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.

The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (>200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (approximately 55-199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18-50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.

A CGG repeat sequence located in the 5' untranslated region of the FMR1 gene is polymorphic with respect to size and stability of the repeat during parent-offspring transmission. When expanded to over 200 repeats, the gene is hypermethylated and silenced, leading to fragile X syndrome (FXS). Recently, alleles with large unmethylated repeat tracts (premutations) have been associated with ovarian failure and a late-onset tremor/ataxia syndrome, symptoms unrelated to FXS. To further investigate the phenotype consequence of high repeat alleles, we have analyzed Wechsler adult intelligence scales-III (WAIS-III) measures on 66 males and 217 females with a wide range of repeat sizes. Among females only, we found that FMR1 repeat size and transcript level significantly explained approximately 4% of the variance in the Verbal IQ summary measure, suggesting that this polymorphism is one of many factors that influence variation in cognitive performance. Because of the well established association of increasing repeat size with decreasing age at menopause, we also investigated the reproductive stage and use of hormone replacement therapy (HRT) as a covariate to model verbal intelligence quotient (VIQ). We found that it explained an additional 5% of the variance in VIQ, but did not interact with FMR1 repeat and transcript level.

Carriers of expanded, but unmethylated, premutation alleles of the fragile X mental retardation gene are at risk for a late-onset tremor/ ataxia syndrome, mostly affecting men over age 50. However, the general neuropsychological and neurobehavioral impact of carrying a premutation allele in younger adults not affected by the tremor/ataxia syndrome remains unclear. Past studies have utilized varying study designs resulting in inconsistent conclusions. To better understand the current evidence of the influence of the premutation on such traits in adult carriers, we reviewed the literature and identified 16 studies that met conservative inclusion criteria, including molecular measures of the fragile X mental retardation gene CGG triplet repeat length and standard measures of neurobehavioral and neurocognitive phenotypes. A review of these studies is presented to assess the evidence for possible premutation-associated neuropsychological deficits among adult men and women who do not meet diagnostic criteria of the tremor/ataxia syndrome. Results of these studies, and possible reasons for inconsistent conclusions, are discussed. The primary conclusion from this review is the need for further research using a standard protocol in a large multisite project to ensure the necessary sample size. Genet Key Words: FMR1, CGG repeat, premutation, fragile X syndrome, FXTAS, neuropsychology, cognition, anxiety, depression T he X-linked fragile X mental retardation gene (FMR1) contains a triplet CGG repeat in the 5Ј untranslated region that is associated with the mental retardation syndrome, fragile X (FXS). [1][2][3] The most common alleles of FMR1 contain Ͻ40 repeats and are stable when transmitted from generation to generation. 4,5 Because of mechanisms that are presently unclear, the triplet repeat can become unstable and expand from one generation to the next. Expansion to Ͼ200 repeats results in hypermethylation of the FMR1 gene and subsequent loss of gene expression. 6 -9 The loss of the protein product, fragile X mental retardation protein (FMRP), is responsible for FXS. 8,10 Males with FXS typically have mild to severe mental retardation, developmental delay, hyperactivity, social anxiety and other anxiety disorders, and autistic-like features. In addition, males with FXS display a pattern of memory deficits, particularly for short-term, or working memory, and visual memory. [11][12][13][14] Expanded, but unmethylated, repeats in the range of about 55-200 are unstable across generations 5 and are associated with increasing levels of transcript and decreasing levels of FMRP. [15][16][17][18] These FMR1 alleles, termed premutation alleles, have recently been found to be associated with a late-onset fragile X-associated tremor ataxia syndrome (FXTAS), mostly affecting men after the age of 50. 19,20 Men with FXTAS typically develop a progressive tremor and/or ataxia and experience cognitive decline, loss of executive function and short-term memory, as well as irritability and anxiety. 19,20 Thus cognitive, mem...

Background-Carriers of the FMR1 premutation allele are at a significantly increased risk for a