A neuropsychological profile of attention deficits in young males with fragile X syndrome

Abstract

Different processes of attention were examined in a group of 25 fragile X boys with FMR-1 full mutation and compared with three control groups: a learning disabled comparison group comprising 25 boys with Down’s syndrome, matched to the fragile X boys on verbal mental age; and 50 mainstream school boys (controls) matched to the fragile X boys on verbal mental age. The controls were further divided into those matched on “poor attention” to the fragile X boys and a “good” attention group, as rated by the ACTeRS questionnaire. Four categories of attention tasks were employed: selective attention, divided attention, sustained attention and executive functioning. The main findings of the study indicate that fragile X boys display an attention deficit at higher levels of attention function/executive functioning and that this profile is different from the profile identified in Down’s syndrome boys and more extreme than the profile identified in the poor attention control group. These findings are discussed in the context of functional neuroimaging and brain-behaviour correlates in fragile X syndrome.

Introduction

Fragile X syndrome is the most common inherited genetic condition causing developmental and learning disabilities [34]. Recent evidence suggests that fragile X syndrome affects approximately 1:4000 males and 1:6000 females [24], and is associated with the dysfunction of a gene — known as the fragile X mental retardation 1 (FMR-1) gene — on the X chromosome related to the fragile site Xq27.3. This site involves the abnormal amplification of a DNA segment containing a trinucleotide sequence of CGG repeats [27], [45], [48]. Between six and 58 CGG repeats are typically observed in the general population. In individuals who have the fragile X mutation, an expansion or amplification occurs in this segment of their DNA from 59 to up to several hundred CGG repeats. Those who have between 59 and 200 CGG repeats have a pre-mutation and are known as “carriers” but with no overt clinical effects. It appears that the pre-mutation is functionally silent with the non-methylated gene still being transcribed. Individuals with more than 200 CGG repeats however, have a full mutation whereby the gene becomes methylated at the fragile site Xq27.3 leading to a lack of mRNA and FMR-1 protein (FMRP) synthesis [29], [45]. Males with the full mutation are invariably clinically affected. Females who carry the full mutation on the other hand, may be clinically unaffected. It is the lack of FMRP that results in the clinical manifestation of the fragile X syndrome. While the specific function of FMRP is not known, it is strongly expressed in brain tissues [45] and may be responsible for an impairment or lack of structural development in brain functioning in affected fragile X males and females.

The neuropsychological-cognitive profile of fragile X boys (full mutation) appears to be more complex than originally thought. This directly impacts on the current understanding of the disorder in terms of brain development and function and the genetic factors underlying the disorder. Past studies suggested deficits in short-term non-verbal memory, visual motor and spatial skills, with relative strengths in verbal labelling, verbal memory and comprehension [12], [13], [17] thus indicating cognitive deficits that may be attributed to poor right-hemisphere functioning [9].

More recent comprehensive studies, however, suggest a pattern of deficits that are task specific rather than global in nature. Spatial skills for example, are not globally impaired in fragile X males. Instead, the deficit appears to be specific to those skills that require visuo-spatial orientation and constructional abilities, with visuo-perceptual skills relatively intact [7], [8], [12]. Similarly, verbal skills are not a global strength in fragile X males, with specific deficits reported on tasks that require short-term memory for complex sequential information, and particular strengths on tasks that require short-term memory for simple, meaningful information [13], [37]. Further evidence for a possible discrepancy in cognitive functioning suggests fragile X males display relatively intact skills for learning simple verbal and non-verbal tasks, but are greatly impaired on tasks which require the manipulation of internal representations [16]. Likewise, on tasks of working memory (the ability to temporarily hold information in mind while processing same or other information), fragile X males can temporarily maintain and recall simple meaningful information, but not abstract non-sequential information irrespective of the verbal or non-verbal working memory subsystem [26].

Current studies therefore suggest that fragile X males can perform relatively simple tasks but cannot manipulate more complex information regardless of its modality. It is not known why these specific cognitive skills are affected in fragile X males. One possibility may lie in the direction of higher control processes of attention such as the ability to modulate complex or novel information and plan and organise information in the mind. Indeed, neuroanatomical studies of full mutation fragile X males and females report abnormalities in both left and right parietal regions as well as in the prefrontal regions [37], [40] and the caudate nucleus [33]. Significantly, these structures appear to be involved in attention [5], [6], [30] and higher control processes of attention such as executive functioning [2] indicating that these mechanisms may be impaired in those with fragile X syndrome. These neuroanatomical findings are in accord with neuropsychological findings in fragile X females, where a consistent pattern of difficulties in visual–spatial attention and executive functioning has been documented [21], [22], [24], [39].

In contrast, comparatively few studies have taken a similar direction in terms of identifying a neuropsychological profile of the attention deficit in fragile X males. This is somewhat surprising given that attentional problems, impulsive behaviour and hyperactivity are frequently cited as core features of the behaviour phenotype in fragile X males [4], [14], [19], [42]. As a result, relatively little is known about the precise nature of the attention deficits, although recent studies have indicated the importance of teasing apart cognitive aspects of attention. For example, selective attention refers to the ability to select relevant stimuli from irrelevant information, while divided attention refers to the ability to attend to more than one source of information simultaneously [36], [38]. In contrast, maintaining attention over a period of time is referred to as sustained attention; and problem-solving, planning, inhibiting and manipulating mental representations of tasks and goals are seen as higher control processes of attention or executive functioning [31], [46]. Neuroanatomic studies further suggest that these different aspects of attention are subserved by different regions of the brain [5], [18], [32].

The main objective of the present study was to investigate the nature of cognitive impairment in young fragile X males (full mutation) on a range of attention and executive functioning tasks: selective attention, divided attention, sustained attention, inhibition and response organisation. Young males with Down’s syndrome (Trisomy 21) matched with the fragile X group for chronological age and mental age were chosen as the comparison group. This syndrome group was especially included because Down’s syndrome also presents a genetic chromosome abnormality, but distinct from fragile X syndrome, and both syndrome groups represent two of the most common causes of mental impairment for which aetiology is known [10]. Two normal functioning control groups matched closely on mental age to the fragile X males were also included. The first group was selected to match the fragile X group on a similar behaviour profile of hyperactivity and attention problems but with no known genetic condition. This group was included so that differences in performance between the two groups would establish a cognitive profile of attention deficit specific to the fragile X syndrome or similar to those with hyperactive behaviour without fragile X syndrome. The second control group, also matched on mental age, was selected from boys with above average attentional ability.