Profiling Fragile X Syndrome in males: Strengths and weaknesses in cognitive abilities
Introduction
Fragile X Syndrome (FXS) is the most frequently reported inherited type of mental retardation in males (Turner, Webb, Wake, & Robinson, 1996), and is most often caused by transcriptional silencing of the Fragile X Mental Retardation 1 (FMR-1) gene (Fu et al., 1991, Oostra and Chiurazzi, 2001, Verkerk et al., 1991). In the FXS full mutation this single-gene defect results in reduced or absent FMR-1 protein (FMRP) expression (Koukoui & Chaudhuri, 2007). FMRP is argued to be specifically involved in synaptic and dendritical refinement during early brain development (Christie, Akins, Schwob, & Fallon, 2009). Absence of FMRP is primarily associated with abnormal maturation of synaptic connectivity (Oostra & Chiurazzi, 2001), and is argued to be the primary cause of the cognitive deficits frequently observed in FXS (Loesch et al., 2004, Visootsak et al., 2005). Although the cognitive profile of FXS males has been extensively studied over the years, little is known about the relation between performance level and cognitive profile. The goal of the present study was: (a) to examine the cognitive profile of FXS full mutation males of different performance levels over a wide range of cognitive abilities; and (b) to investigate whether such a cognitive profile would be similar for FXS males of different levels of performance.
Over the years, the neuropsychological phenotype of full mutation FXS has been well documented and is characterized by a general impairment in cognitive performance, with some cognitive abilities more strongly affected than others (Cornish et al., 2008, Hodapp et al., 1991, Maes et al., 1994). Relative strengths in cognitive performance are frequently reported for vocabulary capacity (Dykens et al., 1987, Maes et al., 1994, Philofsky et al., 2004), visuo-perceptual abilities (Cornish et al., 1999, Hodapp et al., 1992, Maes et al., 1994), and the processing and recall of simultaneous and meaningful information (Backes et al., 2000, Dykens et al., 1987, Freund and Reiss, 1991, Maes et al., 1994, Munir et al., 2000a, Powell et al., 1997). In contrast, consistent deficits have been reported for verbal short-term memory (Freund and Reiss, 1991, Munir et al., 2000a), visuo-spatial memory (Munir et al., 2000a), linguistic processing (Abbeduto et al., 2007, Abbeduto and Hagerman, 1997, Ferrier et al., 1991), selective and divided attention (Munir et al., 2000b, Scerif et al., 2007, Wilding et al., 2002), and the processing of sequential and abstract information (Dykens et al., 1987, Freund and Reiss, 1991, Powell et al., 1997).
Accumulating evidence suggests a fundamental deficiency in executive control (Cornish et al., 2004a, Cornish et al., 2004b, Wilding et al., 2002). That is, those processes that provide top-down guidance for orchestrating the more basic cognitive processes to accomplish goal-directed behavior. Executive control exerts its influence on cognition by modulating information processing in different cognitive modalities, driven by a prefrontal neural network (Miller and Cohen, 2001, Posner and Petersen, 1990, Posner and Rothbart, 2007). Importantly, deficits in executive control have their repercussions for performance across a wide range of cognitive abilities. Illustrative in this respect is that within the domain of executive function FXS males show difficulties in inhibiting pre-potent responses (Cornish et al., 2007, Hooper et al., 2008, Loesch et al., 2003, Munir et al., 2000b, Wilding et al., 2002), impaired cognitive flexibility (e.g., task-switching; Cornish et al., 2001, Hooper et al., 2008, Woodcock et al., 2009), and weak problem solving abilities (Hooper et al., 2008, Maes et al., 1994). In addition, within the domain of working memory, deficits have been attributed to a general limitation in working memory capacity (Munir et al., 2000a, Ornstein et al., 2008). That is, the amount of attention available to maintain and manipulate information, mediated by executive control processes. Furthermore, the pattern of deficits reported for more complex verbal abilities (e.g., perseverations in speech; Abbeduto & Hagerman, 1997) and non-verbal reasoning abilities (processing of abstract information; Maes et al., 1994), seem to implicate a specific deficit for cognitive abilities relying on executive control. Together, these findings point to inefficient executive control as a core-deficit in FXS males.
The observed pattern of strengths and weaknesses in FXS cognitive functioning may suggest a specific cognitive profile for FXS. That is, the cognitive profile in FXS might well be different from cognitive profiles seen in other mental retardation syndromes (Cornish et al., 2007, Cornish et al., 2008). However, syndrome-specificity of a cognitive profile is also determined by heterogeneity in cognitive performance levels. More specifically, FXS males functioning at higher performance levels may be characterized by a different cognitive profile compared to FXS males functioning at lower performance levels. Such differences constrain the notion of syndrome-specific cognitive profiles. For example, FXS is characterized by an increased heterogeneity in the level of intellectual functioning, corresponding to moderate-to-severe levels of mental retardation (Abbeduto et al., 2007, Bailey et al., 2001, Dykens et al., 1987, Loesch et al., 2004, Mazzocco, 2000). The question arises whether high-functioning FXS males show similar or distinct strengths and weaknesses in cognitive performance relative to low-functioning FXS males.
The primary objective of the present study was to examine the relative strengths and weaknesses in a wide range of cognitive abilities in FXS full mutation males functioning at different performance levels. More specifically, we investigated whether such a cognitive profile would differ between FXS males of different performance levels. Cognitive performance was examined in a large sample of FXS males for the following cognitive domains: non-verbal (reasoning and performal) abilities, verbal abilities, memory performance, and aspects of executive function. Test results were converted into mental age (MA) equivalents, which allowed for comparing between cognitive abilities within, as well as between participants. To interpret the cognitive abilities in terms of relative strengths and weaknesses, each performance measure was contrasted to a non-verbal and verbal MA reference measure (NVMA and VMA respectively). Two reference measures were employed to avoid interpretation-bias resulting from comparison to a single reference measure. For example, reference to a single measure of intelligence can result in serious interpretation problems, as this reference or cognitive ability could reveal as a significant strength or weakness (see Mottron, 2004, for a detailed discussion on this issue).
Since full mutation males share the same genetic cause of mental retardation, we expected that FXS males functioning at different performance levels would show similar cognitive profiles. In addition, based upon previous studies on cognitive functioning in FXS males, we anticipated FXS males to be more impaired on tasks that require higher levels of executive control. Thus, specific deficits were expected for cognitive abilities relying on executive functions and working memory processes. These deficits were expected to be evident for all FXS males, regardless of cognitive performance level. In contrast, relative strengths were expected for visuo-perceptual recognition (i.e., Gestalt closure) and vocabulary.
Section snippets
Participants
The present study included 43 adult males, ranging in age from 18 to 48 years (mean age = 28.7, SD = 8.5). Participants were recruited through the Dutch Fragile X Parent Network. The FXS full mutation was established by DNA testing. All participants were free from additional diagnosed psychiatric disorders, based on DSM-IV-TR classifications (American Psychiatric Association, 2000), and had normal or corrected-to-normal vision. None of the participants were taking (prescribed) medication. Informed
Floor performance
Exploration of the data was conducted for all participants to ensure that statistical analyses were performed only on the data for participants performing above floor level. Table 1 presents the proportion of participants performing below floor level for each subtest. It can be seen that performance below floor level is most frequent for STM, working memory and EF subtests. Inspection of the data indicated that none of the participants performed above floor level on all of the tests
Discussion
The current study aimed at determining the specific profile of relative strengths and weaknesses of cognitive functioning in a large sample of full mutation FXS males. Our primary aim was to investigate whether subgroups could be identified in our sample of FXS males and to examine whether these subgroups would show distinguishable cognitive profiles. By means of an extensive neuropsychological assessment, we found that FXS is associated with a disharmonic cognitive profile, characterized by
Acknowledgements
This study was supported by grant number 051.04.090 from the Cognition Program of the Netherlands Organization for Scientific Research (NWO) awarded to G.J.A. Ramakers. We thank Marlou Kwaks for collecting part of the data. We pay our gratitude to Mieke van Leeuwen of the Netherlands Federation of Parent Organizations for assisting in the recruitment of subjects, and we thank the participating families for their support and contribution to this study.
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