American Journal of Medical Genetics 116A:44–51 (2003) A Distinct Neurocognitive Phenotype in Female Fragile-X Premutation Carriers Assessed With Visual Attention Tasks Jean Steyaert, 1 Eric Legius, 2 Martine Borghgraef, 2 and Jean-Pierre Fryns 2 * 1 Department of Clinical Genetics, University of Maastricht, The Netherlands 2 Center for Human Genetics, University of Leuven, Belgium Premature ovarian failure (POF) and under- lying hormonal changes are recognized as a distinct phenotype in female fragile-X pre- mutation carriers. Neurocognitive deficits, in particular mental retardation, are asso- ciated with the full mutation in males and females. In female full mutation carriers this neurocognitive phenotype is expressed more mildly than in males. Research on whether the fragile-X premutation is associated with a particular neurocognitive phenotype or not has been equivocal. By means of the Sonneville Visual Attentions Tasks (SVAT) computer-based battery of neurocognitive tasks, we assessed reaction time on different tasks in three groups of subjects: female premutation carriers, female full mutation carriers, and female control subjects. The results show that a fraction of the female premutation carriers perform poorly on several selective attention tasks, but not on other tasks. Their neurocognitive profile is different from that of control subjects and of the majority of female premutation carriers. It may also be different from the phenotype of female full mutation carriers, though in that respect this study remains inconclusive. These findings support earlier findings that the fragile-X premutation may affect neuro- cognitive functioning, in particular aspects of attention. ß 2002 Wiley-Liss, Inc. KEY WORDS: fragile-X; premutation; men- tal retardation; FMR1; FMRP; FRAXA INTRODUCTION Fragile-X syndrome is the most frequent inherited cause of mental retardation in males [Rousseau et al., 1994, 1995]. The molecular defect consists of an unstable expansion of a CGG trinucleotide repeat within the 5 0 untranslated region of the FMR1 gene situated at the Xq27.3 fragile-X site of the X chromosome, or FRAXA site [Verkerk et al., 1991]. Depending on the size of the expansion, the mutation is categorized into two types [Fu et al., 1991; Heitz et al., 1992]: the full mutation, with an expansion of more than 200 repeats (>0.6 kb), and the premutation, with an expansion between 55 and 200 CGG repeats (0.15–0.6 kb). The full mutation is associated with the fragile-X syndrome in males, and less frequently in females [Riddle et al., 1998; Bardoni et al., 2000]. In patients with fragile-X syndrome, the expanded CGG triplet repeats in the FMR1 promotor region of the full mutation are hypermethylated and the expression of the FMR1 gene is repressed, which leads to the absence of FMR1 protein (FMRP) and subsequent mental retardation [Jin and Warren, 2000]. The pre- mutation is not associated with hypermethylation, and the gene is transcribed to messenger RNA (mRNA). Recently, it has been demonstrated that premutation carriers have increased levels of FMR1 gene transcrip- tion [Tassone et al., 2000a] and reduced level of FMRP [Kenneson et al., 2001]. Initially, the premutation was thought not to affect the phenotype of male and female premutation car- riers [Cianchetti et al., 1992; Reiss et al., 1993; Mazzocco and Holden, 1996]. However, this view was challenged gradually, as minor anthropomorphic anomalies were described in female premutation carriers [Hull and Hagerman, 1993] and neurocognitive signs in male pre- mutation carriers [Hagerman et al., 1996] and recently also in a subgroup of premutation carriers [Bennetto et al., 2001]. The most striking and robust finding in female premutation carriers, however, was the occur- rence of menopause before the age of 40 due to pre- mature ovarian failure (POF) in approximately one in six female premutation carriers [Allingham-Hawkins et al., 1999; Murray et al., 2000]. Moreover, the preva- lence of premutation carriers is significantly increased amongst women with idiopathic POF [Murray et al., *Correspondence to: Prof. Dr. J.-P. Fryns, Centre for Human Genetics, University of Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: jean-pierre.fryns@med.kuleuven.ac.be Received 29 October 2001; Accepted 7 June 2002 DOI 10.1002/ajmg.a.10821 ß 2002 Wiley-Liss, Inc.