Autism Spectrum Disorder in Fragile X Syndrome: A Longitudinal Evaluation

Kennedy Krieger Institute, Baltimore, MD 21211, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2009; 149A(6):1125-37. DOI: 10.1002/ajmg.a.32848
Source: PubMed


The present study extends our previous work on characterizing the autistic behavior profile of boys with fragile X syndrome (FXS) who meet Diagnostic and Statistical Manual for Mental Disorders, 4th Edition criteria for autism spectrum disorder (ASD) into a longitudinal evaluation of ASD in FXS (FXS + ASD). Specifically, we aimed to determine the stability of the diagnosis and profile of ASD in FXS over time. Through regression models, we also evaluated which autistic and social behaviors and skills were correlates of diagnosis and autistic behavior severity (i.e., Autism Diagnostic Interview-Revised total scores). Finally, we assessed the evolution of cognitive parameters in FXS + ASD. A population of 56 boys (30-88 months at baseline) with FXS was evaluated using measures of autistic, social, and cognitive behaviors and skills at three yearly evaluations. We found that the diagnosis of ASD in FXS was relatively stable over time. Further emphasizing this stability, we found a set of behaviors and skills, particularly those related to peer relationships and adaptive socialization, that differentiated FXS + ASD from the rest of the FXS cohort (FXS + None) and contributed to autistic severity at all time points. Nevertheless, the general improvement in autistic behavior observed in FXS + ASD coupled with the concurrent worsening in FXS + None resulted in less differentiation between the groups over time. Surprisingly, FXS + ASD IQ scores were stable while FXS + None non-verbal IQ scores declined. Our findings indicate that ASD is a distinctive subphenotype in FXS characterized by deficits in complex social interaction, with similarities to ASD in the general population.

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Available from: Richard E Thompson, Jun 03, 2014
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    • "Furthermore, there was a significant decrease on the repetitive behavior and social interaction domains between T1 and T2. Stability of diagnostic classifications of ASD in FXS has been reported in previous studies (Hatton et al., 2006; Hernandez et al., 2009; Sabaratnam et al., 2003). "
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    ABSTRACT: Little is known about the way in which the characteristics of autism spectrum disorder (ASD) develop and manifest across the age span in individuals with genetic syndromes. In this study we present findings from a two and a half year follow-up of the characteristics associated with ASD in three syndromes: Cornelia de Lange (CdLS), Fragile X (FXS), and Cri du Chat (CdCS). Parents and carers of 251 individuals (CdLS = 67, CdCS = 42, and FXS = 142) completed the Social Communication Questionnaire (SCQ) at Time 1 (T1) and again two and a half years later (T2). The FXS and CdLS groups were more likely to meet the cut-offs for both autism and ASD and show greater severity of ASD related behaviors, at both T1 and T2, compared to the CdCS group. Older individuals (>15yrs) with CdLS were more likely to meet the cut off for ASD than younger individuals (≤ 15yrs) with the syndrome and more likely to show greater severity of social impairments. In FXS repetitive behaviors were found to become less prominent with age and in CdCS social impairments were reported to be more severe with age. There were no significant changes between T1 and T2 in the severity of ASD characteristics in the CdCS and CdLS groups. The FXS group showed significantly fewer repetitive behaviors and less severe impairments in social interaction over this time frame. The findings suggest that while there may be similarities in overall severity and presentation of ASD characteristics in CdLS and FXS, these characteristics have divergent patterns of development within these groups. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 05/2015; 169(2). DOI:10.1002/ajmg.c.31438 · 3.91 Impact Factor
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    • "Research has investigated the impact of comorbid ASD in FRAX by comparing individuals with comorbid ASD to those with FRAX only. Such research has reported lower IQ (Hagerman et al., 1986), greater deficits in adaptive functioning (Turk & Graham, 1997), and greater deficits in socialization (Hernandez et al., 2009) in those with comorbid ASD when compared to those with FRAX only. This research suggests that presence of comorbid ASD in FRAX may result in a poorer prognosis. "
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    ABSTRACT: The present study sought to investigate the relationship between challenging behavior, comorbid psychopathology, and Attention-Deficit/Hyperactivity Disorder (AD/HD) in Fragile X Syndrome (FRAX). Additionally, this study sought to examine how such disorders are predicted by gender, presence of autism spectrum disorder (ASD), and presence of intellectual disability (ID). A total of 47 children and adolescents with FRAX were assessed. Results revealed high levels of challenging behavior and AD/HD symptoms within the sample, with some participants exhibiting symptoms of comorbid psychopathology. Further analysis revealed that challenging behavior and comorbid psychopathology were positively correlated, with stereotypy correlating most strongly with comorbid psychopathology. In addition, ASD was found to predict challenging behavior, and gender was found to predict AD/HD symptoms. The implications of these findings are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Research in Developmental Disabilities 12/2014; 38C:7-17. DOI:10.1016/j.ridd.2014.11.003 · 3.40 Impact Factor
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    • "Different combinations of these three disorders have also occurred together in patients. Numerous studies have reported a range of percentages for the prevalence of such overlapping patient groups, and are shown in Figure 2. The co-diagnosis rate of an ASD disorder in male Fragile X patients ranges from 25 to 46% (Muhle et al., 2004; Abrahams and Geschwind, 2008; Bailey et al., 2008; Hernandez et al., 2009). The corresponding rate for epilepsy in male Fragile X patients is lower, ranging from 10 to 18% (Musumeci et al., 1999; Muhle et al., 2004; Bailey et al., 2008), whereas the occurrence of epilepsy in ASD patients varies more widely from 6.6 to 37% (Amiet et al., 2008; Yasuhara, 2010; Jokiranta et al., 2014). "
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    ABSTRACT: The sodium-activated potassium KNa channels Slack and Slick are encoded by KCNT1 and KCNT2, respectively. These channels are found in neurons throughout the brain, and are responsible for a delayed outward current termed I KNa. These currents integrate into shaping neuronal excitability, as well as adaptation in response to maintained stimulation. Abnormal Slack channel activity may play a role in Fragile X syndrome, the most common cause for intellectual disability and inherited autism. Slack channels interact directly with the fragile X mental retardation protein (FMRP) and I KNa is reduced in animal models of Fragile X syndrome that lack FMRP. Human Slack mutations that alter channel activity can also lead to intellectual disability, as has been found for several childhood epileptic disorders. Ongoing research is elucidating the relationship between mutant Slack channel activity, development of early onset epilepsies and intellectual impairment. This review describes the emerging role of Slack channels in intellectual disability, coupled with an overview of the physiological role of neuronal I KNa currents.
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