Background
Autism spectrum disorder (ASD) affects 50–70% of males with fragile X syndrome [
1‐
4] (FXS), which is the leading heritable cause of intellectual disability (ID) [
5]. FXS is an X-linked disorder caused by a mutation in the
Fragile X Mental Retardation 1 (FMR1) gene [
6,
7] that affects approximately 1 in 4000 to 8000 individuals [
8,
9]. There are many shared features between FXS and ASD, including impairments in language, social communication, and adaptive functioning; however, there is an important phenotypic distinction as well. For example, virtually all individuals with FXS experience ID [
9], compared to only approximately 30% of individuals with ASD [
10]. Several decades of research highlight the complex relationships between ASD and FXS, with some debate as to whether ASD should be conceptualized as part of the FXS phenotype, versus distinct comorbidity [
11]. Most of this debate has focused on children and adolescents with FXS and/or ASD; however, prior work on ASD in young children with FXS [
12,
13] suggests that a subset of children with FXS do in fact follow a differentiable developmental trajectory consistent with a clinical diagnosis of ASD. Nevertheless, many questions remain about the nature of ASD in FXS, particularly during early development. As such, prospective longitudinal examination of infants with FXS provides opportunities for increased understanding of the onset and early developmental course of ASD among children with increased genetic liability for ASD.
Motor impairments are commonly reported among individuals with non-syndromic ASD (nsASD, ASD unassociated with FXS or any other particular syndrome) [
14] as well as in FXS, irrespective of comorbid outcomes [
15]. In typical development, motor skills provide a critical developmental foundation for many of the abilities that are impaired in ASD, including language and communication [
16], imitation, attentional control [
17], and social cognition [
18‐
21]. Early motor experiences afford greater opportunities for interaction with the environment, the development of representations of the self and others as agents, and an expansion of one’s attention and communication repertoire [
20‐
22]. Accordingly, emergent evidence suggests that early motor impairments in some children may contribute to the development or enhanced severity of certain ASD features [
19,
21,
23‐
25].
Gross motor skills are in fact associated with social communication and language development in ASD and high-risk populations [
23,
26,
27]. For example, high-risk infants who have acquired independent walking have better social communication skills than high-risk infants of the same age and cognitive level who are not yet walking [
23]. For these infants, motor delays may directly influence social communication skills; or, alternatively, these infants may experience a propensity for both motor and social communication delays resulting from added genetic liability [
28]. Recent work substantiates a link between motor impairments and increased genetic liability in some children with ASD [
29,
30]. Specifically, delayed onset of independent walking in children with ASD ascertained via the Simons Simplex Collection (SSC) is associated with an increased likelihood of an ASD-associated de novo mutation [
29,
30]. Further delineation of motor impairments in FXS may therefore contribute to an enhanced understanding of the link between genetic liability, motor impairment, and ASD.
Motor impairments emerge during infancy in FXS and, unlike most cases of ASD, are often one of the first notable signs of atypical development, with parents reporting increased atypical motor behaviors [
31] and delayed motor skill acquisition [
15,
32]. Fine motor skills diverge from typical development as early as 6 [
33] and 9 months in FXS [
34], and impairments in fine, as well as gross motor, persist across development [
13,
33,
35,
36]. Motor impairments may be even more pronounced in children with co-occurring FXS and ASD [
12,
32,
35], as parent-report gross motor skills are significantly more delayed in children with FXS with ASD than those with FXS only [
32]. In addition, motor impairments have emerged as the most salient predictor in the infancy of a later diagnosis of ASD in FXS [
12]. On direct assessment measures, fine motor skills are associated with ASD severity in children with FXS between 8 and 68 months old [
34], and motor impairments observed via direct assessment in 12-month-old infants predict ASD outcomes at 24 months of age in FXS [
12]. Thus, it is possible that motor impairments may also serve as an early sign of co-occurring ASD in FXS.
A major challenge in this area of research is that motor and cognitive development are inextricably linked, informing one another across development [
20,
37‐
40]. In addition, motor and cognitive ability are more closely related in populations with ID relative to typical development [
40]. Thus, the role of motor vulnerabilities as a unique facilitator or indicator of the development of ASD in FXS, independent of overall cognitive impairments characteristic of FXS, has not been firmly established. For example, Zingerevich et al. [
35] (2009) found that differences in directly observed fine motor skills in children with FXS between 12 and 76 months old with and without co-occurring ASD were accounted for by differences in visual reception skills. Furthermore, direct assessment of fine and gross motor skills in younger children (i.e., 21 and 48 months) with FXS indicated no significant differences as a function of ASD comorbidity, but both FXS groups showed significantly poorer motor repertoires than children with ASD without a genetic diagnosis [
13].
With growing evidence that early trajectories may provide insights into different etiologies of ASD, it is critical to understand the role of motor impairments in ASD in FXS while also considering cognitive abilities. Thus, the current study aims to identify potential differences in developmental trajectories in both gross and fine motor skills between infants and young children with FXS with and without ASD. In addition, we examine motor impairments across both direct assessment and parent-report measures to capture the unique information about motor development provided by these two sources. Furthermore, we aim to isolate motor impairments as a potential mechanism of ASD by controlling for nonverbal cognitive abilities using a nonverbal developmental quotient (NVDQ).
Our specific research questions are as follows:
1)
At what point do fine and gross motor trajectories in children with FXS, with and without ASD, diverge from typical development?
2)
Do early trajectories of fine and gross motor development differ between children with FXS who do and do not go onto be diagnosed with ASD?
Discussion
The present study takes an initial step towards characterizing the role of motor impairments and their implications for ASD in FXS. This study is the first to examine divergence in motor trajectories between children with FXS with and without comorbid ASD across direct observation and parent-report measures of both fine and gross domains of motor development. Furthermore, this study is also among the first to account for delays in cognitive development, a construct closely related to motor development, using a measure of nonverbal cognition that is relatively independent of motor skills.
Trajectories of children with FXS with co-occurring ASD diverged from those of typically developing children in both gross and fine motor domains by 9 months old, and these differences were consistent across direct assessment and parent-report measures (see also ref. [
12,
32]). Interestingly, the FXS-only group began to show differences by 9 months, but only directly assessed gross motor and parent-report fine motor differences were statistically significant prior to 12 months. We also found significant divergence in fine and gross motor trajectories between FXS + ASD and FXS early in life, even after accounting for general cognitive delays. Infants with FXS + ASD showed decelerated fine and gross motor development compared to those with FXS-only, resulting in lower skills as early as 12 months, differences which reached statistical significance by 18 months and became greater over time. Trajectories diverged even when controlling for NVDQ, indicating that motor differences could not be fully explained by greater cognitive delays in those with FXS and ASD. These results provide initial insight into fundamental differences in the motor skills of those with FXS + ASD and those with FXS-only, indicating a potential key role of motor in the development of ASD in children with FXS.
As this is a first step in identifying differences in motor repertoires of children with FXS who go on to develop ASD versus those that do not, unanswered questions regarding these motor differences remain. Motor may serve as a catalyst for a disrupted developmental cascade [
48], leading to an enhanced presentation of ASD features for some children with FXS, who already have an underlying vulnerability to develop ASD. That is, early motor impairments may place constraints on other developmental processes, specifically attention, that lead to less optimal social [
18,
23] and cognitive [
37,
49‐
51] outcomes evident in those with FXS and ASD [
12,
13]. Given that motor development is a self-refining process that requires system-level organization along with input from one’s environment [
20], motor delays with concurrent ASD and additional genetic liability may enact a multiplicative effect [
52], resulting in diminished developmental outcomes for those with FXS and ASD. The disruption in this developmental pathway may account for generally lower cognitive abilities in those with FXS and ASD compared to those with FXS-only [
13]. The timing and persistence of motor differences as a function of ASD status across both direct assessment and parent-report measures suggests that motor impairments may also play a vital role in development for children with FXS and ASD, particularly related to language [
26,
27], social communication [
23], and adaptive outcomes [
53]. It is also possible that poorer motor skills in the FXS + ASD partially resulted from, or were made even worse by having ASD. For example, deficits in imitation skills and reduced motivation to perform certain activities could have negatively affected the acquisition of more advanced motor skills for children with FXS and ASD.
There is an additional possibility that motor impairments identified in those with FXS with ASD signal rare genetic mutations not present in those with FXS only [
29,
30]. Additional damaging de novo mutations are associated with motor impairments in children with ASD [
29,
30], and these associations are the target of future research. Thus, it is possible that motor impairments in those with FXS and ASD reflect an undetected genetic etiology [
30]. Characterizing potential underlying de novo mutations in the present sample was beyond the scope of this study and further work is necessary to determine underlying etiological mechanisms of motor impairments in FXS, in general, but particularly in those with FXS and ASD.
Limitations
Although the present study was the first to examine prospective longitudinal trajectories of both gross and fine motor development in children with FXS with and without ASD across direct assessment and parent report, it is not without limitations. One limitation includes the lack of comparison to another neurogenetic group also at risk for ASD. Such comparisons can yield better insight into the role of motor impairments in the development of ASD by elucidating what impairments may exist as a feature of neurogenetic etiology versus ASD risk with greater specificity than in FXS alone. Another potential limitation is the focus on motor development specifically, rather than other aspects of motor impairments such as motor stereotypies, which should be included in future work on FXS and concurrent ASD as this may also further delineate these groups [
31]. An additional limitation relates to the measurement of motor skills while accounting for general cognitive ability. Assessment of motor abilities is somewhat constrained by currently available measures, designed to assess broad development rather than precise motor skills. While additional work is necessary to more carefully characterize the nature of motor impairments in FXS, longitudinal examination of gains in motor abilities over time contribute to our fundamental understanding of motor impairments in FXS and their role in the presence of concurrent FXS and ASD. In addition, although a close estimate of cognitive functioning, the visual reception domain of the MSEL is not a comprehensive estimate of cognitive level and requires motor planning in some responses. Future work to develop more precise motor measures may circumvent collinearity issues with other measures of the cognitive level. Finally, although the present sample size is quite robust considering the prevalence of FXS, it may impose limits on the statistical power to detect small to medium effects. Furthermore, our sample was variable across age intervals, and relatively sparse at some ages. As such, findings related to the timing of developmental divergence in motor trajectories between FXS and FXS + ASD identified in the present study are, in some cases, based on relatively small samples. Future work should aim for replication in larger samples.
Future directions and conclusions
Increased attention has focused on characterizing the nature and role of motor impairments in ASD. Examining prospective longitudinal trajectories of motor development in an etiologically distinct genetic subgroup of ASD, such as FXS, can further our understanding of what role motor impairments serve as a catalyst or consequence of ASD, or alternatively, a result of additional genetic risk, ID, and/or ASD. The present study findings suggest that divergence in motor development may occur independently of cognitive impairment and therefore contribute to and/or serve as a marker of concurrent ASD in FXS. Future work should aim to identify the direction of influence between motor and other important areas of development, such as cognition, language, and attention, as well as the underlying mechanisms and long-term consequences of motor impairments in FXS. These efforts may provide insight into the role of motor impairments as a catalyst or outcome of ASD-related risk in FXS.
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