Innovating diagnoses: American researchers assess autism with eye reflex exam

Scientists in California have linked the disruption of a sensitive eye reflex to profound autism.

This, they said, offers opportunities for faster diagnosis and new treatment of the disease – a developmental disability caused by differences in the problem. Usually diagnosed around the age of two years, people with autism spectrum disorder (ASD) often have problems with social interaction and communication and restricted or repetitive behaviors or interests. They may also have different ways of learning, moving, or paying attention.

Since the UN General Assembly designated April 2 as World Autism Awareness Day (WAAD) in 2007, it and member nations have marked the day as a means to affirm and promote the full realization of all human rights and fundamental freedoms for autistic people on an equal basis with others.

Now, scientists at the University of California at San Francisco believe they may have discovered a new way to test for autism by measuring how children’s eyes move when they turn their heads.

They found that children who carry a variant of a gene that is associated with severe autism are hypersensitive to this motion. The discovery could help to diagnose kids earlier and faster with a method that only requires them to don a helmet and sit in a chair.

“This could be a game-changer in both the clinic and the lab,” they enthused.

“We can measure it in kids with autism who are non-verbal or can’t or don’t want to follow instructions,” said neuroscience Prof. Kevin Bender, who was the co-senior author of the study. The research has appeared in the journal Neuron under the title “Impaired cerebral plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD.”

Advancing research into autism

The gene, SCN2A, makes an ion channel that is found throughout the brain including the cerebellum that coordinates movement. Ion channels allow electrical charges in and out of cells and are fundamental to how they function. Several variants of this gene are also linked with severe epilepsy and intellectual disability. Of the hundreds of gene mutations associated with autism, variants of the SCN2A gene are among the most common.

The researchers found that children with these variants have an unusual form of the reflex that stabilizes the gaze while the head is moving and is called the vestibulo-ocular reflex (VOR). In autistic children, it seems to go overboard, and this can be measured with a simple eye-tracking device.

The discovery could help to advance autism research, which affects 1 out of every 36 children in the US. According to data from Israel’s National Insurance Institute, the number of children and youths with a formal diagnosis of ASD who were aged one year to 17 who were eligible for services increased from 14,914 in 2017 to 32,222 in 2021. This does not include adults with ASD.

The increase represents a two-fold increase in ASD prevalence from 0.49% to 0.96% over the five years. This does not mean that there is such a huge growth in autistic children, but greater awareness of the disorder and parents bringing their toddlers for testing.

SINCE AUTISM affects social communication, ion-channel experts like Bender focused on the frontal lobe of the brain that controls language and social skills in people. However, mice with an autism-associated variant of the SCN2A gene did not show marked behavioral differences associated with this brain region.

Chenyu Wang, a graduate student in Bender’s lab and first author of the study, decided to look at what the SCN2A variant was doing in the mouse cerebellum. Dr. Guy Bouvier, a cerebellum expert at the university and co-senior author of the paper, already had the equipment needed to test behaviors influenced by the cerebellum like the VOR.

This reflex is easy to provoke. Shake your head and your eyes will stay roughly centered. In mice with the SCN2A variant, however, the researchers discovered that this reflex was unusually sensitive. When these mice were rotated in one direction, their eyes compensated perfectly, rotating in the opposite direction.

However, this increased sensitivity came at a cost. Normally, neural circuits in the cerebellum can refine the reflex when needed, for example, to enable the eyes to focus on a moving object while the head is also moving. In SCN2A mice, however, these circuits got stuck, making the reflex rigid.

Wang and Bender had uncovered something rare – a behavior that arose from a variant of the SCN2A gene that was easy to measure in mice. But would it work in people? They decided to test it with an eye-tracking camera mounted on a helmet. It was a “shot in the dark,” Wang said, given that the two scientists had never before conducted such a study in humans.

Bender asked several families from the FamilieSCN2A Foundation – the leading US family advocacy group for children with SCN2A variants, to participate. Five children with SCN2A autism and 11 of their unaffected siblings volunteered.

They took turns rotating the children to the left and right in an office chair to the beat of a metronome. The VOR was hypersensitive in the children with autism, but not in their neurotypical siblings. The scientists could tell which children had autism just by measuring how much their eyes moved in response to their head rotation.

The scientists also wanted to see if they could restore the normal eye reflex in the mice with a CRISPR-based technology that restored SCN2A gene expression in the cerebellum. When they treated 30-day-old SCN2A mice – equivalent to late adolescence in humans – their VOR became less rigid but was still unusually sensitive to body motion. But when they treated 3-day-old SCN2A mice – early childhood in humans – their eye reflexes were completely normal.

“These first results, using this reflex as our proxy for autism, point to an early window for future therapies that get the developing brain back on track,” Wang said. It’s too early to say whether such an approach might someday be used to directly treat autism. But the eye reflex test, on its own, could clear the way to more expedient autism diagnosis for kids today, saving families from long diagnostic odyssey.

“If this sort of assessment works in our hands, with kids with profound, nonverbal autism, there is hope it could be more widely adopted,” Bender concluded.