Women who carry premutations in the FMR1 gene have poorer language-related abilities, similar to those found among parents of individuals with autism spectrum disorder (ASD), a fragile X syndrome-related condition, a study has found.
The study, “Language processing skills linked to FMR1 variation: A study of gaze-language coordination during rapid automatized naming among women with the FMR1 premutation,” was published in the journal PLOS ONE.
Fragile X syndrome is caused by mutations in the FMR1 gene, which provides instructions to make a protein called fragile X mental retardation protein (FMRP). This protein plays a critical role in brain development and function.
Typically, people with fragile X have the FMR1 gene disturbed by what is known as a “full mutation” — copies of a DNA sequence termed CGG, repeated more than 200 times. This shuts down the production of FMRP, leading to the symptoms and signs of the disease, including intellectual disability, motor and language delays, and autistic behaviors.
Other people may carry “premutations” consisting of 55 to 200 CGG repeats within FMR1. This is more common than a full mutation, and may occur in up to one in 150–390 females, and less frequently in males.
While premutation carriers are at greater risk of having offspring with fragile X, they usually have no symptoms of the disease. However, they can develop some fragile X-related disorders, such as fragile X tremor-ataxia syndrome (FXTAS), and primary ovarian insufficiency (POI).
Some studies suggest that premutation carriers may have subtle but detectable alterations in cognitive and language abilities. Given the relatively high prevalence of premutations among women, finding out which features mark this population “has important public health implications,” the researchers wrote.
Northwestern University researchers investigated gaze and language coordination in female premutation carriers as a proxy of underlying cognitive deficits.
They looked at the performance 48 adult women carriers while they completed a language processing test called rapid automatized naming (RAN), and compared their performance with 56 women who did not carry premutations (control group).
During RAN, each participant was asked to serially name arrays of numbers, letters, colors, and objects, as quickly and accurately as possible, while an eye tracker recorded their eye movements.
RAN taps fundamental language-related neuropsychological skills, so inefficient performance on this test can implicate broader problems in language and executive skills, such as pragmatic language (the social language skills people use in daily interactions with others).
Results showed that women with premutations had a poorer RAN performance, with an insufficient pattern of language processing, compared to controls.
Specifically, they had a greater number of eye fixations and a reduced eye-voice span, showing less lead in the eyes compared to the voice, during naming of letters and numbers. The latter was “indicative of decreased automaticity,” researchers noted. (Eye-voice span refers to when, during oral reading, the eyes tend to be ahead of the voice).
Those deficits were apparent during RAN tasks at which cognitive processes were “most heavily taxed” — when working memory and processing load were at their greatest — indicating vulnerabilities in executive skills.
To detect alterations in pragmatic language, participants were asked questions related to their life history and examined if their answers had any language violations, such as failure to provide enough background information to understand a certain topic.
Poorer RAN performances were associated with greater impairments in pragmatic language, suggesting that the broader deficits in speech and language abilities reported in premutation carriers could be explained by changes at fundamental skills.
Worse RAN results also were related to specific FMR1 variations, namely with longer CGG repeats, lower gene activation, and increased levels of FMRP.
In addition, researchers noted that premutation carriers had deficits similar to parents of children with ASD, consistent with the known overlap between ASD and fragile X symptoms.
These findings “contribute to an understanding of the neurocognitive profile of [premutation] carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes,” the researchers wrote.
Measuring these deficits “may help to provide clinically and biologically meaningful targets in future molecular-genetic studies of the impact of FMR1-related molecular variation,” they said.
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