ADHD more likely in certain fragile X premutation carriers: Study

Genetic instability linked to higher rates of ADHD in women, girls

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Attention-deficit/hyperactivity disorder (ADHD) is more common among female carriers of a fragile X premutation who have more cell-to-cell variation in the number of mutational CCG repeats in the premutation, a new study reveals.

Indeed, according to researchers, “the degree of [genetic] instability (expansion) was significantly higher … in participants with a diagnosis of [ADHD] compared to those without.”

ADHD is a common neurodevelopmental disorder typically characterized by symptoms of inattention, hyperactivity, and impulsivity.

These findings “suggest a potential role of the CGG expansion in the clinical [pattern] of [premutation carriers] and may potentially guide clinical prognosis and management,” the researchers wrote.

The study, “Clinical implications of somatic allele expansion in female FMR1 premutation carriers,” was published in Scientific Reports.

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Study focus: the clinical implications of genetic instability

Fragile X syndrome is caused by a mutation, called a CCG repeat expansion, in the FMR1 gene, which provides instructions to produce a protein called FMRP.

In a specific region of this gene, one set of nucleotides — two cysteines (C) and one guanine (G) — are normally repeated about five to 40 times. When there are more than 200 of this repeat of nucleotides, which are the building blocks of DNA, it can cause fragile X.

A premutation occurs when there are between 55 and 200 CCG repeats. People who carry a premutation don’t develop fragile X, but they are at risk of other disorders. These include fragile X-associated tremor/ataxia syndrome, known as FXTAS — a movement disorder characterized by coordination issues and tremor — and fragile X-associated primary ovarian insufficiency (FXPOI), in which the function of the ovaries is reduced much earlier than a normal menopause.

Premutation carriers also are disproportionately more likely to develop fragile X-associated neuropsychiatric disorders (FXAND) like autism, anxiety, depression, and ADHD.

In a study published last year, a team led by scientists at the University of California Davis showed that the vast majority of female premutation carriers exhibited somatic FMR1 instability.

Put simply, by analyzing the number of FMR1’s CCG repeats in each cell from participants’ blood samples, they found that a few cells in each female showed slightly more repeats than the majority of cells. In other words, there was instability in their somatic cells, which includes all bodily cells except sperm and egg cells used in reproduction.

In the new study, the scientists conducted analyses to explore connections between somatic FMR1 instability and premutation-associated conditions.

“This study sought to assess the clinical implications, if any, of somatic [FMR1] expansion in a large [group] of female PM [premutation-carrying] participants,” the team wrote.

The analysis included data on 424 female premutation carriers, ranging in age from a few months old to 90 years.

More than 80% had at least one FXAND, most commonly anxiety or depression. A total of 26.2% — about 1 in 4 — had been diagnosed with ADHD. There were 51 females with FXTAS and 43 with FXPOI.

Premutation carriers had a mean of 92.1 CCG repeats in the FMR1 gene. Somatic instability was detected in about 92% of them.

For each participant, the researchers calculated the degree of somatic instability. This basically involved comparisons to assess the degree to which the CCG repeat number varied from cell to cell.

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No condition except ADHD was linked to genetic instability in this study

Statistical analyses showed that the degree of somatic instability, or repeat number variance across cells, was significantly higher among premutation carriers with ADHD relative to those without this psychiatric diagnosis.

No other assessed conditions, including FXPOI and FXTAS, showed a statistically significant association with the degree of somatic instability.

“Our main findings suggest that [somatic instability] is associated with significantly higher occurrence of ADHD among female PM,” the researchers wrote.

Further analyses showed no significant associations between any psychiatric diagnosis and the total number of CCG repeats, though there was a greater prevalence of ADHD among females with more than 105 repeats. Also, the rate of FXPOI was highest among females with 71 to 90 repeats, compared with those with more or fewer repeats.

In line with prior studies, the researchers found an association between more CCG repeats and higher levels of FMR1’s messenger RNA (mRNA), an intermediary molecule derived from DNA that guides protein production.

Previous data showed that higher CCG repeat numbers tend to result in lower levels of the resulting FMRP protein, likely due to problems in the protein production process.

“This combination of elevated mRNA levels and lowered FMRP levels could create a ‘double-hit’ phenomenon resulting in greater occurrence of disorders associated with both the reduced FMRP [production] … and RNA toxicity due to the presence of elevated levels of FMR1 mRNA,” the team wrote.

Our main findings suggest that [genetic instability] is associated with significantly higher occurrence of ADHD among female [premutation carriers].

Other analyses showed that average FMR1 mRNA levels were significantly higher in patients with FXAND, particularly ADHD and depression, compared with those without these diagnoses.

“Higher levels of FMR1 mRNA are associated with an occurrence of neuropsychiatric conditions including depression and ADHD,” the scientists wrote, adding that these findings “likely reflect the toxicity of elevated levels of mRNA,” which has been shown to have detrimental effects on brain health.

While these preliminary results should be confirmed in future studies, the team noted that these findings could lay the basis for future work to better understand the consequences of somatic FMR1 instability in fragile X premutation carriers.

“This preliminary data suggest a potential role of [somatic instability] as a biomarker that may be useful for assessing prognosis and clinical management” of premutation carriers, the researchers concluded.

“Further research on the clinical implications of expansion could potentially help to discern the clinical phenotype and guide prognostication and management of these conditions in these individuals.”