Review
Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X

https://doi.org/10.1016/j.neubiorev.2006.09.007Get rights and content

Abstract

The distributions of scores for autistic behaviours obtained from the Autism Diagnostic Observation Scale—Generic (ADOS-G) were investigated in 147 males and females affected with the full mutation in the fragile X mental retardation 1 (FMR1) gene, in 59 individuals with the premutation, and in 42 non-fragile X relatives, aged 4–70 years. The scores representing communication and social interaction were continuously distributed across the two fragile X groups, and they were significantly elevated compared with the non-fragile X controls. Strong relationships were found between both these scores and FMRP deficits, but they became insignificant for social interaction, and the sum of social interaction and communication scores, when FSIQ was included as another predictor of autism scores. Other significant predictors of these scores in both sexes were those executive skills which related to verbal fluency, and to the regulation and control of motor behaviour. Overall, our data have shown that cognitive impairment, especially of verbal skills, best explains the comorbidity of autism and fragile X. This implies some more fundamental perturbations of specific neural connections which are essential for both specific behaviours and cognition. We also emphasize that FXS offers a unique molecular model for autism since FMRP regulates the translation of many other genes involved in synaptic formation and plasticity which should be natural targets for further exploration.

Introduction

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, with cognitive and behavioural impairments of varying degree associated with distinct physical features (Hagerman, 2002). FXS is caused by an unstable mutation in the fragile X mental retardation 1 (FMR1) X-linked gene (Verkerk et al., 1991), and involves the expansion of trinucleotide (CGG) repeats in the promoter region of this gene if transmitted from mothers to their offspring (Fu et al., 1991). Small expansions ranging from 55 to 200 CGG repeats (premutation) do not typically cause obvious developmental delay, but they tend to further expand into a ‘full mutation’ (>200 CGG repeats) if transmitted through a female (Fu et al., 1991). This usually leads to an inactivation of the FMR1 gene and gross deficit of its specific protein product, FMR1 protein (FMRP) (Pieretti et al., 1991), which is important for normal brain development (Irwin et al., 2000; Weiler and Greenough, 1999). FMRP is involved in synaptogenesis, especially in the cerebral cortex, cerebellum, and hippocampus, and more specifically, in synaptic pruning (Comery et al., 1997; Weiler et al., 1997; Weiler and Greenough, 1999). Hence, developmental delay in FXS is primarily caused by the deficit of this protein.

FXS occurs in both sexes, but females are usually less affected because of the presence of a normal FMR1 gene on the second X chromosome which, if active, generates normal levels of FMRP. This is why only 50–71% of females with the full mutation demonstrate a significant cognitive deficit (de Vries et al., 1996; Loesch and Hay, 1988).

Behavioural features displayed by both male and female individuals affected with FXS, such as impairments in social interaction and communication, social anxiety, gaze avoidance, hand and finger mannerisms, repetitive and tangential speech, and other stereotypic behaviours (Hagerman, 2002; Lachiewicz et al., 1994; Miller et al., 1999; Sudhalter et al., 1990), resemble those seen in autism. These features may occur in a number of other conditions of known genetic background, such as tuberous sclerosis, phenylketonuria, and a wide range of chromosomal anomalies (Dykens and Volkmar, 1997; Fombonne et al., 1997; Gillberg, 1998), but they may also develop in the absence of any detectable cause (idiopathic autism). Therefore, the psychiatric diagnosis of autistic disorder (AD) is heterogeneous in genetic aetiology and is usually associated with general cognitive impairment. However, approximately 20% of individuals with idiopathic autism have an IQ in the normal range as measured by standard cognitive tests, and they are classified as ‘high functioning autism’, HFA (Fombonne, 2003).

Behavioural features in three domains, comprising impairments in social interaction, verbal and non-verbal communication, and restricted repetitive and stereotyped patterns of behaviour, interests, and activities, characterize autism (APA manual, 2000). A spectrum of autistic manifestations tends to occur in relatives of the probands affected with AD. The increased recurrence rate in siblings and MZ and DZ twins, as well as evidence from chromosomal, genome screen and linkage studies, have given evidence for significant multiple genetic factors predisposing to idiopathic autism (Muhle et al., 2004).

The frequency of autism amongst males with fragile X varies widely, from 18.5% in the first estimate by Brown et al. (1982), and ranging from 5% to 60% in subsequent studies depending on the diagnostic criteria used (Hagerman, 2002). The occurrence of autism diagnosed using stringent DSM criteria was between 15% and 28% across a wide range of ages (Baumgardner et al., 1995; Cohen, 1995; Hagerman et al., 1986; Reiss and Freund, 1990; Turk and Graham, 1997). The percentage of autism is lower (averaging 4%) in females with FXS (Bailey et al., 1993; Hagerman, 2002), although the rate of these behaviours in females is significantly higher than in controls (Mazzocco et al., 1997). However, all these estimates were based on older standardized autism measures and DSM criteria, and on samples where a diagnosis of fragile X was not always accurate.

An important development in autism research has been the introduction of new diagnostic tools: the Autism Diagnostic Interview—Revised (ADI-R) (Lord et al., 1994) and the Autism Diagnostic Observation Scale—Generic (ADOS-G) (Lord et al., 1999). Both instruments have been validated across ages and severity of the disorder, and jointly provide the gold standard assessment of autism. The ADI-R, a semi-structured parent interview, assesses the presence and severity of early childhood symptoms of autism across the three domains, which essentially correspond to the diagnostic criteria in DSM. The ADOS-G is a semi-structured standardized assessment administered directly to an individual, and it is complimentary to the ADI-R in providing diagnostic classification (Lord et al., 2000). Using both the ADI-R and ADOS-G assessment tools, the frequency of autism amongst a sample of (primarily) male American children affected with FXS, aged 21–48 months, was 33% (Rogers et al., 2001). Similar rates were determined in older boys with FXS using the ADI-R (Kaufmann et al., 2004). Our own study, in a large Australian sample of male and female children and adults with FXS, showed that 18% of males and 10% of females with the full mutation met the AD criteria on both the ADI-R and ADOS-G, and that 67% of males and 23% of females in this category met either the AD criteria on at least one of these two tests, or autism spectrum disorder (ASD) criteria on the ADOS (Clifford et al., 2006). Our results also showed that 14% of males and 5% of females carrying the FMR1 premutation met the criteria for ASD on the ADOS.

In the current study, we explore the distributions of the major ADOS domain scores across the whole range of CGG repeat expansions in the FMR1 gene (full mutation and premutation included) in an unselected sample of fragile X males and females. This quantitative approach allows us not only to consider a wide range of autism-related behaviours, but also to test hypotheses concerning possible mechanisms underlying these behaviours in individuals affected with FXS. Thus, rather than being concerned with diagnostic issues, the aim in this study was, firstly, to assess the relationships between the major ADOS-G domain scores and the levels of FMRP depletion, which is a direct result of mutation in the FMR1 gene, and highly specific to FXS. Secondly, we examine the relationship between the major ADOS-G domain scores and standard and higher cognitive function deficits, which are common amongst different neurodevelopmental disorders and not unique to FXS.

Section snippets

The participants

All aspects of this study were approved by the ethics committees of La Trobe University and the Royal Children's Hospital in Melbourne, and the Institutional Review Board of the University of California at Davis. Participants and/or their parents signed written informed consent. The Australian subjects were recruited from the register of 59 extended families, who participated in a major Australia–USA fragile X genotype–phenotype relationship study supported by an NIH grant over a long time

ADOS-G standard statistics

Means for the two major ADOS domains (COM, RSI), and their sum (CSIT) are listed in Table 1, and the distributions of the CSIT scores in males and females in the combined premutation and full mutation sample are illustrated in Fig. 1. It is evident from Table 1 that in males, the means for each of the domain scores are generally higher in the full mutation group compared to either the premutation or normal groups. It is important to note that the RSI and CSIT scores are also significantly

Discussion

Although there is strong evidence for an association between the autism spectrum and fragile X, the underlying cause of this co-morbidity is not known. In order to shed some light on this issue, we explored the distributions of two major aspects of autistic behaviour, as assessed by the ADOS-G, in two categories of fragile X allele status, full mutation and premutation, compared with the non-fragile X controls. We also explored the relationship of these distributions with standard and higher

Acknowledgements

We thank the study participants and their family for their contribution. This study was supported by the National Institute of Child Health and Human Development Grant HD36071.

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