How do the Behaviors Seen in Persons with Fragile X Relate to Those Seen in Autism?
Many parents are confused about their child's diagnosis. On the one hand, they've been told that their child has autism, "autistic spectrum disorder," or some degree of autistic-like characteristics. In addition, they may have also been told that their child has fragile X syndrome or that he or she is going to be tested for fragile X.
The association between autism and fragile X was first reported by Brown et al. (1982) and was subsequently
confirmed by many others leading to an extensive field of research.
In discussing this association it is important to remember that autism is defined behaviorally using the criteria of the DSM IV manual which include lack of social reciprocity or responsiveness, abnormal use of language and communication, and a restricted repertoire of activities and interests. Autism is a heterogenous disorder which means that there are several known causes of autism including phenylketonuria (PKU), tuberous sclerosis and 15q duplications. However fragile X is the most common known cause of autism so far identified. Autism is strongly genetic and it is likely that the inheritance of multiple genes predisposing an individual to autism is necessary in many cases for the full behavioral syndrome to be manifested.
 The typical features of fragile X syndrome (FXS) i.e. hand biting, hand flapping, poor eye contact, shyness, and social anxiety are probably related to the sensory hyperarousal that has been documented by many investigators including Belser and Sudhalter (1995),
Miller et al. (1999), and Roberts et al.(2002). These features are often also referred to as autistic-like features because they can be seen in individuals who have autism without fragile X. Most children with fragile X, however, are interested in social interactions and do not meet the diagnostic criteria for autism.
However, a subgroup of children with fragile X do meet diagnostic criteria for autism.
Over the last decade many studies have evaluated this issue and the percentage of children with FXS who have autism has varied from 15 to 33%, mainly because the diagnostic criteria for autism has varied and the diagnostic tools used have changed.
Recent work by Don Bailey and colleagues has found that in young boys with FXS, 25%
met the criteria for autism using the Childhood Autism Rating Scale (CARS) and that their profile of behaviors was very similar to that of children with autism and without fragile X. They also found that children with autism and FXS together, had a lower IQ than children with either FXS alone or autism alone (Bailey, Hatton et al. 2001). Furthermore, the level of the fragile X protein (FMRP) did not correlate with the presence or absence of autism. (Bailey, Hatton et al.
2000) This suggests that autism with fragile X may relate to additional genetic or environmental factors that could be additive to the FMR1 mutation.
Our studies also agree with this hypothesis. We recently reported a comparison study of preschoolers with FXS, and age matched children (controls) with autism but without fragile X and another set of children (controls) who had developmental disabilities but without autism or FXS. (Rogers, Wehner et al. 2001
) We evaluated all of these children with what are the agreed gold standard diagnostic tools for autism including the Autism Diagnostic Observation Schedule-Generic (ADOS-G) and the Autism Diagnostic Interview-Revised (ADI-R) and also utilized the the DSM IV criteria, IQ and adaptive behavior measures.
We found that 15% to 33% of the children with FXS met the full criteria for autism. Their profile of autistic features was indistinguishable from the children
with autism without FXS. Children with FXS who were not autistic had a behavioral profile that was similar to the controls with developmental disabilities. In addition, the group with both FXS and autism were the lowest of all the groups on developmental testing, results similar to the studies of Bailey and colleagues.
The reason why some children with FXS have autism too, may relate to additional background gene effects (other genes inherited from their mother and
father) and further studies are underway. There also are effects of the fragile X protein deficit that predispose children to autism including the hyperarousal to stimuli and the shyness and social anxiety. When these problems are severe in FXS, then autism is more likely to occur.
A recent report by Roberts et al. 2002 demonstrated more autonomic dysfunction (problems with the sympathetic or parasympathetic nervous system such as
increased heart rate when scared or stressed) and hyperarousal in children with both FXS and autism compared to FXS alone. Also of note is a recent neuroimaging study in females which demonstrated that the size of the posterior cerebellar vermis (an area of the brain involved in motor function, cognition and sensory perception) on MRI correlated inversely with the number of autistic features. In addition, the number of autistic feature also correlated with the
severity of anxiety (Mazzocco, Kates et al. 1997).
More research is needed regarding treatment of children with both FXS and autism. Preliminary studies in autism suggest that early treatment with a selective serotonin reuptake inhibitor (medications like Prozac, Paxil, Luvox and others) is beneficial for both language and socialization skills (DeLong,
Teague et al. 1998) and this possibility needs to be studied in children with FXS and autism. Intensive behavioral interventions are helpful in young children with autism and this too needs to be evaluated in young children with FXS and autism together (Scharfenaker, O'Connor et al. 2002).
Finally, it is important to identify the children with FXS among those who have been diagnosed with autism alone to provide genetic counseling and access to
treatments and interventions known to be beneficial for individuals with FXS. Previous screening studies have shown that 2.5% to 6% of boys with autism have FXS. (Brown, Jenkins et al. 1986; Bailey, Phillips et al. 1996; Hagerman 2002) Therefore all children with autism and or mental retardation should have fragile X DNA testing. Such screening may also identify individuals with the fragile X premutation in association with autism and we are currently evaluating
the additive effect of the premutation which can be associated with mild gene dysfunction (Tassone, Hagerman et al. 2000).
In summary, the association of fragile X syndrome and autism is a strong association which requires assessment in each child and will guide future treatment endeavors. References Randi Hagerman, MD
Medical Director, UC Davis Medical Center, M.I.N.D. Institute
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