are also being tested for autism but may not have any benefits for the latter.

“I started off thinking that it didn’t really matter. If kids with fragile X syndrome met diagnostic criteria for autism, it was autism and that was the end of the story,” says Leonard Abbeduto, director of the University of California, Davis MIND Institute in Sacramento.

“I’ve come to appreciate that that’s not a fruitful approach,” Abbeduto says. “They are not exactly the same thing and I think that’s really important for treatments.”   

Social anxiety:

One key distinction between the disorders, for example, is in social interactions. Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them.

But children with fragile X syndrome often sneak a peek when the other person turns his back, researchers say. Children with autism, in contrast, seem mostly uninterested in social interactions.

“Children with fragile X syndrome all have very severe social anxiety that plays a big role in the perception that they have autism,” says Stephen Warren, professor of human genetics at Emory University School of Medicine in Atlanta. “They are actually interested in their environment; they are just very shy and anxious about it.”

Likewise, children with autism and those with fragile X syndrome both show repetitive behaviors — a core diagnostic feature of autism — but the nature of the repetitive behaviors differs between the two disorders. Children with fragile X syndrome show basic repetitive behaviors such as hand-flapping, whereas children with autism can have one or more of a range of behaviors, including compulsive organizing of their toys and restricted interests3.

“We have someone who has hand movements and slaps their face, compared with someone who doesn’t have any of this and just likes to line their toys up,” says Joseph Piven, professor of psychiatry at the University of North Carolina, Chapel Hill. “We lump them into the same domain, but they’re really different phenomena.”

Fragile X syndrome is also distinct from autism in that nearly all boys with the disorder have low intelligence quotients (IQs). This intellectual disability leads to poor language skills and communication, which can easily be mistaken for autism, experts say.

Intellectual disability may also worsen the social deficits or repetitive behaviors associated with fragile X syndrome, making them more likely to be picked up by tests used to diagnose autism, says Scott Hall, assistant professor of psychiatry at Stanford University School of Medicine in California4. “As the IQ goes down, they are going to start to hit more and more on particular impairments that are designed to categorize kids with autism,” he says. In line with this hypothesis, low IQ seems to accompany the social symptoms seen in fragile X syndrome5. In autism, by contrast, social deficits dominate even in children of average intelligence.

Careful comparison:

One way to avoid IQ confusing the results is to only compare children who have fragile X syndrome with children who have autism and comparable IQs, says Warren.

In two studies published this year, Abbeduto and his colleagues followed just this approach. They found that at a given IQ level, children with fragile X syndrome have fewer inherent social deficits than do children with autism.

For example, boys with fragile X syndrome are more likely to smile at and to try to engage others than are boys with autism. They are also more anxious and hyperactive, perhaps causing them to avoid social situations.

Imaging studies also suggest that there are structural differences between the brains of children with autism and those with fragile X syndrome6.

In particular, several studies point to an enlarged caudate nucleus in children with fragile X syndrome7. This region organizes brain circuits that are primarily involved in movement. By contrast, the brains of children with autism are larger overall than those of controls, but have a caudate nucleus of average size8.

Brain imaging studies may be an objective measure for classifying children with autism or fragile X syndrome, instead of relying on superficial behaviors, says Piven.

For example, in a study published in April, Piven and his colleagues found that a group of boys with fragile X syndrome who have an enlarged caudate are also the most likely to have low IQs and severe autism symptoms9.

Ultimately, understanding how fragile X syndrome and autism are alike and different may help scientists treat the disorders.  

“It’s sort of a plodding-along process; it feels like peeling an onion,” he says. “We need to do better and do more than just lump all these things together as the ‘autisms.’”

References:

1: McDuffie A. et al. J. Autism Dev. Disord. Epub ahead of print (2014) PubMed

2: Thurman A.J. et al. Res. Dev. Disabil. 35, 1072-1086 (2014) PubMed

3: Wolff J.J. et al. J. Am. Acad. Child Adolesc. Psychiatry 51, 1324-1332 (2012) PubMed

4: Hall S.S. et al. J. Am. Acad. Child Adolesc. Psychiatry 49, 921-933 (2010) PubMed

5: McDuffie A. et al. Am. J. Intellect. Dev. Disabil. 115, 307-326 (2010) PubMed

6: Hoeft F. et al. Arch. Gen. Psychiatry 68, 295-305 (2011) PubMed

7: Wolff J.J. et al. J. Neurodev. Disord. 5, 12 (2013) PubMed

8: Hazlett H.C. et al. J. Am. Acad. Child Adolesc. Psychiatry 51, 921-933 (2012) PubMed

9: Romano D. et al. Hum. Brain Mapp. Epub ahead of print (2014) PubMed


7 responses to “Fragile X symptoms don’t add up to autism, studies suggest”

  1. Anonymous says:

    We also need to remember that Fragile X Syndrome is a spectrum disorder and that not all boys who are affected have intellectual disability.

  2. Claire Wolstencroft says:

    It is also possible for a person to have the two conditions as distinct entities.

  3. Bob says:

    Interesting article about an intriguing research study. If you’d like to stay on top of the various research projects and initiatives, I invite you to visit http://www.NationalAutismNetwork.com. The National Autism Network is the largest online resource for the autism community and provides updated information daily on all aspects of autism.

  4. Jonathan Sebat says:

    Fragile-X Syndrome is one of hundreds of different genetic disorders for which a subset of individuals are on the autism spectrum. Other examples include Sotos syndrome, Tuberous Sclerosis, Duplications of 15q11-13 and microdeletions of 16p11.2. In every case, only a fraction of the carriers of a given mutation meet criteria for autism. By saying that Fragile-X is different from autism, one is simply pointing to two components of a Venn Diagram and saying A is different from B. http://upload.wikimedia.org/wikipedia/commons/7/7a/Venn_diagram_cmyk.svg

    I think Abraham Lincoln said it best. Some Autism IS Fragile X. And Some Fragile X is Autism. But you can’t say ALL Fragile X is ALL Autism.

  5. Adam FL says:

    Excellent points. We need to move on from the idea that by studying those with Fragile X and autism information gleaned is transferable to the vast majority of those with autism. A tremendous amount of research money has been spent on this hypothesis, with little success. Recently two long anticipated Fragile X autism drugs failed. We need to focus more on treating symptoms, whether it autoimmune dysfunction, metabolic disorders and gastrointestinal problems with drugs and or dietary interventions available now. All too often our families are living in crisis. Fragile X research is not the way forward. It is time to go a different route.

  6. bessie says:

    “One key distinction between the disorders, for example, is in social interactions. Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them.”
    The article was a good attempt to differentiate between fragile X and Autism. However, when I read the above statement I was surprised at the researcher’s limited knowledge of Autism. We now have a broader understanding of autism and his description here of social behavior and autism is totally inaccurate.

  7. Kathy Isaacs says:

    I’ve only just read this article, and find the author’s knowledge of both Fragile X and autism to be surprisingly deficient for someone writing about the topics.

    My family has Fragile X running through it. My brother is significantly affected (academic age of around 5, with a physical age of 42), and my uncle is also affected, although he was able to drive and hold a basic job. I have Autism but *not* the Fragile X gene. I have read extensively on both topics.

    The article says “Children with fragile X syndrome show basic repetitive behaviors such as hand-flapping, whereas children with autism can have one or more of a range of behaviors, including compulsive organizing of their toys and restricted interests.”

    My brother flapped, but also lined up his toys and counted them regularly, and he has (and always had) a few very strong interests which he pours all his energy into. I realise anecdotal evidence is less than convincing, but any rudimentary study of children and adults with Fragile X will discover a range of autistic behaviours, not just basic ones.

    Also, “Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them. But children with fragile X syndrome often sneak a peek when the other person turns his back, researchers say. Children with autism, in contrast, seem mostly uninterested in social interactions.”
    “They [children with Fragile X] are actually interested in their environment; they are just very shy and anxious about it.” The article appears to be contrasting this with autistic children, implying that Fragile X children are interested and autistic children are not. This may be a misinterpretation of Prof Warren’s original statement, but as there is no reference for this statement, it is hard to ascertain.

    Children with autism are frequently *exceptionally* interested in their environment, and are certainly not ‘mostly uninterested in social interactions’. They may be very interested, but unable to initiate or maintain those interactions.

    The understanding of autism in this piece is outdated by a couple of decades at least.

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