Clear Neuroanatomical Differences Between Autism, Fragile X

Similarities End With Behavior

Deborah Brauser

March 31, 2011

March 31, 2011 — Distinct neuroanatomical patterns exist between fragile X syndrome (FXS) and autism of unknown cause, even though both disorders appear to share overlapping behaviors, a new imaging study suggests.

In a comparison study of 165 male toddlers, investigators found that compared with healthy controls, those diagnosed as having FXS or idiopathic autism (iAUT) had significant differences in the frontal and temporal gray and white matter regions often associated with social cognition.

However, the iAUT group had greater volume levels in these regions than controls, and the FXS group had lower volume levels.

"To better treat children who have these autistic syndromes, it's important to identify the neurodevelopmental pathways that go awry. It then gives us a template to understand not only how things have gone wrong, but it can potentially tell us how to make it right," coinvestigator Allan L. Reiss, MD, director of the Center for Interdisciplinary Brain Sciences Research and professor of psychiatry at Stanford University School of Medicine, California, told Medscape Medical News.

Dr. Allan L. Reiss

The investigators also found that the overall morphometric brain patterns in iAUT more closely resembled those in the controls than those with FXS.

"In other words, these multivariate analysis techniques demonstrate that...young boys with FXS represent a more unique and homogenous group with respect to neuroanatomy than do boys with iAUT," they write.

"The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can significantly alter the FXS phenotype in affected individuals," add the researchers.

Calling the overall findings "striking," Dr. Reiss said they show that "we really have to get in gear in further breaking down this concept of idiopathic autism in meaningful constructs."

The study was published in the March issue of Archives of General Psychiatry.

Great Debate

FXS arises "from mutations of a specific gene on the X chromosome" and is currently "the most common known single-gene cause of autism," write the investigators.

They note that many behaviors exhibited by those with FXS and with iAUT appear to be similar, including poor social interaction and communication abnormalities. That these behaviors could actually be caused by "differing morphological brain changes" is a subject of much debate.

"The concept of autism is an evolving one in psychiatry and neuroscience. Compared with 30 or even just 20 years ago, we have much more of a sense that that diagnosis is one that represents an aggregation of symptoms that tend to cluster together but does not represent shared or even specific etiology," said Dr. Reiss.

"We now see an autism diagnosis as a collection of, mostly as yet unidentified, neurobiological conditions — of which [FXS] is an important one."

The study included 165 boys between the ages of 1 and 4 years who were enrolled at sites in Sanford and at the University of North Carolina, Chapel Hill.

The participants included those with a diagnosis of FXS (n = 52; mean age, 2.9 years), iAUT (n = 63; mean age, 2.77 years), idiopathic developmentally delayed (DD; n =19; mean age, 2.96 years), or typically developing (TD; n = 31; mean age, 2.55 years). The investigators combined those with TD and DD to form the "controls" group for this study.

Whole brain analyses were conducted for all participants to evaluate regional gray matter volume and white matter volume differences between the groups.

"This is key because white matter differences are thought to play an especially important role in autism," said Dr. Reiss.

Novel Evidence

Behaviors were also measured using the Autism Diagnostic Interview (ADI), the Autism Diagnostic Observation Schedule (ADOS), Mullen Scales of Early Learning, and Vineland Adaptive Behavior Scales.

Results showed that "the ADI and ADOS measures of social, communication, and repetitive behavior indicated greater behavioral problems with iAUD as compared with FXS," write the investigators.

However, no significant differences were found between these 2 groups for IQ or for repetitive behaviors based on the Repetitive Behavior Scale.

Compared with the combined control group, the medial prefrontal cortex, orbitofrontal cortex, superior temporal region, temporal pole, amygdala, insula, and dorsal cingulum were all significantly reduced in those with FXS and significantly increased in those with iAUT.

"In this study, we show novel evidence that...brain volumes of boys with FXS and iAUT are on opposite extremes relative to controls for some gray and white matter regions," write the investigators.

"Further, we demonstrate that morphometric spatial patterns are significantly different between FXS and iAUT, even at this very young age," they add.

Implications for DSM-5?

James C. Harris, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, writes in an accompanying editorial that the study's findings bring up several critical questions for the field of clinical neuroscience.

"How should we consider the relationship of brain and behavior in the diagnosis of autism when the comparison is between a known neurogenetic disorder and a behaviorally defined diagnosis of unknown etiology?"

Dr. Harris writes that current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4), criteria is very broad, which "raises questions about the continued use of the term 'autism' itself for neurogenetic disorders. Perhaps a renewed emphasis on the specificity of behavioral phenotypes will signal the beginning of the death knell in seeking out the cause of idiopathic autism in [these known] disorders and allow a revised approach to diagnosis that takes developmental trajectory into account."

"Investigators from this same academic group in [a past] article ask if we are dealing with a category error in diagnosing autism in FXS and comment that in the future 'the practice of diagnosing children with FXS as autistic may become increasingly obsolete,'" he concludes.

The study was funded by grants from the National Institute of Mental Health and the National Institute of Child Health and Human Development and by the Canel Family Fund, the NARSAD Young Investigator Award, and the Stanford Child Health Spectrum. Dr. Reiss reports being a consultant for Novartis but that this study was conducted and the manuscript written before his consultancy. Dr. Harris has disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2011;68:230-231, 295-305.


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