Mothers of Fragile X Children Have Cognitive Problems Linked to Their Genetic Profile and Older Age, Study Finds

Specific cognitive deficits in mothers of children with fragile X syndrome are significantly linked to their genetic profile and are worse in older age, a study has found.

The study, “Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome,” was published in the journal Brain and Cognition. 

Fragile X is caused by an expansion of CGG repeats within the FMR1 gene in the X chromosome. In these repeats, C refers to cytosine and G to guanine, two of the four building blocks of DNA.

A person with fragile X typically has more than 200 CGG repeats, called a full mutation. Women with a premutation in FMR1, which is made of 56 to 200 of such repeats, may pass on an expanded version of the affected gene to their children.

Although they do not have the same symptoms as people with the full mutation, carriers of the premutation may have difficulties in social cognition and communication. 

In particular, problems with memory, attention, and cognitive inhibition have been reported in female carriers of the premutation. Cognitive inhibition refers to the ability to suppress impulses and behavior in order to focus on completing a task. 

Understanding how the premutation affects mothers of children with fragile X is important not only for the mother’s health but also for her ability to care for her children. However, studies to understand how the premutation affects cognitive inhibition have shown mixed results. 

To get a clearer picture, a group of researchers studied whether cognitive inhibition in premutation carriers who have children with fragile X is associated with the length of CGG repeats and age. 

The team recruited 134 women with a mean age of 56.8 years (range 39–88). They were assessed with an audio-recorded telephone interview using the Hayling Sentence Completion Test — a measure of inhibition deficits in premutation carriers. 

In this test, participants listened to 15 sentences with the last word missing and were asked to provide a word that did not fit the meaning of each sentence as quickly as possible. This required suppression of natural, or prepotent, responses. The researchers measured both the time it took to answer (latency) and the number of errors. 

The women also completed the Behavior Rating Inventory of Executive Function- Adult Version (BRIEF-A), which assesses inhibition. This questionnaire consisted of eight items measuring impulse control and the ability to stop behavior at the appropriate time, such as waiting in line. 

Participants also a provided a cheek swab for genetic analysis. 

Results showed that the number of CGG repeats was significantly associated with response latency but not with the number of errors in the Hayling test.

Response latency was increased in women with mid-range CGG lengths of around 80 to 90 CGG repeats, lowered (meaning less cognitive inhibition) in those carrying between 90 and 115 repeats, and increased again in women with more than 130 repeats. 

Similar findings were seen in the correlation between CGG lengths and results from the self-reported BRIEF-A questionnaire. Again, inhibition deficits were most pronounced in those with mid-sized repeats. 

Further analysis found that these deficits were aggravated with older age.

“This study supports older age and mid-range CGG repeat length as personalized risk factors that may be used to tailor the clinical monitoring and management of executive [cognitive] deficits” in female premutation carriers of children with fragile X, the team wrote.