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J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: J Autism Dev Disord. 2016 June ; 46(6): 2088–2099. doi:10.1007/s10803-016-2737-1.
Infant Development in Fragile X Syndrome: Cross-Syndrome Comparisons Jane E. Roberts, Ph.D.1, Lindsay M. McCary, Ph.D.1, Svetlana V. Shinkareva, Ph.D.1, and Donald B. Bailey Jr., Ph.D.2 1University
Author Manuscript
2RTI
of South Carolina
International
Abstract This study examined the developmental profile of male infants with fragile X syndrome (FXS) and its divergence from typical development and development of infants at high risk for autism associated with familial recurrence (ASIBs). Participants included 174 boys ranging in age from 5 to 28 months. Cross-sectional profiles on the Mullen Scales of Early Learning indicated infants with FXS could be differentiated from typically developing infants and ASIBs by 6 months of age. Infants with FXS displayed a trend of lower developmental skills with increasing age that was unique from the typically developing and ASIB groups. Findings suggest infants with FXS present with more significant, pervasive and early emerging delays than previously reported with potentially etiologically distinct developmental profiles.
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Keywords fragile X syndrome; autism; early development; infants; Mullen
Author Manuscript
Fragile X syndrome (FXS) is the most common heritable condition associated with intellectual disabilities and autism spectrum disorder (ASD; Hagerman, Rivera, & Hagerman, 2008). Nearly all post-pubertal males with FXS have an intellectual disability (Bailey et al., 2008) and up to 50 – 75% of males with FXS meet diagnostic criteria for ASD (Kaufmann et al., 2004; Hall, Lightbody, & Reiss, 2008; Harris et al., 2008; Klusek, Martin, & Losh). Despite the high association of intellectual disabilities and ASD in FXS, few studies have examined the emergence of these co-occurring conditions in FXS, and no work has contrasted the developmental profiles of infants with FXS to those at established risk for ASD or developmental delays. In this paper, we examine broad indicators of early development in infants with FXS contrasted to typically developing infants and infants at high risk for adverse developmental outcomes given a family history of ASD. Our goal was
Correspondence to: Jane Roberts, Ph.D., The University of South Carolina, 1512 Pendleton St., Barnwell 224, Columbia, SC 29208, USA. [email protected]. Lindsay McCary, PhD, Waisman Center, University of Wisconsin-Madison, [email protected] Svetlana Shinkareva, PhD, The University of South Carolina Department of Psychology, [email protected] Donald Baily, Jr., PhD, RTI International, [email protected] Lindsay McCary is now at the Waisman Center, University of Wisconsin, Madison.
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to determine if specific profiles of early development could be identified across etiologically distinct groups of infants at elevated risk for ASD and developmental delays.
Author Manuscript
Prospective studies of developmental trajectories in infants later diagnosed with FXS, ASD or developmental delays are critical for a number of reasons. First, in the absence of a family history, the average age of diagnosis for both ASD and FXS is at 3 years of age despite symptoms present in the first year of life (Bailey, Raspa, Bishop, & Holiday, 2009; Matthews, Goldberg, & Lukowski, 2013). Thus, refined characterization of the infant phenotype in ASD and FXS has the potential to identify markers that could be useful for earlier and more specific diagnosis resulting in early treatment. Second, describing early developmental profiles of etiologically distinct groups of infants at high risk for ASD is important to address the latent heterogeneity present in ASD. Studies targeting crosssyndrome comparisons in ASD are notably lacking particularly work with young children and infants. This work can be highly informative to address commonalities and similarities across “the autisms”. Third, documenting early developmental profiles can identify behavioral or cognitive factors associated with vulnerability to later-emerging symptoms or secondary disorders (e.g., attention deficits, anxiety) both within and across etiology-specific groups. Fourth, cross-syndrome developmental studies can document individual differences or unanticipated age-related patterns of development that could affect treatment response (e.g., shift from hypo to hyper-arousal) that could be etiologically distinct.
Early Development in Fragile X Syndrome
Author Manuscript
Two longitudinal studies of broad development including toddlers or young children with FXS exist. In the first study, 46 boys with FXS between the ages of 24 and 72 months were followed every 6 months for an average of 2 years and a total of 185 assessments (Bailey, Hatton, & Skinner, 1998). As reflected on the Battelle Developmental Inventory (Newborg, Stock, Wnek, Guidubaldi, & Svinicki, 1984), boys with FXS made stable developmental gains; however, their rate of development was approximately half that expected for typically developing children. Boys with FXS were significantly delayed in Cognitive, Communication, Adaptive, Motor and Personal-Social domains at all ages, with Motor and Adaptive Behavior scores consistently higher than Communication and Cognitive scores. No comparison group, measures of autistic behavior or participants less than 2 years of age were included in this study.
Author Manuscript
A subsequent study included repeated assessments of 55 boys with FXS between the ages of 8 and 68 months of age using the MSEL with a mean of 3.4 assessments per child for a total of 189 assessments (Roberts et al., 2009). Results indicated that infants and young children with FXS made developmental gains over time, albeit at a rate about half that of typically developing children as shown in the initial study with older aged children (Bailey et al., 2008). A decline in the rate of development was not evident as had been reported elsewhere with older aged children with FXS (Lachiewicz, Gullion, Spiridigliozzi, & Aylsworth, 1987). Delays were initially evident by 9 months of age in the total score and in the Receptive and Expressive Language domains with delays in Visual Reception emerging at 10 months of age followed by delays in Fine Motor emerging at 13 months of age. Increased severity of autistic behavior, as measured by the Childhood Autism Rating Scale (CARS;
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
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Schopler et al., 1988), was strongly associated with more severe delays across all domains particularly in Communication and Fine Motor domains (Roberts et al., 2009).
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Given the clear co-occurrence of ASD diagnoses and features in FXS, studies that examine early development and the emergence and stability of ASD features are important both for refining the phenotype of FXS and for contributing to the disassociation of these two syndromes. However, few studies have been published on the development of children with FXS less than 5 years of age and only a handful of recent studies have examined early emerging features of autism or cross-syndrome comparisons of early development in FXS. Initial work examining broad developmental indicators in young children with FXS compared to those with idiopathic ASD and those with both FXS and ASD, report mixed findings. Some work suggested that children (21 months of age and older) with FXS and comorbid ASD exhibited more significant delays, particularly in Fine and Gross Motor domains, than children with FXS alone and those with ASD alone (Bailey, Hatton, Mesibov, Ament, & Skinner, 2000). However, a different study found that young children with FXS and ASD were highly similar to those with idiopathic ASD and that young children with FXS without ASD resembled those with non-specific developmental delays (Rogers, Wehner, & Hagerman, 2001). More recent work focusing on infants and the emergence of autistic features in FXS suggests that visual attention is atypical in infants with FXS as young as 9 months of age and is associated with later emerging autistic behavior (Roberts, Hatton, Long, Anello, & Colombo, 2012) with arousal dysregulation implicated mechanistically (Roberts, Tonnsen, Robinson, & Shinkareva, 2012).
Author Manuscript
In summary, there are few studies of early development in FXS, and no studies exist that contrast broad development in infants with FXS to infants at risk for ASD. Existing work suggests that developmental delays emerge by 9 months of age and that development in these first 2 years of life is strongly negatively impacted by the severity of autistic behavior suggesting some similarities to early developmental patterns of infants with an older sibling diagnosed with ASD (ASIBs); however, syndrome specific differences have not been directly investigated during infancy.
Early Development in Autism
Author Manuscript
Given that the presence of an intellectual disability is one of the primary factors accounting for outcomes in children with ASD (Vivanti, Barbaro, Hudry, Dissanayake, & Prior, 2013) with 37% of preschool children with ASD meeting criteria for an intellectual disability (Rivard, Terroux, Mercier, & Parent-Boursier, 2015), efforts to document the early developmental profiles in young children at risk for ASD have accelerated. In fact, the emergence of empirically grounded diagnostic algorithms has been proposed based, in part, on developmental trajectories to predict the primary classifications of unaffected (~59%), social/communication delay or broader autism phenotype (11%) and ASD with and without co-morbid intellectual disability (~25%) (Landa, Gross, Stuart, & Bauman, 2012). Thus, studies that examine the developmental diversity within high risk groups without regard to diagnostic status are highly informative (Landa et al., 2012) with cross-syndrome comparisons as an important component of these efforts.
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
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The bulk of recent work describing the early development of children with ASD has been prospective and longitudinal typically targeting ASIBs as a high risk group, given the increased recurrence rate of autism in approximately 20% of cases (Jones, Gliga, Bedford, Charman, & Johnson, 2014; Landa & Garrett-Mayer, 2006; Rice et al., 2007). The bulk of the prospective longitudinal work (Landa & Garrett-Meyer, 2006; Landa, Gross, Stuart & Fahery, 2013; Zwaigenbaum et al., 2005; see Jones et al., 2014 for a review) report a general absence of developmental markers at 6 months with features emerging between 12 −14 months in communication domains for ASIBs later diagnosed with ASD compared to typical controls and ASIBs who did not meet later diagnostic criteria for autism. Developmental profiles unique to diagnostic outcome have begun to emerge with evidence suggesting 4 distinct classes of high risk infants. Classes include a normative development group, a language/motor delay group, a developmental slowing group, and an accelerated development group (Landa et al., 2012). Unaffected ASIBs primarily fell in the accelerated and normative classes, and most ASIBs with the broader autism phenotype fell in the normative or language delay class. The majority of ASIBs later diagnosed with autism fell in the developmental slowing class. However, there was more variability in class placement for those diagnosed late who were distributed fairly equally across the normative, language/ motor delay and developmental slowing classes in contrast to those identified early who primarily fell in the developmental slowing class.
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Taken together, research on the early development of infants later diagnosed with autism reflects important age-related trajectories. Developmental skills appear generally intact through 6 months of age followed by a pattern of increasing divergence from non-ASD samples with divergence first observed at 12–14 months of age using broad developmental measures (Landa et al., 2006, 2013; Sacrey, Bryson, & Zwaigenbaum, 2013; Zwaigenbaum et al., 2005). As noted by Landa (2012), the atypical developmental trajectories of infants and toddlers later diagnosed with ASD represent a continuum of developmental disruption including developmental deceleration, plateauing, and regression.
Current Study
Author Manuscript
Identification of early developmental profiles in FXS and determination of their shared and unique features in contrast to samples at risk for autism and developmental delay is critical for informing developmental surveillance efforts not only for infants with FXS but also for those groups with features that overlap with those observed in FXS. In the absence of a family history, FXS is diagnosed years after initial symptoms emerge, potentially resulting in a delay of early intervention services which may exacerbate the severity of symptoms over time and increase the likelihood of secondary conditions emerging and uninformed family planning. However, to date, no published study has examined early development of FXS to infants at risk for developmental delay or ASD in the first year of life. Thus, the overarching aim of the current study is to identify the developmental profile in infants with FXS focusing on the age and domain in which delays emerge. Also, we contrast the FXS developmental profile to a typically developing sample and to a sample of ASIBs who are also at high risk for both developmental delays and ASD diagnoses. This cross-group comparison design will enable us to identify divergence from typical development and
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
Roberts et al.
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whether etiology specific developmental profiles can be identified across the high risk etiologically distinct groups. Three research questions guided this work. 1.
Does divergence from typical development differ in infants with FXS contrasted to infant ASIBs?
2.
Are developmental profiles in infants with FXS distinct from typically developing infants and infant ASIBs?
3.
Can developmental profiles on broad developmental domains differentially predict group membership in infants with FXS contrasted to typically developing infants and infant ASIBs?
Author Manuscript
We hypothesized that group differences would be evident by 9 months of age with the FXS group showing greater delays than the ASIB and typically developing group. Additionally, we hypothesized that group membership for the infants with FXS would be accurately discriminated from the typically developing and ASIB groups with clearer distinctions apparent between the infants with FXS and those who are typically developing.
Methods
Author Manuscript
This cross-sectional study was not a single planned study, but rather an amalgamation of data from three sources. The first source was an ongoing longitudinal study on early indicators of ASD in high-risk populations (PI: Roberts; FXS, ASIBs, typically developing), the second was an extant database from a study examining family adaptation to FXS (PI: Bailey; FXS) and the third was the National Database for Autism Research (NDAR), a collective national database for autism research funded by the National Institutes of Health (FXS, ASIBs, typically developing). A more detailed description of the NDAR database, including all relevant child questionnaires, can be found at http://ndar.nih.gov/. Combining data across sources allowed us to examine development across a range of ages for all groups and to maximize our sample size; however, these procedures limited the measures we could include given the variability across sources. Based on the available data we have identified all males 2 years old (up to 28 months) and younger who were unambiguously characterized as falling into one of the three groups of interest and had a complete developmental assessment and basic descriptive data. Outcome data in terms of ASD status were not routinely available; thus, our sample represents infants at high risk for ASD rather than those of known ASD status. Also, our focus was on detection of etiological specific patterns of disrupted development in high risk groups regardless of outcome. Participants
Author Manuscript
Data from a total of 174 infant boys ranging in age from 5 to 28 months (mean age = 15 months) were included in this study. Of the 174 infants, 63 had FXS, 36 were ASIBS, and 75 had no developmental concerns (typical controls). Data ascertainment for the FXS group was primarily through our two research studies (74%) with the rest drawn from the NDAR database. Of the typical group, 36% were recruited through the research studies with the rest sampled from NDAR. For the ASIB group, 69% were recruited through the two large scale studies and the rest drawn from NDAR. Children with FXS were diagnosed through genetic
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testing and all had the full mutation. Autism siblings were identified by having an older sibling with ASD diagnosed by a licensed clinician and documented in a written diagnostic report. Among the ASIBs drawn from our own studies (25:36), we ruled out FXS through a lack of family history or genetic report. For participants drawn from our studies, 45% of the FXS infants and 17% of the ASIBs were receiving early intervention primarily in the form of speech-language intervention and general developmental stimulation. These data are not available from other sources. Typical controls were infants with no family history of ASD or developmental delays, born full-term with no medical complications and with domain and composite scores within 1 standard deviation of the normative mean. In instances where there were multiple assessments for any given participant, we generally selected the earliest age for which complete data were available, given our interest in detecting the emergence of delays. All infants were administered the Mullen Scales of Early Learning (MSEL). Parents provided written consent. Participant ages are summarized in Table 1.
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Measure
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The MSEL (Mullen, 1995), a standardized measure of development for children birth to 69 months of age, was available for all participants. The MSEL was chosen because of its strong reliability and validity and high correlations (r = 0.70) with the Bayley’s Mental Development Index (Bayley, 1993). The MSEL consists of five subscales including gross motor (GM), visual reception (VR), fine motor (FM), receptive language (RL), and expressive language (EL) domains. T-scores are derived for each domain and an Early Learning Composite (ELC) score is derived as a summary of overall development. The Visual Reception, Fine motor, Receptive Communication and Expressive Communication scales contribute to the ELC, a norm-referenced, standardized score (M = 100, SD = 15). The gross motor subdomain was not included in the present study as these data were not available for all participants and are not included in the calculation of the ELC score. For the FXS sample, 11% had scores that met the floor on the ELC (standard score of 49) with the other groups not having participants at the floor. Participants with scores at the floor were not excluded from the analyses because they did show variability on subtest scores and accounted for a minority of our sample. Descriptive statistics on performance on the five Mullen Domains are summarized in Table 2. Procedures
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Assessments for the FXS, typical and ASIB groups recruited through the two large-scale studies were conducted in the participants’ homes by two researchers, with the primary examiner administering the MSEL during the first day of the two-day assessment with completion of the Mullen on the second day as needed (e.g., child fussiness, inattention). Protocols were scored using the computerized scoring software and checked for reliability by trained research assistants. All families gave informed consent before participation. Analyses Statistical analyses were generated using SAS software, version 9.3 of the SAS system for windows (SAS Institute Inc., Cary, NC, USA). Descriptive statistics were used to characterize the sample. First, linear regression models were conducted to investigate the divergence from the typical reference group for the two clinical groups: FXS and ASIBs. J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
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Differences were examined in the Early Learning Composite (ELC) of the MSEL followed by separate examination on the four domains of the MSEL: VR, FM, RL, and EL. Clinical group (FXS, ASIB, or TD), child chronological age and an age by clinical group interaction were included in each regression model. Within each model, to probe the interaction, regions of significance were estimated using Johnson-Neyman techniques (Johnson and Fay, 1950; Hayes and Matthews, 2009) to determine the ages at which MSEL scores diverged from the typical group in our two at risk samples. Results were considered significant at alpha level of .05.
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Second, linear regression models were used to contrast the developmental profiles of infants with FXS to ASIBs at a composite and domain level. Third, discriminant analyses were conducted to predict group membership for the FXS group contrasted to ASIBs from the four Mullen subdomains. Discriminant function analyses are adversely affected by unequal group sizes; thus, we constrained our groups to equal sizes using the sample with the smallest size as the target. If more than one participant matched in age, we randomly selected from the eligible participants. This resulted in 34 ASIBs and 36 TD matched to an equal number of FXS for each analysis. The assumption of equality of the variancecovariance matrices for the groups was not violated, and a linear classification procedure with leave-one-person-out cross validation was used.
Results Divergence from Typical Development in FXS contrasted to ASIBs The first set of analyses contrast the divergence from typical development in infants with FXS and infant ASIBs using both composite and domains of broad development.
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Early Learning Composite—Regression analyses for the ELC revealed a significant difference by group, F (5, 168) = 60.37, p =
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: J Autism Dev Disord. 2016 June ; 46(6): 2088–2099. doi:10.1007/s10803-016-2737-1.
Infant Development in Fragile X Syndrome: Cross-Syndrome Comparisons Jane E. Roberts, Ph.D.1, Lindsay M. McCary, Ph.D.1, Svetlana V. Shinkareva, Ph.D.1, and Donald B. Bailey Jr., Ph.D.2 1University
Author Manuscript
2RTI
of South Carolina
International
Abstract This study examined the developmental profile of male infants with fragile X syndrome (FXS) and its divergence from typical development and development of infants at high risk for autism associated with familial recurrence (ASIBs). Participants included 174 boys ranging in age from 5 to 28 months. Cross-sectional profiles on the Mullen Scales of Early Learning indicated infants with FXS could be differentiated from typically developing infants and ASIBs by 6 months of age. Infants with FXS displayed a trend of lower developmental skills with increasing age that was unique from the typically developing and ASIB groups. Findings suggest infants with FXS present with more significant, pervasive and early emerging delays than previously reported with potentially etiologically distinct developmental profiles.
Author Manuscript
Keywords fragile X syndrome; autism; early development; infants; Mullen
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Fragile X syndrome (FXS) is the most common heritable condition associated with intellectual disabilities and autism spectrum disorder (ASD; Hagerman, Rivera, & Hagerman, 2008). Nearly all post-pubertal males with FXS have an intellectual disability (Bailey et al., 2008) and up to 50 – 75% of males with FXS meet diagnostic criteria for ASD (Kaufmann et al., 2004; Hall, Lightbody, & Reiss, 2008; Harris et al., 2008; Klusek, Martin, & Losh). Despite the high association of intellectual disabilities and ASD in FXS, few studies have examined the emergence of these co-occurring conditions in FXS, and no work has contrasted the developmental profiles of infants with FXS to those at established risk for ASD or developmental delays. In this paper, we examine broad indicators of early development in infants with FXS contrasted to typically developing infants and infants at high risk for adverse developmental outcomes given a family history of ASD. Our goal was
Correspondence to: Jane Roberts, Ph.D., The University of South Carolina, 1512 Pendleton St., Barnwell 224, Columbia, SC 29208, USA. [email protected]. Lindsay McCary, PhD, Waisman Center, University of Wisconsin-Madison, [email protected] Svetlana Shinkareva, PhD, The University of South Carolina Department of Psychology, [email protected] Donald Baily, Jr., PhD, RTI International, [email protected] Lindsay McCary is now at the Waisman Center, University of Wisconsin, Madison.
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to determine if specific profiles of early development could be identified across etiologically distinct groups of infants at elevated risk for ASD and developmental delays.
Author Manuscript
Prospective studies of developmental trajectories in infants later diagnosed with FXS, ASD or developmental delays are critical for a number of reasons. First, in the absence of a family history, the average age of diagnosis for both ASD and FXS is at 3 years of age despite symptoms present in the first year of life (Bailey, Raspa, Bishop, & Holiday, 2009; Matthews, Goldberg, & Lukowski, 2013). Thus, refined characterization of the infant phenotype in ASD and FXS has the potential to identify markers that could be useful for earlier and more specific diagnosis resulting in early treatment. Second, describing early developmental profiles of etiologically distinct groups of infants at high risk for ASD is important to address the latent heterogeneity present in ASD. Studies targeting crosssyndrome comparisons in ASD are notably lacking particularly work with young children and infants. This work can be highly informative to address commonalities and similarities across “the autisms”. Third, documenting early developmental profiles can identify behavioral or cognitive factors associated with vulnerability to later-emerging symptoms or secondary disorders (e.g., attention deficits, anxiety) both within and across etiology-specific groups. Fourth, cross-syndrome developmental studies can document individual differences or unanticipated age-related patterns of development that could affect treatment response (e.g., shift from hypo to hyper-arousal) that could be etiologically distinct.
Early Development in Fragile X Syndrome
Author Manuscript
Two longitudinal studies of broad development including toddlers or young children with FXS exist. In the first study, 46 boys with FXS between the ages of 24 and 72 months were followed every 6 months for an average of 2 years and a total of 185 assessments (Bailey, Hatton, & Skinner, 1998). As reflected on the Battelle Developmental Inventory (Newborg, Stock, Wnek, Guidubaldi, & Svinicki, 1984), boys with FXS made stable developmental gains; however, their rate of development was approximately half that expected for typically developing children. Boys with FXS were significantly delayed in Cognitive, Communication, Adaptive, Motor and Personal-Social domains at all ages, with Motor and Adaptive Behavior scores consistently higher than Communication and Cognitive scores. No comparison group, measures of autistic behavior or participants less than 2 years of age were included in this study.
Author Manuscript
A subsequent study included repeated assessments of 55 boys with FXS between the ages of 8 and 68 months of age using the MSEL with a mean of 3.4 assessments per child for a total of 189 assessments (Roberts et al., 2009). Results indicated that infants and young children with FXS made developmental gains over time, albeit at a rate about half that of typically developing children as shown in the initial study with older aged children (Bailey et al., 2008). A decline in the rate of development was not evident as had been reported elsewhere with older aged children with FXS (Lachiewicz, Gullion, Spiridigliozzi, & Aylsworth, 1987). Delays were initially evident by 9 months of age in the total score and in the Receptive and Expressive Language domains with delays in Visual Reception emerging at 10 months of age followed by delays in Fine Motor emerging at 13 months of age. Increased severity of autistic behavior, as measured by the Childhood Autism Rating Scale (CARS;
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
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Schopler et al., 1988), was strongly associated with more severe delays across all domains particularly in Communication and Fine Motor domains (Roberts et al., 2009).
Author Manuscript
Given the clear co-occurrence of ASD diagnoses and features in FXS, studies that examine early development and the emergence and stability of ASD features are important both for refining the phenotype of FXS and for contributing to the disassociation of these two syndromes. However, few studies have been published on the development of children with FXS less than 5 years of age and only a handful of recent studies have examined early emerging features of autism or cross-syndrome comparisons of early development in FXS. Initial work examining broad developmental indicators in young children with FXS compared to those with idiopathic ASD and those with both FXS and ASD, report mixed findings. Some work suggested that children (21 months of age and older) with FXS and comorbid ASD exhibited more significant delays, particularly in Fine and Gross Motor domains, than children with FXS alone and those with ASD alone (Bailey, Hatton, Mesibov, Ament, & Skinner, 2000). However, a different study found that young children with FXS and ASD were highly similar to those with idiopathic ASD and that young children with FXS without ASD resembled those with non-specific developmental delays (Rogers, Wehner, & Hagerman, 2001). More recent work focusing on infants and the emergence of autistic features in FXS suggests that visual attention is atypical in infants with FXS as young as 9 months of age and is associated with later emerging autistic behavior (Roberts, Hatton, Long, Anello, & Colombo, 2012) with arousal dysregulation implicated mechanistically (Roberts, Tonnsen, Robinson, & Shinkareva, 2012).
Author Manuscript
In summary, there are few studies of early development in FXS, and no studies exist that contrast broad development in infants with FXS to infants at risk for ASD. Existing work suggests that developmental delays emerge by 9 months of age and that development in these first 2 years of life is strongly negatively impacted by the severity of autistic behavior suggesting some similarities to early developmental patterns of infants with an older sibling diagnosed with ASD (ASIBs); however, syndrome specific differences have not been directly investigated during infancy.
Early Development in Autism
Author Manuscript
Given that the presence of an intellectual disability is one of the primary factors accounting for outcomes in children with ASD (Vivanti, Barbaro, Hudry, Dissanayake, & Prior, 2013) with 37% of preschool children with ASD meeting criteria for an intellectual disability (Rivard, Terroux, Mercier, & Parent-Boursier, 2015), efforts to document the early developmental profiles in young children at risk for ASD have accelerated. In fact, the emergence of empirically grounded diagnostic algorithms has been proposed based, in part, on developmental trajectories to predict the primary classifications of unaffected (~59%), social/communication delay or broader autism phenotype (11%) and ASD with and without co-morbid intellectual disability (~25%) (Landa, Gross, Stuart, & Bauman, 2012). Thus, studies that examine the developmental diversity within high risk groups without regard to diagnostic status are highly informative (Landa et al., 2012) with cross-syndrome comparisons as an important component of these efforts.
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
Roberts et al.
Page 4
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The bulk of recent work describing the early development of children with ASD has been prospective and longitudinal typically targeting ASIBs as a high risk group, given the increased recurrence rate of autism in approximately 20% of cases (Jones, Gliga, Bedford, Charman, & Johnson, 2014; Landa & Garrett-Mayer, 2006; Rice et al., 2007). The bulk of the prospective longitudinal work (Landa & Garrett-Meyer, 2006; Landa, Gross, Stuart & Fahery, 2013; Zwaigenbaum et al., 2005; see Jones et al., 2014 for a review) report a general absence of developmental markers at 6 months with features emerging between 12 −14 months in communication domains for ASIBs later diagnosed with ASD compared to typical controls and ASIBs who did not meet later diagnostic criteria for autism. Developmental profiles unique to diagnostic outcome have begun to emerge with evidence suggesting 4 distinct classes of high risk infants. Classes include a normative development group, a language/motor delay group, a developmental slowing group, and an accelerated development group (Landa et al., 2012). Unaffected ASIBs primarily fell in the accelerated and normative classes, and most ASIBs with the broader autism phenotype fell in the normative or language delay class. The majority of ASIBs later diagnosed with autism fell in the developmental slowing class. However, there was more variability in class placement for those diagnosed late who were distributed fairly equally across the normative, language/ motor delay and developmental slowing classes in contrast to those identified early who primarily fell in the developmental slowing class.
Author Manuscript
Taken together, research on the early development of infants later diagnosed with autism reflects important age-related trajectories. Developmental skills appear generally intact through 6 months of age followed by a pattern of increasing divergence from non-ASD samples with divergence first observed at 12–14 months of age using broad developmental measures (Landa et al., 2006, 2013; Sacrey, Bryson, & Zwaigenbaum, 2013; Zwaigenbaum et al., 2005). As noted by Landa (2012), the atypical developmental trajectories of infants and toddlers later diagnosed with ASD represent a continuum of developmental disruption including developmental deceleration, plateauing, and regression.
Current Study
Author Manuscript
Identification of early developmental profiles in FXS and determination of their shared and unique features in contrast to samples at risk for autism and developmental delay is critical for informing developmental surveillance efforts not only for infants with FXS but also for those groups with features that overlap with those observed in FXS. In the absence of a family history, FXS is diagnosed years after initial symptoms emerge, potentially resulting in a delay of early intervention services which may exacerbate the severity of symptoms over time and increase the likelihood of secondary conditions emerging and uninformed family planning. However, to date, no published study has examined early development of FXS to infants at risk for developmental delay or ASD in the first year of life. Thus, the overarching aim of the current study is to identify the developmental profile in infants with FXS focusing on the age and domain in which delays emerge. Also, we contrast the FXS developmental profile to a typically developing sample and to a sample of ASIBs who are also at high risk for both developmental delays and ASD diagnoses. This cross-group comparison design will enable us to identify divergence from typical development and
J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
Roberts et al.
Page 5
Author Manuscript
whether etiology specific developmental profiles can be identified across the high risk etiologically distinct groups. Three research questions guided this work. 1.
Does divergence from typical development differ in infants with FXS contrasted to infant ASIBs?
2.
Are developmental profiles in infants with FXS distinct from typically developing infants and infant ASIBs?
3.
Can developmental profiles on broad developmental domains differentially predict group membership in infants with FXS contrasted to typically developing infants and infant ASIBs?
Author Manuscript
We hypothesized that group differences would be evident by 9 months of age with the FXS group showing greater delays than the ASIB and typically developing group. Additionally, we hypothesized that group membership for the infants with FXS would be accurately discriminated from the typically developing and ASIB groups with clearer distinctions apparent between the infants with FXS and those who are typically developing.
Methods
Author Manuscript
This cross-sectional study was not a single planned study, but rather an amalgamation of data from three sources. The first source was an ongoing longitudinal study on early indicators of ASD in high-risk populations (PI: Roberts; FXS, ASIBs, typically developing), the second was an extant database from a study examining family adaptation to FXS (PI: Bailey; FXS) and the third was the National Database for Autism Research (NDAR), a collective national database for autism research funded by the National Institutes of Health (FXS, ASIBs, typically developing). A more detailed description of the NDAR database, including all relevant child questionnaires, can be found at http://ndar.nih.gov/. Combining data across sources allowed us to examine development across a range of ages for all groups and to maximize our sample size; however, these procedures limited the measures we could include given the variability across sources. Based on the available data we have identified all males 2 years old (up to 28 months) and younger who were unambiguously characterized as falling into one of the three groups of interest and had a complete developmental assessment and basic descriptive data. Outcome data in terms of ASD status were not routinely available; thus, our sample represents infants at high risk for ASD rather than those of known ASD status. Also, our focus was on detection of etiological specific patterns of disrupted development in high risk groups regardless of outcome. Participants
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Data from a total of 174 infant boys ranging in age from 5 to 28 months (mean age = 15 months) were included in this study. Of the 174 infants, 63 had FXS, 36 were ASIBS, and 75 had no developmental concerns (typical controls). Data ascertainment for the FXS group was primarily through our two research studies (74%) with the rest drawn from the NDAR database. Of the typical group, 36% were recruited through the research studies with the rest sampled from NDAR. For the ASIB group, 69% were recruited through the two large scale studies and the rest drawn from NDAR. Children with FXS were diagnosed through genetic
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testing and all had the full mutation. Autism siblings were identified by having an older sibling with ASD diagnosed by a licensed clinician and documented in a written diagnostic report. Among the ASIBs drawn from our own studies (25:36), we ruled out FXS through a lack of family history or genetic report. For participants drawn from our studies, 45% of the FXS infants and 17% of the ASIBs were receiving early intervention primarily in the form of speech-language intervention and general developmental stimulation. These data are not available from other sources. Typical controls were infants with no family history of ASD or developmental delays, born full-term with no medical complications and with domain and composite scores within 1 standard deviation of the normative mean. In instances where there were multiple assessments for any given participant, we generally selected the earliest age for which complete data were available, given our interest in detecting the emergence of delays. All infants were administered the Mullen Scales of Early Learning (MSEL). Parents provided written consent. Participant ages are summarized in Table 1.
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Measure
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The MSEL (Mullen, 1995), a standardized measure of development for children birth to 69 months of age, was available for all participants. The MSEL was chosen because of its strong reliability and validity and high correlations (r = 0.70) with the Bayley’s Mental Development Index (Bayley, 1993). The MSEL consists of five subscales including gross motor (GM), visual reception (VR), fine motor (FM), receptive language (RL), and expressive language (EL) domains. T-scores are derived for each domain and an Early Learning Composite (ELC) score is derived as a summary of overall development. The Visual Reception, Fine motor, Receptive Communication and Expressive Communication scales contribute to the ELC, a norm-referenced, standardized score (M = 100, SD = 15). The gross motor subdomain was not included in the present study as these data were not available for all participants and are not included in the calculation of the ELC score. For the FXS sample, 11% had scores that met the floor on the ELC (standard score of 49) with the other groups not having participants at the floor. Participants with scores at the floor were not excluded from the analyses because they did show variability on subtest scores and accounted for a minority of our sample. Descriptive statistics on performance on the five Mullen Domains are summarized in Table 2. Procedures
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Assessments for the FXS, typical and ASIB groups recruited through the two large-scale studies were conducted in the participants’ homes by two researchers, with the primary examiner administering the MSEL during the first day of the two-day assessment with completion of the Mullen on the second day as needed (e.g., child fussiness, inattention). Protocols were scored using the computerized scoring software and checked for reliability by trained research assistants. All families gave informed consent before participation. Analyses Statistical analyses were generated using SAS software, version 9.3 of the SAS system for windows (SAS Institute Inc., Cary, NC, USA). Descriptive statistics were used to characterize the sample. First, linear regression models were conducted to investigate the divergence from the typical reference group for the two clinical groups: FXS and ASIBs. J Autism Dev Disord. Author manuscript; available in PMC 2017 June 01.
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Differences were examined in the Early Learning Composite (ELC) of the MSEL followed by separate examination on the four domains of the MSEL: VR, FM, RL, and EL. Clinical group (FXS, ASIB, or TD), child chronological age and an age by clinical group interaction were included in each regression model. Within each model, to probe the interaction, regions of significance were estimated using Johnson-Neyman techniques (Johnson and Fay, 1950; Hayes and Matthews, 2009) to determine the ages at which MSEL scores diverged from the typical group in our two at risk samples. Results were considered significant at alpha level of .05.
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Second, linear regression models were used to contrast the developmental profiles of infants with FXS to ASIBs at a composite and domain level. Third, discriminant analyses were conducted to predict group membership for the FXS group contrasted to ASIBs from the four Mullen subdomains. Discriminant function analyses are adversely affected by unequal group sizes; thus, we constrained our groups to equal sizes using the sample with the smallest size as the target. If more than one participant matched in age, we randomly selected from the eligible participants. This resulted in 34 ASIBs and 36 TD matched to an equal number of FXS for each analysis. The assumption of equality of the variancecovariance matrices for the groups was not violated, and a linear classification procedure with leave-one-person-out cross validation was used.
Results Divergence from Typical Development in FXS contrasted to ASIBs The first set of analyses contrast the divergence from typical development in infants with FXS and infant ASIBs using both composite and domains of broad development.
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Early Learning Composite—Regression analyses for the ELC revealed a significant difference by group, F (5, 168) = 60.37, p =
