The emerging fragile X premutation phenotype:
Evidence from the domain of social cognition
Kim Cornisha,*, Cary Koganb, Jeremy Turkc, Tom Manlye, Nicole Jamesf,
Andrea Millsd, Ann Daltong
aNeuroscience Laboratory for Research and Education in Neurodevelopmental Disorders, McGill University, Montreal, Canada
bDepartment of Psychology, McGill University, Montreal, Canada
cMedical Research Council Cognition and Brain Sciences unit, Cambridge, United Kingdom
dUniversity of London, United Kingdom
eUniversity of Cambridge, United Kingdom
fUniversity of Nottingham, United Kingdom
gNorth Trent Molecular Genetics Laboratory, Sheffield, United Kingdom
Accepted 12 August 2004
Available online 28 October 2004
Fragile X syndrome is a neurodevelopmental disorder that is caused by large methylated expansions of a CGG repeat (>200)
region upstream of the FMR1 gene that results in the lack of expression of the fragile X mental retardation protein (FMRP).
Affected individuals display a neurobehavioral phenotype that includes a significant impairment in social cognition alongside deficits
in attentional control, inhibition and working memory. In contrast, relatively little is known about the trajectory and specificity of
any cognitive impairment associated with the fragile X premutation (‘‘carrier-status’’) (approximately 55–200 repeats). Here, we
focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. The results
suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full muta-
tion. However, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes. The find-
ings are discussed in the context of functional neuroimaging and brain-behaviour-molecular correlates. We speculate that the
deficiencies in social cognition are attributable to impairment of neural pathways modulated by the cerebellum.
? 2004 Elsevire Inc. All rights reserved.
Fragile X syndrome is the most common form of her-
itable mental retardation, affecting approximately 1 in
4000 males and 1 in 6000 females (Turner, Webb, Wake,
& Robinson, 1996). In recent years, it has become one
netic conditions. In nearly all cases, the syndrome is
caused by an expansion of the CGG repeat at the begin-
ning of the FMR1 gene on the X chromosome. This
expansion leads to methylation of the promoter sequence
and loss of the ‘‘fragile X mental retardation protein’’
(FMRP) (Verkerk et al., 1991). In normal individuals,
there are 7–60 repeats, with 30 repeats found on the most
common allele (DNA sequence at FMR1 gene site). Al-
tions’’ and generate some protein. When 200 or more
CGG repeats are present, there is hypermethylation and
a subsequent silencing of the FMR1 gene. This is com-
monly referred to as the FMR1 full mutation. However,
unlike females affected by the mutation, full mutation
males are hemizygous and therefore often display a more
developmental delay. In contrast, individuals with a pre-
mutation (an expansion of 50–200 CGG repeats) possess
0278-2626/$ - see front matter ? 2004 Elsevire Inc. All rights reserved.
E-mail address: email@example.com (K. Cornish).
Brain and Cognition 57 (2005) 53–60
unmethylated versions of the FMR1 gene and therefore
have normal or near-normal levels of FMRP (Devys,
Lutz, Rouyer, Bellocq, & Mandel, 1993). The frequency
of the fragile X premutation in the general population is
estimated at 1 in 250 females (Rousseau, Rouillard, Mor-
browski et al., 2002) and has generally been associated
with normal intellectual functioning. Although the vari-
ous phenotypic effects of the premutation are likely to
prevalence of this condition warrants investigation of
possible neurocognitive and neurobehavioral effects.
In terms of the neurological expression of the full
mutation, studies have revealed decreased size of the
posterior vermis of the cerebellum in males and females
(Mostofsky et al., 1998; Reiss, Aylward, Freund, Joshi,
& Bryan, 1991). Other structures affected by FMR1 sta-
tus include the caudate nucleus (Eliez, Blasey, Freund,
Hastie, & Reiss, 2001) and the hippocampus (Kates,
Abrams, Kaufmann, Breiter, & Reiss, 1997; Reiss,
Lee, & Freund, 1994). In addition, several studies re-
ported a correlation between neuroanatomical abnor-
malities and the degree of functional impairment in
the full mutation. For example, posterior vermis vol-
umes are positively correlated with performance on spe-
cific measures of intelligence, visual–spatial ability, and
executive function suggesting a putative functional role
for this structure (Mostofsky et al., 1998). Taken to-
gether the purely structural and combined structural/
functional studies implicate the cerebellum, caudate nu-
cleus, and hippocampus as potential sites for phenotypic
effects from abnormal FMR1 gene expression.
Another source of valuable information regarding
vulnerable candidate brain structures comes from the
expression profile of FMRP in the unaffected brain.
For example, Kogan et al. (2004) showed a relationship
between local higher basal FMRP expression levels in
the magnocellular pathway of the thalamus—a pathway
associated with visual deficits in full mutation individu-
als. Identified areas with relatively higher FMR1 gene
expression include in the mouse, the hippocampus and
cerebellum (Hinds et al., 1993), in human embryos, dif-
ferentiating neurons of the nucleus basalis magnocellu-
laris, the hippocampus, discrete cortical areas, and to
a lesser extent the cerebellum (Abitbol et al., 1993). Such
findings are consistent with imaging studies showing
structural abnormalities in the same brain regions of
individuals with the full mutation. However, it is impor-
tant to stress that abnormal structures form part of
widely distributed networks and that deficits may be ob-
served across a broad range of activities. For example,
in addition to motor control and the acquisition of com-
plex motor sequences, the cerebellum in its connection
with the frontal lobes has more recently been implicated
in higher order processes, including social cognition
(Riva & Giorgi, 2000).
Recent work by Hagerman and colleagues indicate
that a subgroup of older males (>50 years) with the pre-
mutation may have an increased risk of developing a
progressive cerebellar ataxia and tremor (Berry-Kravis
et al., 2003; Jacquemont et al., 2003). Associated neuro-
biological findings in this subgroup include generalised
brain atrophy, elevated FMR1 messenger RNA levels
and autopsy findings of widespread eosinophilic nuclear
inclusion bodies in CNS neurons and glia (Greco et al.,
2002). Such findings suggest that that brain regions com-
promised in full mutation males and females may be sus-
ceptible in some carriers.
At the cognitive level, there are relatively few studies
that have examined the pattern of any deficit in the frag-
ile X premutation—fewer still have defined the premuta-
tion male phenotype. In contrast, the profile of males
with the FMR1 full mutation is now well documented
and there is an abundance of evidence showing that
fragile X is not a syndrome characterised by global men-
tal retardation. Instead, the profile can be characterised
by uneven abilities within and across cognitive domains.
Relative strengths in vocabulary (Dykens, Hodapp, &
Leckman, 1987), verbal working memory (Jakala
et al., 1997), and long-term memory for meaningful
and learned information (Freund & Reiss, 1991) are
accompanied by relative weaknesses in attentional con-
trol (Cornish et al., 2004; Scerif, Cornish, Wilding, Dri-
ver, & Karmiloff-Smith, 2004; Wilding, Cornish, &
Munir, 2002), executive functions (Cornish, Munir,
& Cross, 2001; Estevez-Gonzalez, Roig, Piles, Pineda,
& Garcia-Sanchez, 1997), and linguistic processing
(Ferrier, Bashir, Meryash, Johnston, & Wolff, 1991;
Sudhalter, Cohen, Silverman, & Wolf-Schein, 1990).
In the domain of social cognition, recent findings indi-
cate that individuals with the full mutation demonstrate
deficits in mentalising (‘‘theory of mind’’) abilities, (Cor-
recognition and emotion perception (Cornish, Munir, &
ies did not report comparable levels of impairment to
those typically associated with autism, strong similarities
between the two syndromes exist. Commonalities include
echolalia, repetitive speech, social avoidance, and hand
flapping in response to anxiety and excitement (Ferrier
et al., 1991; Turk & Graham, 1997).
1.1. The present study
Here, the main objective was to examine whether the
FMR1 premutation has a phenotypic effect in adult-
hood and, in particular, whether there are subtle abnor-
malities in the social cognition of this group. In contrast
to previous studies, we aimed to use a sample with suf-
ficient power to examine the relationship between CGG
repeat size and postulated cognitive deficit. By looking
K. Cornish et al. / Brain and Cognition 57 (2005) 53–60
across a wide age range, we could also establish whether,
as with the motor control results discussed above, there
may be a trajectory moving from subtle to more obvious
impairment over the years.
Perhaps particularly for social cognition tests, vari-
ability may arise from cultural factors in addition to
more individual differences in ?basic? perceptual, seman-
tic and intellectual capacities. Selecting an appropriate
control group is therefore crucial. Here, we adopted
two. The first was recruited from genetically normal
(6–39 CGG repeats) male relatives of our index group
who, in general, would share socio-economic and cul-
tural backgrounds with the premutation participants.
A slight drawback of this approach is that, if the premu-
tation is associated with subtle impairments in intellec-
tual as well as social function, this group may not be
well matched to the experimental population on general
factors such as IQ. A second possibility is that the con-
trol group—through having an affected relative or
through showing subtle problems themselves—may un-
der-represent the difficulties faced by the premutation
group in any comparison. Accordingly, we recruited a
second control group from members of the general pop-
ulation with no family history of fragile X who were
matched on age and IQ with the premutation group.
We used two measures designed to tap ‘‘mentalising
abilities’’ (see below) and facial expression recogni-
withthe fullFMR1expression.In addition, giventheevi-
dence of communication difficulties in boys with full
mutations (Turk & Graham, 1997), boys with premuta-
tions (Aziz et al., 2003) and girls with the full mutation
(Keysor & Mazzocco, 2002; Mazzocco, Baumgardner,
Freund, & Reiss, 1998) we employed the self-report Aut-
ism Spectrum Quotient instrument.
Group 1 comprised 22 adult males with a fragile X
premutation (‘‘carrier’’) who were recruited through the
UK Clinical Genetic Service Centres and the UK Frag-
ile X Society. Participant?s ages ranged from 18 to 69
years with a mean age of 47.91 years (SD 15.79). Group
2 comprised 22 non-affected adult males from FXS fam-
ilies (familial controls) who were age matched (within a 5
year window) to the premutation males. Their ages ran-
ged from 20 to 67 years, with a mean age of 40.8 years
(SD 12.9). Group 3 comprised 22 non-affected adult
males with no family history of FXS (non-familial con-
trols) who were recruited from the local area and
matched individually on age to the premutation group.
Ages ranged from 20 to 68 years, with a mean age of
44.6 years (SD 14.8).
All participants were tested (individually) on the
Wechsler Abbreviated Scale of Intelligence (WASI;
Wechsler, 1999). This test provides a composite IQ score
based on four subtests tapping both verbal and perfor-
mance domains. Table 1 shows a summary of mean
choronological age (CA) and IQ across the three groups.
The three groups were well matched on age
(F(1.306) = 0.278, ns). There were significant differences
between the groups for IQ (F(4.960) = 0.010). Post hoc
analysis (Scheffe) revealed that the Premutation group
had a lower mean IQ than the familial (p = .025) and
non-familial control groups (p = .043). There was no sig-
nificant difference in IQ between the two control groups.
2.2. Fragile X DNA testing
Direct PCR was carried out using primers F50CACG
CAGG, R50GAGAGGTGGGCTGCGGGCGCT, mod-
ified from Wang, Green, Bobrow, and Mathew (1995) at
0.5 pmol final concentration. Conditions were as fol-
lows: Final concentration 1 mM MgCl2, dATP, dCTP,
and dTTP at 0.2 mM, 7-deazaGTP (Amersham Phama-
cia Biotech) at 0.4 mM supplemented with 5% DMSO in
a total volume of 20 ll. Cycling conditions were 32 cy-
cles at 67 ?C annealing. Products were separated on
PAGE gels and visualised by silver staining according
to standard protocols. Where the premutation was
visible on PCR the repeat size was calculated according
to size markers and by electrophoresing the products
in size order and aligning the stutter bands. Southern
blotting was carried out according to standard protocols
on genomic DNA using a double digest of EcoR1 (NEB)
and the methylation sensitive enzyme Eag1 (NEB) and
probed with O·1.9 (Knight et al., 1993).
Sizing was relative to a female control of known re-
peat size. Where possible, repeat sizes derived from SB
were compared to those obtained from direct PCR. Re-
peat sizes of those individuals who gave a result on di-
rect PCR and on SB were congruent. Blots were
overexposed to detect any evidence of mosaicism against
a known mosaic control. A premutation was an allele
between 55 CGG repeats up to approximately 200 re-
peats without any evidence of abnormal methylation.
Mosaicism was considered present when there was evi-
dence of a methylated cell line as well as an unmethy-
lated premutation cell line.
Mean CA (SD) and IQ scores across the three groups: Premutation
males, familial and non-familial controls
K. Cornish et al. / Brain and Cognition 57 (2005) 53–60
2.3. Test materials
In the present study, tasks that tapped both simple
and complex mental states were administered to partic-
ipants. These tasks were chosen because they had been
developed for use with normal adults and are powerful
enough to detect subtle individual differences in social
2.4. Facial expression recognition test (Ekman &
To test for the ability of judging simple mental states
in human faces, the present study used the well-known
and cross-cultural concept of seven basic emotional
states by Ekman and Friesen (1971). This test consists
of 70 black and white photographs of actors? faces pos-
ing happy, sad, fearful, angry, surprised, disgusted, or
neutral emotional expressions. Participants were re-
quired to look at each photograph and choose the verbal
label that best described the emotion. All pictures were
shown for 3 s, followed by a 5-s pause for the subject
to give his response. The maximum score was 70.
2.5. Revised eyes test (Baron-Cohen, Wheelwright,
Hill, Raste, & Plumb, 2001)
The Revised Eyes Test is a more extensive version of
the original test developed by Baron-Cohen, Jolliffe,
Mortimore, and Robertson (1997) and comprises items
related only to complex mental states. The stimuli for
this test consist of 35 black and white photographs taken
from larger photographs in popular magazines. Each
pair of eyes is digitised and cropped such that the
remaining image was black and white and measured 2
by 5 in, showing the eye region of faces, from just above
the eyebrows to the bridge of the nose. Baron-Cohen,
Wheelwright, Skinner, Martin, and Clubley (2001) and
Baron-Cohen, Wheelwright, Hill et al. (2001) asked
two judges to generate target words and foils for each
picture in open discussion. These target words were then
tested with their semantic opposites as foils on groups of
eight judges (four male and four female). The criterion
adopted was that at least five out of the eight judges
agreed that the target word was the most suitable
description for each stimulus and that no more than
two judges picked any single foil.
Participants were asked to look at each photograph
one at a time and to choose the word (from a choice
of 4) that best describes what that individual may be
thinking or feeling. For example, the correct response
of ‘‘panicked’’ needed to be selected from three foil
terms, ‘‘jealous’’, ‘‘arrogant,’’ and ‘‘hateful’’. All pic-
tures were shown for 3 s, followed by a 5-s pause for
the participants to give his response. Immediately before
the test, participants were asked to read through the
glossary and indicate any word meanings of which they
were unsure (in practice, none of the participants asked
for clarification). The maximum score was 35.
2.6. Autism spectrum quotient (AQ) (Baron-Cohen
et al., 2001)
The AQ is a self-assessment screening instrument
developed by Baron-Cohen, Wheelwright et al. (2001)
to measure the degree to which an individual of normal
intelligence shows autistic traits. Participants were pre-
functioning: social skill, attention switching, attention to
detail, communication, and imagination. Each subscale
comprised 10 statements, with participants being asked
to either agree, slightly agree, slightly disagree, or defi-
nitely disagree with each. In addition to individual sub-
scale scores, an overall score can be derived.
tees, and after receiving informed consent, the partici-
pants were tested in a quiet setting, generally their own
homes. Feedbackwas not
given on individual
3.1. Revised eyes test
To examine whether premutation was associated with
difficulties in reading emotions from the eyes, the perfor-
mance of the three groups on the Revised Eye Test was
compared using ANCOVA. To establish whether any
difference was greater than one would expect based on
the observed IQ differences, both IQ and age were covar-
ied out. There was a statistically significant group effect
[F(2,64) = 5.27, p = .008]. Post hoc Scheffe ´ tests con-
firmed that the FXS premutation group performed sig-
nificantly worse (p < .001) than either of the control
groups. There was no significant difference between the
premutation and familial control group or between the
familial and non-familial control groups. The percentage
of errors across groups is shown graphically in Fig. 1.
3.2. Facial expression recognition test
Performance of the three groups on the Facial Expres-
sion Recognition task was again compared using AN-
COVA with age and IQ covaried out. There was a
statistically significant effect of group F(2,64) = 4.23,
p = .02. Scheffe ´ post hoc analysis revealed that the differ-
ence between the premutation group and the non-famil-
ial controls was statistically significant (p < .05), whilst
K. Cornish et al. / Brain and Cognition 57 (2005) 53–60
the difference between the premutation and familial con-
trol group was insufficient to reach statistical signifi-
cance. Analysis of the seven emotion categories of the
task revealed a group difference specifically on faces
depicting neutral expressions only (F(2,64) = 3.199,
p = .05); with the critical difference again between the
premutation group and the non-familial controls. Nota-
bly, however, the categorisation of neutral expressions
was not the most challenging of the categories for the
control groups and the effect is therefore unlikely to stem
from a simple ?level of difficulty?. In addition, the absence
of a difference on other expressions suggests that basic vi-
sual processing/discrimination problems are very unli-
kely to account for this or the Eyes Test results. There
were no other significant differences (see Fig. 2).
3.3. Autism spectrum quotient
There were no significant group differences in the to-
tal score from this self-report measure [F(2,64) = 1.928,
p = .2]. However, analysis of the five categories showed
a significant group difference for the Attention Switching
subscale (F = 4.068, p < .02). The statements in this cat-
egory refer to a preference for rather fixed routines,
emotional distress at changes in routine, and a tendency
to focus on details (for example, ‘‘I tend to have very
strong interest, which I get upset about if I can?t pursue’’,
and ‘‘I prefer to do things the same way over and over
again’’). Scheffe ´ tests revealed a similar pattern to that
reported above, with the critical difference in perfor-
mance between the premutation group and non-familial
controls (p < .012). There were no other significant
group differences across the categories.
3.4. Relationship between chronological age and
performance on the Revised Eyes task, Facial Expression
task, and the AQ
Previous research examining motor function in males
with the premutation has suggested an exaggeration of
relative impairment with increasing age. Here, we exam-
ined relationships with age across this measures using
correlation within the premutation group. With IQ co-
varied out, a robust relationship with age emerged on
the Facial Expression task (r = ?.63; p = .002), with
older participants experiencing more difficulty on this
measure. A similar pattern emerged for familial controls
(r = ?.44; p = .05). Previous research has shown normal
ageing effects on a similar test of facial recognition that
particularly compromise the recognition of fear and, to
a lesser extent, anger expressions (Calder et al., 2003). In
the premutation group here, the relationship between
fear recognition and age was minimal (r = ?.164
p = .466), and indeed no single face category–age rela-
tionship reached statistical significance in isolation.
The results therefore suggest a general decline in sensi-
tivity to emotional expression with age that cannot be
explained purely on the basis of general intellectual de-
cline. There were no other significant correlations.
3.5. Relationship between the premutation CGG repeat
length and performance on the revised eyes task, facial
expression task, AQ, and IQ
There were no significant correlations between num-
ber of CGG repeats in the premutation range and per-
formance on the Revised Eyes task (r = .27; p = .34),
the Facial Expression task (r = ?.14; p = .63), or on
the AQ (r = ?.04; p = .88). There was no also no corre-
lation between IQ and CGG repeats (r = 19; p = .52).
To date, this is the first study to investigate social
cognition in FMR1 premutation adults and one of the
few studies to incorporate a population-based, non-clin-
ical sample together with age-matched familial and non-
familial controls. Our primary aim was to establish
PremutationFamilial controls Non-familial controls
Revised Eyes Task
Fig. 1. Percentage of errors on the Revised Eyes Test by Group:
premutation males, familial control males and non-familial control
PremutationFamilial controlsNon-familial controls
Facial Expressions Task
Fig. 2. Percentage of errors on the Facial Expressions Task by Group:
premutation males, familial control males and non-familial control
K. Cornish et al. / Brain and Cognition 57 (2005) 53–60
whether individuals with the FMR1 premutation show
subtle impairments on tasks of social cognition, tasks
that are typically impaired in individuals with the full
mutation. In addition, we sought to identify the trajec-
tory and specificity of any such impairment—in particu-
lar, whether phenotypic effects become more severe with
age. Finally, we assessed the extent to which variability
in performance might be explained by the size of the
expansion in the FMR1 gene.
The results may be summarised as follows:
1. Males with the premutation performed significantly
more poorly than males without the premutation on a
of mental state from photographs of eyes. This relative
impairment was over and above that which might be
anticipated on the basis of general ability, as indexed in
IQ. A similar pattern was observed on a task requiring
recognition of emotion from the whole face. Notably,
most apparent when categorising neutral expressions. As
these were not the most difficult for the control group, it
suggests that task difficulty per se cannot account for
the finding. Similarly, the adequate performance of the
premutation group on some but not all expressions sug-
gests that basic perceptual problems are unlikely to ac-
count for the effect. Importantly, this finding is
consistent with previous research reporting similar but
more severe problems in individuals with the FMR1 full
mutation (Cornish et al., in press; Garner et al., 1999;
Turk & Cornish, 1998). This suggests that social percep-
tion difficulties may lie on a continuum. Although this
idea is not supported by the correlation analysis between
CGG repeat expansion size and performance on the Re-
sizes (78–164) of the premutation males in the present
study may preclude establishing such a relationship.
2. On a self-report questionnaire of social difficulties,
the strongest difference between the premutation and the
non-familial control group lay in the attention switching
factor. At a cognitive level, problems in attention
switching and control have been reported as a funda-
mental deficit in the FMR1 full mutation (Munir, Cor-
nish, & Wilding, 2000; Wilding et al., 2002). It is has
been suggested that this control requires a balance of
excitation and inhibition, to enable switching from one
attentional focus to another, or from one emitted re-
sponse to the next response in a sequence. In the present
study, premutation males may display a subtle yet sim-
ilar profile to that of full mutation males. At the
behavioural level, this may result in problems in over
focusing and a fixation on details, whilst at the cognitive
level, our preliminary analysis of attention and executive
functioning in this group is strongly suggestive of exec-
utive dysfunction (Cornish, Manly, James, Mills, & Hol-
lis, 2003). Although speculative, it is possible that the
subtle impairments in executive functioning can be ac-
counted for by disturbances in the cerebellum, which
can modulate executive functions subserved by frontal
cortex. Such deficits have been described previously
for patients with cerebellar atrophy (Grafman et al.,
1992), impairments normally attributed to damage of
the frontal lobe. Schmahmann and Pandya (1997) have
demonstrated that there are indeed corticopontine path-
ways from prefrontal areas suggesting that the cerebel-
lum contributed to the network of brain areas critical
for higher-order cognitive processes.
3. Previous research has demonstrated that, for mo-
tor abilities, there is an interaction between premutation
status and age—with abnormalities becoming marked in
older age. There was a remarkably strong relationship
between worsening performance in categorising emo-
tional expressions and increasing age in the premutation
and—to a lesser degree—in the familial control group.
The direction of the relationship in the Revised Eyes
Test was consistent with this finding for both groups,
although insufficient to reach statistical significance. Un-
like normal ageing effects that disproportionately com-
promise the recognition of fear and anger expressions
(e.g., Calder et al., 2003); the decline in the premutation
group appeared to be more general. This effect is unli-
kely to be explicable on the basis of more general intel-
lectual decline with age and, given the relatively good
performance of many members of this group on some
aspects of this task, unlikely to result from basic percep-
tual processing problems.
4. A notable trend across the emotional cognition
tasks employed here is that, although differences be-
tween the relatives of participants with the FMR1 pre-
mutation and non-related controls were not sufficient
to reach statistical significance, often the performance
of this group fell somewhere between the premutation
and non-familial groups. This occurred despite the ‘‘un-
affected’’ relatives being well matched in terms of gen-
eral ability. This raises the question of whether, across
a large sample, there are subtle effects of having one
or more relatives affected with full mutation fragile X,
whether there are other social factors that interact with
fragile X prevalence, or whether indeed these relatives
may themselves show very subtle problems with no cur-
rently obvious cause.
Our finding of a selective deficit in social cognition in
premutation carriers raises the interesting possibility
that the cerebellum might serve as a neurobiological lo-
cus for these abilities. Evidence from aging premutation
carriers indicates that abnormal FMR1 mRNA levels in
this population have their greatest impact on cerebellar
functioning (Berry-Kravis et al., 2003; Hagerman et al.,
2001; Jacquemont et al., 2003; Jacquemont et al., 2004).
Although premutation status does not appear to guar-
antee development of ataxia and tremor in later life,
K. Cornish et al. / Brain and Cognition 57 (2005) 53–60
there seems to be a significant increased vulnerability of
this brain structure with increased CGG repeat number.
Moreover, one of the most consistent findings from re-
search into the neuroanatomical abnormalities associ-
ated with autism, a condition where similar deficits in
social cognition have been reported, (e.g., Baron-Cohen,
Wheelwright, Hill et al. (2001)), indicates that there are
structural abnormalities of the cerebellum. Furthermore,
mounting evidence implicates the cerebellum, as being
critical for non-motor functions, including language,
rgi (2000), for example, observed that children with
rior lobules had autistic-like disruptions of social and
communicative behaviour. Finally, the expression pat-
of the protein in the cerebellum, suggesting that altera-
tions in the function of FMRP might have a detrimental
impactonthisbrainstructure (Abitboletal., 1993;Hinds
et al., 1993). Future research should examine the contri-
bution of the cerebellum to the social cognition deficits
in fragile X syndrome. Specifically, these studies should
investigate the relationship among mutation status,
neuroanatomical variations in the cerebellum, and per-
formance on neuropsychological measures of social
In conclusion, the findings of the present study pro-
vide evidence of a subtle yet measurable effect of the
FMR1 premutation on aspects of social cognition,
namely for skills that require accurate social perception.
Consistent with previous research, the pattern of deficit
is similar in profile, albeit milder in presentation, to that
of the full mutation, indicating that the premutation
does not come without some degree of cognitive risk.
Future research will need to address whether there is
an increased risk of impairment to individuals who have
CGG repeat sizes in the higher premutation range
(>150), whether the effects generally worsen with age.
It is possible that the severe clinical profiles of ataxia
and tremor reported in previous studies included males
in the upper premutation range and that the potential
of developing such pathology is directly related to
FMR1 repeat size. Finally, it is crucial that future re-
search address the phenotypic consequence of premuta-
tion status in childhood as well as the developmental
timing of any impairment. This will allow interventions
to be targeted more appropriately and prior to the devel-
opment of irreversible neuropathology. Furthermore, it
may allow for identification of at risk premutation indi-
viduals for the development of more serious pathology
later in life. A longitudinal study of premutation males
may assist in our understanding of the impact of the re-
peat expansion on the neurobiology as well as the un-
ique features of perception, cognition, emotion, and
behaviour in this population.
This research was supported by a grant from the
Wellcome Trust, UK to K.C., J.T., and A.D. We ex-
press our thanks to the all the regional genetics centres
that took part in the study and to the fragile X Society
for their support in recruitment. We would also like to
thank Amira Rahman and Danielle Ostield for their
helping in the editing of the manuscript.
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