Psychiatric symptoms in boys with fragile X syndrome: A comparison with nonsyndromic autism spectrum disorder

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Highlights

Abstract

In the present study, we examined the profile of psychiatric symptoms in boys with fragile X syndrome (FXS) using a parent report instrument. In addition, by comparing boys with FXS to boys with nonsyndromic autism spectrum disorder (ASD) utilizing multiple matching strategies, we examined between-group differences in the types of psychiatric symptoms observed and in the strength of their concurrent associations. Across all matching strategies, symptoms of manic/hyperactive behaviors and general anxiety were more frequently reported for boys with FXS than for boys with nonsyndromic ASD. Results also indicated a positive association between social avoidance and general anxiety in FXS that was stronger than that observed in nonsyndromic ASD across all matching strategies. Theoretical and treatment implications are discussed.

Introduction

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (Crawford, Acuña, & Sherman, 2001) and is the second only to Down syndrome as a genetic cause of intellectual disability. The syndrome results from an expansion of the cytosine-guanine-guanine (CGG) sequence of nucleotides within the FMR1 gene on the X chromosome to more than 200 repeats (Oostra & Willemson, 2003). This expansion typically leads to the reduction or absence of FMRP, the protein normally produced by the FMR1 gene, which is essential for synaptic plasticity and experience-dependent learning (Bassell & Warren, 2008). In addition to cognitive impairments, a variety of behavioral difficulties have a high comorbidity with FXS, especially in males, including hyperactivity and attentional difficulties (e.g., Baumgardner, Reiss, Freund, & Abrams, 1995; Cornish, Scerif, & Karmiloff-Smith, 2007; Scerif, Longhi, Cole, Karmiloff-Smith, & Cornish, 2012; Turk, 1998) and anxiety and withdrawal (e.g., Bregman, Leckman, & Ort, 1988; Cordeiro, Ballinger, Hagerman, & Hessl, 2011; Kau, Reider, Payne, Meyer, & Freund, 2000). Moreover, the vast majority of males with FXS are likely to display some behaviors that are characteristically observed in individuals with nonsyndromic autism spectrum disorder (ASD), that is, individuals with ASD for whom there is no known etiology (Bailey et al., 2004, Baumgardner et al., 1995, Hartley et al., 2011). In the present study, we sought to clarify the behavioral symptom profile of FXS and understand the ways in which this profile is similar to and different from that of nonsyndromic ASD. Such data are critical to efforts to develop targeted treatments, especially those that have utility for both FXS and nonsyndromic ASD. Given the moderating effects of the second unaffected X chromosome in females, males with FXS are typically more severely affected across domains of behavioral functioning (Mazzocco, 2000). Thus, the present study focused on males only.

Recent advances in neurobiology have increased our understanding of the pathophysiology of FXS, leading to the development of pharmacological treatments targeting core deficits of this disorder. Such treatments have been shown to rescue many phenotypic features in the FMR1 knock out (KO) mouse and other animal models of FXS (Bagni, Tasonne, Neri, & Hagerman, 2012; Berry-Kravis et al., 2011; Bhakar, Dölen, & Bear, 2012; Dölen, Carpenter, Ocain, & Bear, 2010; Hagerman, Lauterborn, Au, & Berry-Kravis, 2012). Positive effects of several pharmacological agents have been observed in human clinical trials as well, including those involving minocycline (Dziembowska et al., 2013; Leigh et al., 2013), sertraline (Indah Winarni et al., 2012), AFQ056 (an mGluR5 antagonist) (Jacquemont et al., 2011), and arbaclofen (a GABAB agonist) (Berry-Kravis et al., 2012). More generally, the symptom overlap between FXS and nonsyndromic ASD has led to the hope that targeted treatments benefitting FXS will also benefit those with nonsyndromic ASD (Gurkan & Hagerman, 2012). Despite initial positive results and the optimism generated among scientists and families, there have been many disappointments in human clinical trials as well. In general, results for humans with FXS have been modest relative to the impressive findings with the KO mouse. Moreover, the extension of drugs with positive findings for FXS to individuals with nonsyndromic ASD has not always shown benefit, with arbaclofen being a recent high-profile “failure” for nonsyndromic ASD (Pollack, 2013).

There are several reasons for the pattern of human study findings. First, although the impairments that define FXS have been well described for many behavioral domains, there remains much that we do not understand about the phenotype, including the extent to which different behavioral symptoms associated with the FXS phenotype emerge from the same or different underlying neural mechanisms. As a result, decisions about which behavioral endpoints to select for use in clinical trials have often been based on clinical intuition rather than being hypothesis driven. It would be useful, therefore, to understand which symptoms of the FXS phenotype are strongly correlated with one another, which would suggest common underlying mechanisms, and which symptoms are not correlated, which would suggest different underlying mechanisms. Second, despite the findings of shared behavioral symptoms between FXS and nonsyndromic ASD, there is emerging evidence suggesting that the same behavioral symptoms may reflect different underlying mechanisms in the two conditions (Gallagher & Hallahan, 2012; McDuffie, Thurman, Hagerman, & Abbeduto, in press; Wolff et al., 2012). If this is the case, the expectation of finding targeted treatments that are equally efficacious across the disorders might not be reasonable. Direct studies comparing behavioral profiles across FXS and nonsyndromic ASD have been few and existenting studies do not adequately account for other developmental characteristics that differ between the two disorders, such as IQ, which can complicate interpretation of such cross-syndrome comparisons.

The current study was designed to compare the behavioral profiles observed in FXS to the profiles observed in nonsyndromic ASD. To begin to identify characteristics that may be unique to the behavioral phenotype associated with FXS, we examined the psychiatric symptom profile of boys with FXS relative to comparison groups of same-aged children with a diagnosis of nonsyndromic ASD. In the present study, we use the term “nonsyndromic ASD” to refer to boys who display symptoms of autism that are frequent and/or severe enough to exceed behavioral criteria for a research classification of ASD, but for whom a comorbid genetic diagnosis of FXS or other known etiology has been ruled out. To inform our understanding of whether the same behavioral symptoms reflect similar or different underlying psychological mechanisms, we examined concurrent associations across domains of psychiatric symptoms as well as concurrent associations between these symptoms and other domains of functioning across the two disorders. Studies such as these are vital to understanding the extent to which targeted treatments may be similarly efficacious in FXS and nonsyndromic ASD.

Behavioral characteristics typically associated with the presentation of an ASD are frequently observed in males with FXS. As many as 90% of males with FXS are described as displaying at least some behavioral symptoms of an ASD; furthermore, when utilizing standard caseness criteria for research classification of ASD (Risi et al., 2006), it is estimated that 60% of males with FXS have symptoms that are frequent and severe enough to warrant a comorbid diagnosis of ASD (e.g., Harris et al., 2008). Despite these findings, there is disagreement regarding how to interpret the presence or absence of behaviors typically associated with a classification of ASD in the context of an individual with FXS. Currently, there is much debate within the field regarding whether the behavioral symptoms typically interpreted to represent core domains of autism symptomatology are: (1) the result of the same underlying neurological/psychological impairments that affect individuals with nonsyndromic ASD or (2) superficially similar behaviors but arise from different underlying psychological/neurological impairments. Given recent findings of neuroimaging studies suggesting potentially important structural and functional differences between the brains of individuals with FXS and those with nonsyndromic ASD (for review see Gallagher & Hallahan, 2012), research focused on elucidating the similarities and differences between the two disorders and examining at what levels these differences exist is of particular importance. Direct comparisons between appropriately matched FXS and ASD samples are necessary to discern where the behavioral and neurophysiological boundaries lay between these two disorders.

To date, many comparisons between individuals with FXS and individuals with nonsyndromic ASD have focused on the behaviors central to a diagnosis of ASD, examined as either a function of symptom severity and/or categorical diagnostic metrics. Recent findings have begun to identify between-syndrome differences between boys with FXS and boys with nonsyndromic ASD when matched on age and categorical diagnostic status (Wolff et al., 2012) and when matched on age and a continuous metric of autism symptom severity (McDuffie et al., in press). McDuffie and colleagues, for example, recently found that boys with FXS are less impaired in social smiling, gesture use, and offering to share, and more impaired in complex mannerisms than are boys with nonsyndromic ASD, whether matched on age and diagnostic status or autism symptoms severity (McDuffie et al., in press). These results suggest that important differences in social-affective, communicative, and restricted, repetitive behaviors may differentiate boys with FXS from those with ASD and may have important implications for the application of targeted treatments. In order to understand the extent to which symptoms overlap or discriminate between the FXS and nonsyndromic ASD phenotypes, it is necessary for empirical studies to go beyond evaluating the similarities/differences in autism symptoms by directly comparing symptom profiles in other domains of functioning, particularly domains that are frequently implicated in both phenotypes.

Two domains of functioning that are frequently noted as problematic for individuals with FXS are hyperactivity/inattention and anxiety. Increased symptom presentation in these domains is also observed for individuals with nonsyndromic ASD (de Bruin, Ferdinand, Meester, Nijs, & Verheij, 2007; Gevik, Eldevik, Fjæran-Granum, & Sponheim, 2011; Leyfer et al., 2006; Mattila et al., 2010; Siminoff et al., 2008); yet, direct comparisons of the disorders on these domains have yet to be conducted. In the current study, we examined of the profile of symptoms and the interrelations among these symptom domains to shed light on whether similar behavioral challenges reflect the same underlying mechanisms in these two neurodevelopmental disorders.

Males with FXS often display significant hyperactivity as well as attentional difficulties. For example, in their sample of 14 males with FXS (chronological age (CA) range: 3–27 years), Bregman et al. (1988) found that all participants demonstrated significant inattention and hyperactivity and 13/14 participants demonstrated clinically significant impulsivity problems. Fryns, Jacobs, Kleczkowska, and van den Berghe (1984) reported similar findings for a sample of 21 males between 2 and 21 years of age, describing “hyperkinetic behavior with restlessness, overactivity, agitation and poor, superficial attention (Fryns et al., 1984, pg. 133)” as the most salient behavioral characteristics of their sample. Sansone et al. (2012) compared a factor analysis of Aberrant Behavior Checklist-Community (ABC-C; Aman & Singh, 1994) data from individuals with FXS to the original norming data for individuals with general intellectual disability. They found that in the case of FXS, fewer items loaded onto the Hyperactivity factor than had been observed for individuals with general intellectual disability. Items loading on this factor were more explicitly related to elevated activity in the sample of individuals with FXS. For individuals with general intellectual disability, items related to disruptive behavior, impulsivity and inattentiveness/distractibility also loaded on the Hyperactivity factor, whereas for participants with FXS, these items loaded on Irritability and Lethargy/Withdrawal factors.

More generally, multiple studies have compared the rates of hyperactivity, attention problems, and impulsivity in FXS to rates found in other clinical groups. Baumgardner et al. (1995) found that children with FXS between 3 and 16 years of age (mean CA = 8.7 years, SD = 4.3), earned higher maternal ratings of hyperactivity, measured by the Parent-Aberrant Behavior Checklist (ABC; Krug, Arick, & Almond, 1993) than did a group of participants of mixed etiology ID matched on CA and similar in IQ. Furthermore, a greater proportion of children with FXS met DSM-III-R criteria for attention deficit/hyperactivity disorder than did controls of mixed etiology ID. Turk (1998) reported a similar pattern of findings when comparing children with FXS to children with Down syndrome (DS) and children with nonsyndromic developmental disability matched on developmental age. The children with FXS in Turk's study earned higher maternal ratings of restlessness and hyperactivity, as measured by the Children's Behavior Checklist (CBCL; Achenbach & Edelbrock, 1983), than did the children with DS or children with developmental delay. Not all studies have been able to replicate this finding (e.g., Einfeld, Hall, & Levy, 1991; Kau et al., 2000); however, there are several possible explanations for the discrepant findings across studies including the CA of the participants as well as the measures used to assess hyperactivity.

Despite the increased risk for presenting with these symptoms, no studies to date directly compare symptoms of hyperactivity, attention problems, and impulsivity between FXS and nonsyndromic ASD. Consequently, we do not know the extent to which these symptoms influence the similarities and differences observed between the two phenotypes. By exploring the between-group similarities and differences that exist in the hyperactivity and attentional domain and interrelations across domains, we can learn whether their similar behavioral presentations/difficulties reflect the same underlying mechanisms in these two neurodevelopmental disorders.

Males with FXS also are often described as presenting with significant anxiety, gaze aversion, and relative to individuals with other ID syndromes (e.g., Bregman et al., 1988; Cordeiro et al., 2011; Einfeld, Tonge, & Florio, 1994; Kau et al., 2000). For example, in their factor analysis of the ABC-C data from individuals with FXS, Sansone et al. (2012) identified a sixth factor for their FXS sample that was not observed for individuals with general intellectual disability in the original norming sample. Sansone et al. argued that this factor, referred to as Social Avoidance, captured core aspects of the FXS phenotype related to gaze avoidance, social escape behaviors, and social anxiety. Cordeiro et al. (2011), using a diagnostic clinical interview assessing the presence of DSM-IV anxiety disorders, found that 86.2% of their sample met diagnostic criteria for at least one anxiety disorder, most frequently specific phobia and social phobia. Cordeiro et al. found that rates of anxiety disorders were higher in FXS relative to the general population (Schaffer et al., 1996), children with nonsyndromic ID (Dekker & Koot, 2003), and children with Williams syndrome (Leyfer, Woodruff-Borden, & Mervis, 2009), a neurogenetic syndrome in which the rate of General Anxiety Disorder is reported as more than double the rate observed in the general population. In contrast, multiple studies have also reported no difference to decreased rates of Withdrawal (Baumgardner et al., 1995, Kau et al., 2000) and antisocial behavior (Einfeld et al., 1994) relative to IQ-matched participants with mixed etiology ID.

Although the observation of higher ratings of anxiety, gaze aversion, and avoidance behaviors would seem to be inconsistent with lower ratings of withdrawal and antisocial behaviors, these findings correspond to the clinical descriptions of FXS found in the literature and have aided our characterization of the behavioral phenotype observed in males with FXS. A broad range of social difficulties is observed in males with FXS; in addition, the social/behavioral profile in FXS has been characterized as “a portrait of sharp contrasts (Bailey & Nelson, 1995, pg. 240).” On the one hand, “these individuals generally are perceived to engage in prosocial behavior, desire social relationships, and form social attachments (Bailey & Nelson, 1995, pg. 240).” On the other hand, individuals with FXS frequently present with social/gaze avoidance and anxiety, a behavioral presentation that potentially contributes to the frequent reports of symptom overlap between individuals with FXS and those with nonsyndromic ASD. Thus, this domain of functioning is especially important to examine relative to individuals with nonsyndromic ASD as it may provide insights into the neuropsychological underpinnings of many of the social/affective symptoms of ASD observed in FXS.

This clinical presentation is consistent with existing research from typical development, which demonstrates that although sociability and shyness may be linked, these two factors are distinguishable (Cheek & Buss, 1981); that is, one can demonstrate a preference for/interest in interacting with people but still experience discomfort engaging within the social interaction. Given the interest in elucidating the similarities and differences between the FXS and ASD phenotypes, we are brought to an important empirical question yet to be addressed; namely, what role does anxiety play in the similarities and differences observed between these phenotypes? By comparing the profile of symptoms of anxiety and their interrelations with other domains of functioning, the present study may shed light on whether these symptoms reflect the same underlying mechanisms in these two neurodevelopmental disorders. This information can be used as a first step in exploring the role of anxiety in the development of the FXS and nonsyndromic ASD behavioral phenotypes, thereby potentially shedding light on the similarities and differences in the developmental trajectories of these two behavioral phenotypes.

In the current study, we examined the presence and profile of psychiatric symptoms in boys with FXS based upon maternal ratings of these symptoms. In addition, we examined whether between-syndrome differences existed in the types of psychiatric symptoms observed when comparing boys with FXS to boys with nonsyndromic ASD. Finally, we investigated the extent to which between-syndromes differences existed in the associations among psychiatric symptom domains as well as in the associations of these symptoms with other aspects of behavioral functioning. It is important to recognize that a number of methodological challenges arise when focusing on comparisons across neurodevelopmental disorders (e.g., Mervis & Klein-Tasman, 2004). For example, when comparing individuals with FXS to those with nonsyndromic ASD, large and significant differences are observed both in nonverbal reasoning ability and in the presence of the core symptoms of autism, with males with FXS demonstrating, on average, more limited nonverbal reasoning ability and better social functioning than males with nonsyndromic ASD (McDuffie et al., in press; Wolff et al., 2012). Additionally, a negative association has been observed between NVIQ and severity of autism symptoms in FXS (Lewis et al., 2006). To control for these differences, and to allow for a more careful characterization of between-group similarities and differences, the present study utilized three alternate matching strategies resulting in subsamples of participants who were matched groupwise on: (a) CA; (b) CA and NVIQ; and (c) CA, NVIQ, and autism symptom severity. Thus, the current study addressed the following research questions:

  • (1)

    For boys with FXS, what is the observed profile of maternal ratings of current psychiatric symptoms across symptom domains?

  • (2)

    Are there between-group differences in maternal ratings of current psychiatric symptoms? Do the observed group differences vary according to the matching strategy used?

  • (3)

    Do between-group differences exist in the pattern of associations across psychiatric symptom domains? Do the observed group differences vary according to the matching strategy used?

  • (4)

    Do between-group differences exist in the concurrent associations between psychiatric symptoms and other child characteristics (i.e., CA, nonverbal reasoning ability, and autism symptom severity)? Do the observed group differences vary according to the matching strategy used?

Section snippets

Participants

Participants were drawn from a larger study of word learning in males with FXS and males with nonsyndromic ASD. Inclusion in the larger study required participants in both diagnostic groups to meet the following criteria: (a) between 4 and 10 years of age, (b) nonverbal mental age between 2;0 and 5;11, (c) native English speaker with parents who are fluent English speakers, (d) speech is the primary means of communication, (e) no sensory or physical impairments that would limit participation in

Results

The number of items comprising each subscale varied across the five ADAMS subscales. As such, a mean rating was computed for each subscale and utilized in all analyses. Furthermore, examination of the data indicated that the distributions for mean rating scores for the Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, and Obsessive/Compulsive Behavior subscales violated the parametric assumption of normality. Non-parametric tests, therefore, were utilized in all analyses.

Discussion

The overall aim of the current study was to contribute to a more nuanced understanding of how profiles of psychiatric symptoms may be shared or differ between boys with FXS, the leading inherited cause of intellectual disability, and boys with nonsyndromic ASD. These two syndromes are often considered to have substantial behavioral overlap given that the vast majority of boys with FXS also display symptoms that are diagnostic of ASD. Additionally, individuals with either diagnosis are at

Acknowledgement

This research was supported by grant R01 HD054764 from the National Institute of Child Health and Human Development. We wish to thank the children and their families for their participation in this study. We also thank Sara Kover, Ashley Oakes, David Benjamin, Susan Harris, Beth Goodlin-Jones, Claire Hauser, Sara Lifson, Eileen Haebig, and Cecilia Compton for assisting with data collection and Susen Schroeder for coordinating all study visits. Leonard Abbeduto has received financial support to

References (67)

  • S. Risi et al.

    Combining information from multiple sources in the diagnosis of autism spectrum disorders

    Journal of the American Academy of Child and Adolescent Psychiatry

    (2006)
  • J.J. Wolff et al.

    Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism

    Journal of the American Academy of Child and Adolescent Psychiatry

    (2012)
  • T.M. Achenbach et al.

    Manual for the Child Behavior Checklist and revised child behavior profile

    (1983)
  • M.G. Aman et al.

    Aberrant Behavior Checklist-Community. Supplementary manual

    (1994)
  • C. Bagni et al.

    Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics

    American Society for Clinical Investigation

    (2012)
  • D.B. Bailey et al.

    Early development, temperament, and functional impairment in autism and fragile X syndrome

    Journal of Autism and Developmental Disorders

    (2000)
  • D.B. Bailey et al.

    The nature and consequences of fragile X syndrome

    Mental Retardation and Developmental Disability Research Reviews

    (1995)
  • D.B. Bailey et al.

    Research on fragile X syndrome and autism: Implications for the study of genes, environments, and developmental language disorders

  • T.L. Baumgardner et al.

    Specification of the neurobehavioral phenotype in males with fragile X syndrome

    Pediatrics

    (1995)
  • E.M. Berry-Kravis et al.

    Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: A randomized, controlled, phase 2 trial

    Science in Translational Medicine

    (2012)
  • E. Berry-Kravis et al.

    Targeted treatments for fragile X syndrome

    Journal of Neurodevelopmental Disorders

    (2011)
  • A.L. Bhakar et al.

    The pathophysiology of fragile X (and what it teaches us about synapses)

    Annual Review of Neuroscience

    (2012)
  • J.A. Blackman et al.

    Management of preschool children with Attention Deficit-Hyperactivity Disorder

    Topics in Early Childhood Special Education

    (1991)
  • J.D. Bregman et al.

    Fragile X syndrome: Genetic predisposition to psychopathology

    Journal of Autism and Developmental Disorders

    (1988)
  • J.M. Cheek et al.

    Shyness and sociability

    Journal of Personality and Social Psychology

    (1981)
  • L. Cordeiro et al.

    Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: Prevalence and characterization

    Journal of Neurodevelopmental Disorders

    (2011)
  • E.I. de Bruin et al.

    High rates of psychiatric co-morbidity in PDD-NOS

    Journal of Autism and Developmental Disorders

    (2007)
  • M. Dziembowska et al.

    High MMP-9 activity levels in fragile X syndrome are lowered by minocycline

    American Journal of Medical Genetics

    (2013)
  • S. Einfeld et al.

    Hyperactivity and fragile X syndrome

    Journal of Abnormal Child Psychology

    (1991)
  • S.L. Einfeld et al.

    Behavioural and emotional disturbance in fragile X syndrome

    American Journal of Medical Genetics

    (1994)
  • A.J. Esbensen et al.

    Reliability and validity of an assessment instrument for anxiety, depression, and mood among individuals with mental retardation

    Journal of Autism and Developmental Disorders

    (2003)
  • J.P. Fryns et al.

    The psychological profile of the fragile X syndrome

    Clinical Genetics

    (1984)
  • A. Gallagher et al.

    Fragile X-associated disorders: A clinical overview

    Journal of Neurology

    (2012)
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