Why Severe ADHD Symptoms Persist in Some Children

It’s well established that ADHD is genetic. Now, scientists in Lecco, Italy, identified a specific gene mutation that seems to be directly linked to persistent symptoms of ADHD.

The team, who pioneered a five-year longitudinal study on more than 400 Italian children, identified a mutation in the N-methyl-D-aspartate (NMDA) receptor 2B subunit gene — a mouthful that is commonly shortened to Grin2b. Children with the mutation on Grin2b showed persistent ADHD symptoms throughout the study period; they also had smaller anterior cingulate cortexes, a region in the brain involved with attention, error recognition, and motivation.

"My hypothesis is that if you have a persistent ADHD, probably you have some genetic driver as the basis," said Maria Nobile, M.D., Ph.D., one of the lead investigators who presented the study. If the findings can be replicated, she says, it may change the way ADHD is treated.

Not all the children with persistent ADHD had the Grin2b mutation, leading researchers to conclude that even if the mutation is a cause of persistent ADHD, it probably isn’t the only explanation.

"The others [without the Grin2b mutation] are maybe ADHD children with a disrupted family, with socioeconomic disadvantages, so they are very exposed to environmental factors,” Nobile said.

The study focused on 250 children with ADHD, along with 151 of their neurotypical siblings. The study was divided into three phases: The first was a baseline evaluation, to look for the presence of ADHD or related conditions. The second phase — conducted five years later — reevaluated these factors, to track change over time. In the third phase, subjects had morphologic and functional MRIs and neuropsychological testing, as well as genetic analysis.

Persistent ADHD dropped from 29.9 percent of the children in the first phase to 8.7 percent in the second, confirming previous studies and anecdotal evidence suggesting that ADHD symptoms decrease over time. The genetic analysis, however, showed that children with the Grin2b gene were more likely to have severe ADHD symptoms both at the baseline test and at the follow-up five years later.

The Grin2b gene has come up in mental health studies before. It’s been linked to neurologic and psychological disorders, memory difficulties, and was found in children who have attempted suicide.

Nobile and her team plan to conduct follow-up studies to see if these trends regarding Grin2b hold, and to see if more genes can be identified with links to ADHD or behavioral issues. For now, she said, "We have the gene, then we have the brain structure, and then we have the phenotype — so probably the effect of Grin2b on attention is mediated by the brain morphology, but I have to investigate this."

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