No Evidence for a Difference in Neuropsychological Profile among Carriers and Noncarriers of the FMR1 Premutation in Adults under the Age of 50

Abstract

The 5' untranslated region of the fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat. Expansions of this repeat are associated with a spectrum of disorders. Full mutation alleles, repeats >or= 200, are associated with fragile X syndrome. Premutation alleles, repeats of approximately 55-199, are associated with a tremor-ataxia syndrome most commonly in older males and primary ovarian insufficiency in females. However, the neuropsychological impact of carrying a premutation allele is presently unclear in younger adults. In this study, we analyzed neuropsychological scores for 138 males and 506 females ascertained from the general population and from families with a history of fragile X syndrome. Subjects were age 18-50 years and had varying repeat lengths. Neuropsychological scores were obtained from measures of general intelligence, memory, and executive functioning, including attention. Principal component analysis followed by varimax rotation was used to create independent factors for analysis. These factors were modeled for males and females separately via a general linear model that accounted for correlation among related subjects. All models were adjusted for potential confounders, including age at testing, ethnicity, and household income. Among males, no repeat length associations were detected for any factor. Among females, only a significant association with repeat length and self-report attention (p < 0.01) was detected, with premutation carriers self-reporting significantly more attention-related problems compared to noncarriers. No significant interactions between repeat length and age were detected. Overall, these results indicate the lack of a global neuropsychological impact of carrying a premutation allele among adults under the age of 50.

Eye movements reveal impaired inhibitory control in adult male fragile X premutation carriers asymptomatic for FXTAS.

“…Women may also have different population distribution of CGG expansions than males, with more frequent high-repeat alleles (Hunter et al, 2008b). This increased variability in CGG repeat length makes observations of associations between performance and CGG repeat length more likely in women than men.…”

“…Principal components analysis of several executive function tests revealed no differences between fXPCs and controls (Allen et al, 2011, Hunter et al, 2008b). Hunter et al (2012), by combining samples from several preceding studies, found that fXPCs performed worse than controls on the Stroop, BDS, and Hayling Sentence Completion Part B.…”

Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation

“…Conflicting data have been published on the presence of executive function deficits in younger premutation carriers. Hunter et al 17 reported no effect of CGG repeats on neuropsychological performance in males <50 years of age even when only very large alleles (>100 CGG) were taken into account. On the other hand, Cornish et al 15 found deficits in response inhibition and working memory in premutation carriers in their 40s.…”

“…These deficits involve executive cognitive functioning, working and declarative memory as well as inhibition and selective attention. It is unclear whether younger premutation carriers also exhibit dysexecutive symptoms and conflicting data have been published in this regard 15 17. Cognitive impairment and dementia may represent the most debilitating symptom affecting premutation carriers and this is a growing concern for clinicians who provide genetic counselling in fragile X families.…”

Fragile X-associated disorders: a clinical overview

“…FXTAS occurs in a subgroup of patients, with the prevalence of FXTAS estimated at 40-45% of males and 8-16% of females over 50 years of age with penetrance age-related [73,78,79,81]. Whilst an increase in impulsivity and executive function deficits has been reported in male premutation carriers without FXTAS [82], no cognitive deficits have been observed in premutation carriers under 50 years of age [83].…”