Visual Attention Patterns Found to Identify Women With FMR1 Premutation

Eye-tracking technology has identified atypical visual attention patterns in women who carry the FMR1 premutation, a condition related to fragile X syndrome, that occurs later in life, a study reported. 

These findings imply that visual attention patterns might be a meaningful biomarker to identify individuals with this premutation, the scientists said. 

The study, “A Unique Visual Attention Profile Associated With the FMR1 Premutation,” was published in the journal Frontiers in Genetics. 

An FMR1 premutation (PM) is indicated by 55 to 200 CGG repeats within the FMR1 gene, which encodes for the FMRP protein. The C stands for cytosine and the G for guanine — two of the four building blocks of DNA. 

In contrast, the number of repeats in healthy people does not exceed 40. In fragile X syndrome, patients carry more than 200 CGG repeats, which lead to a deficiency in the FMRP protein and cause delays in language development, intellectual ability, and social cognition.

FMR1 PM increases the risk of fragile X-associated tremor and ataxia syndrome (FXTAS), characterized by movement and thinking problems (cognition), which occurs in some older PM carriers. 

Studies suggest women with FMR1 PM display differences in visual fixation patterns, defined as increased attention to the mouth and reduced attention to the eyes when examining faces. This atypical PM fixation pattern was associated with better social language and social cognitive abilities, reflecting different strategies for emotion processing than unaffected individuals.

Atypical visual attention patterns have been observed in people diagnosed with autism spectrum disorder (ASD) and in their parents, children, and siblings — those classified as first-degree relatives — displaying social language and social-cognitive differences. About one-third of fragile X patients are also diagnosed with ASD.

Previous research has suggested that visual attention profiles, which are easy to measure, may be potential biomarkers for FMR1 PM to expand the diagnostic criteria. 

Now, scientists based at Northwestern University, in Illinois, examined patterns of gaze in a group of women with FMR1 PM. They used a series of eye-tracking tasks that included viewing facial expressions, narration from a picture book, and set images designed to evoke strong emotional responses.

The participants included 65 women with FMR1 PM, with a mean age of 45.28, and a mean of 88.76 CGG repeats. As a comparison, 188 parents of ASD individuals were included. They had a mean age of 46.09 and a mean CGG expansion of 30.41. Among them were 119 women. A control group consisted of 84 parents, mean age 41.84 years, of which 53 were women.

Both eyes of participants were tracked and recorded with sensors built into a computer that displayed visual stimuli.

Eye-tracking stimuli included a 24-page wordless picture book, “Frog Where Are You?” — about a boy and his dog searching for the child’s lost pet frog. Tracking measured areas of interest, including all characters, the protagonists (boy, dog, and frog), inanimate settings, and the protagonist’s focus of attention. 

A thematic apperception test (TAT), a psychological measure that uses ambiguous images, included six images viewed for eight seconds. Participants were asked to tell a story about the pictures with details about the character’s actions, thoughts, and feelings.

The third eye-tracking test measured affective facial expressions (AFE) by the NimStim Facial Stimulus Set, in which participants were presented with images depicting happy, calm, and fearful faces. 

The results revealed that women with FMR1 PM showed significant differences in picture book focus of interest (PB-FOA) and the AFE fixations on the mouth (AFE-Mouth) compared with the controls. The independent predictability area under the curve (AUC) was 0.78, in which values of 0.80 or above represent excellent predictability. The sensitivity or true positive rate was 71%, while the specificity or true negative rate was 68%. 

The simplest model that maintained this predictive power included only the PB-FOA and AFE-Mouth, which correctly classified 92% of controls (77/84) and 68% of PM carriers (44/65).

Comparing PM carriers with ASD parents found AFE-Mouth was the only independent significant predictor, with an AUC of 0.74, a specificity of 71%, and a sensitivity of 68%. A statistical model using only AFE-Mouth classified 98% of the ASD parents (183/188) and 62% of the PM carriers (40/65). 

Only PB-FOA was a significant predictor of ASD parents compared with controls, with an AUC of 0.62, specificity 59%, and a sensitivity of 56%. The model correctly classified 98% of the ASD parents (185/188) and 4% of the control participants (3/84).

In those that carried FMR1 PM, there were no significant correlations between CGG repeat length and FMRP protein levels and any of the eye-tracking variables. In contrast, in ASD parents, increased CGG repeats were associated with increased time looking at the mouth and decreased time on the face in the thematic apperception test. 

An exploratory investigation of 25 PM carriers who were misclassified as ASD parents demonstrated greater language violations defined as overly talkative and describing irrelevant details, as well as marginally greater FMRP levels than the correctly classified PM carriers. 

Finally, an analysis of 13 children of the 25 PM carriers who were misclassified as ASD parents and 17 children from 40 correctly classified PM carriers demonstrated that the children of the misclassified PM carriers were marginally more affected by ASD and displayed more ASD-like restrictive and repetitive behaviors. 

“Taken together, results of this study highlight the utility of eye tracking in the context of a face processing task as a tool for prediction of PM status and specific [PM-related] marker,” the researchers concluded.

“Findings also provide evidence of overlap in visual fixation patterns with parents of individuals with ASD, suggesting potentially shared neurobiological mechanisms underlying [characteristics] observed across these populations,” they added.