Apples and oranges: When identifying human emotions, individuals with fragile X show increased activation in the left hippocampus (B) and the right insula (C), compared with people who have autism.

Autism and fragile X syndrome are characterized by very different brain processes, even though the two disorders show similar social deficits, say authors of the first functional imaging study to compare the two disorders¹.

Fragile X syndrome is a form of inherited mental retardation that stems from a rare mutation in a single gene, FMR1, on the X chromosome. Like those with autism, people with the syndrome often have trouble interacting with others, maintaining eye contact, or acquiring language. Fragile X syndrome affects 1 in 4,000 males and half as many females, but as many as a third of them exhibit features of autism².

“Behaviors that appear similar in both conditions suggest to many researchers that autism and fragile X syndrome may also share etiologic factors,” says Ami Klin, director of the Autism Program at the Yale Child Study Center.

But this studyʼs results suggest thatʼs not the case, says lead investigator Kim Dalton, associate scientist at the Waisman Center of the University of Wisconsin-Madison.

“On the surface, [the two disorders] have similar behavioral profiles,” Dalton says. “But our research is showing that in the brain, there are more differences than there are similarities.”

Some studies have shown that certain brain regions ― including the caudate nucleus, which is important for learning and memory, and the cerebellar vermis, which aids in balance and for sensing your own body movement ― are abnormally large in both people with autism and people with fragile X³.

In the current study, researchers used magnetic resonance imaging (MRI) to measure the brain activity and eye-gazing patterns of 9 people with fragile X, 14 with autism and 15 typically developing controls.

The researchers showed each participant a series of human faces, and then asked them to identify the emotion expressed: happiness, fear, or anger, or no emotion. Sophisticated eye-tracking equipment inside the MRI recorded the precise movements of the participantsʼ eyes as they looked at the faces.

Those with fragile X syndrome show similar eye fixation patterns as those with autism, the researchers found. Both groups spend less time looking at eyes compared with typically developing controls, although this difference is more pronounced in the autism group.

However, the exact path of the eye gaze in the fragile X and autism groups is different: the gaze path for those with autism is “quite random,” whereas those with fragile X syndrome initially look at the eyes of a face, but then quickly look away ― a sign of social anxiety.

“It’s as if they’re thinking, ‘Oh, I want to look ― oh, no, I don’t want to look. Want to look. Don’t want to lookʼ,” Dalton says.

This social anxiety is typical in people with fragile X syndrome: they do want to interact with others, but attempting to do so makes them feel extremely anxious.

For example, when offered a hand to shake, people with fragile X will typically extend their own hand while simultaneously turning the rest of their body away from the other person.

“It’s a pretty distinct behavior and very clearly provoked by anxiety,” says Laura Holsen, an instructor in psychiatry at Harvard Medical School, and a collaborator on the study. “That seems qualitatively different from some people with autism who just don’t have the same level of interest in other people, who are just kind of disconnected in their own world,” Holsen adds.

Familiar faces:

The study finds that compared with typically developing controls, the fragile X and autism groups also share an unusually low activation of the fusiform gyrus brain region, which is activated when people think about something familiar, such as a human face.

In other brain regions, however, the fragile X group has markedly different brain activation patterns when asked to identify human facial emotions: they show increased activation in the right insula, a deep brain structure that’s closely linked to experiencing basic emotions, and in the left hippocampus, which is crucial for short-term memory.

Dalton’s team concludes that these relatively large differences in brain activity lead to the subtle differences in behavior between people with fragile X and autism.

“The insula [activation] in particular, for me, that indicates the anxiety and social phobia that we see in fragile X but not in autism,” she says.

Other researchers are more cautious about drawing such broad conclusions from a small sample that includes both sexes and varies widely in age and intelligence quotients (IQ).

“A big question that’s still left here is teasing apart the effects due to fragile X versus autism on the one hand, from the effects due to these confounding factors of sex and IQ and age on the other,” notes Matthew Belmonte, an assistant professor at Cornell University.

The study is the first to group males and females with fragile X in the same analysis, largely because the condition is often too severe in males to make them effective study participants. It includes six females and three males with fragile X, 14 males with autism and 12 males and 3 females in the control group.

But some experts say this could confound the fragile X data because the mental capacities of males and females with fragile X are vastly different.

“I wish that there had been far more patients, and also males with [both] fragile X and autism,” says Randi Hagerman, endowed chair in Fragile X research at the University of California, Davis.

The sample also varies widely in age, averaging 20.7 years for the fragile X group, 15.9 for the autism group, and 16.8 for typically developing controls; and in IQ, which ranges from 35 to 122.

“It’s not clear whether the IQ differences between the groups might not have driven some of the apparent between-group differences,” says Belmonte. “That’s not to say that results aren’t interesting in an exploratory manner, but they have to be taken as exploratory.”

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