Quantitative Measures of Motor Function in Children with Duplications of 15q11.3-13.1 (Dup15q Syndrome) and Typically Developing (TD) Children.

Background: Motor skills are critical for the development of more complex social behaviors and overall cognitive development (Iverson, 2010; Karasik et al, 2012). Impairments in motor skills, specifically in gait, are prevalent in children with Autism Spectrum Disorders (ASD) and represent an important area for intervention to improve functional outcomes. Due to limitations in available standardized assessments, motor impairments in individuals with ASD are poorly quantified and understood. Impairments in gait are quantifiable and translatable measures of motor skills that provide insight into overall motor development and are directly related to social communication skills. In this study we utilize the Protokinetics Zeno Walkway to quantify kinematic variables of gait in children with Dup15q Syndrome, the most common copy number variant associated with ASD, and highly penetrant for motor delays (DiStefano et al, 2016). Preclinical models of Dup15q syndromes have specific gait impairments. We also compare gait variables to social communication skills using the Social Responsiveness Scale (SRS) (Constantino et al, 2012).

Objectives: To compare quantitative measures of gait, including stride width, cadence (steps/minute), and gait variability index (GVI), in children with Dup15q Syndrome and Typically Developing (TD) children and to evaluate the relationship between measures of gait and social communication.

Methods: Participants included 28 children with Dup15q Syndrome ages 3-15 years (Mean, 8 years). TD data included TD siblings and normative gait data. Children completed four trials of walking. Multiple kinematic variables of gait were extracted with specific focus on mean cadence, stride width, and GVI. Differences between group gait variables in Dup15q syndrome and TD were compared using Mann-Whitney U tests. Correlations were used to determine the relationship between cadence and step width to total T Scores on the preschool and school aged SRS.

Results: See table 1 for detailed statistical analysis and results. Significant differences were seen in stride width and GVI but not in cadence between groups. Expected markers of developmental maturity of motor function, such as reduction in cadence, step width, and GVI were not seen in children with Dup15q syndrome. Increased step width was positively correlated with increased preschool and school aged SRS scores (R= 0.38). When looking only at school aged SRS there was greater association with step width (R= 0.57). Cadence was negatively correlated with SRS scores (R= -0.002).

Conclusions: Gait patterns in Dup15q syndrome were strikingly similar to gait patterns reported in the Dup15q mouse model, specifically in increased stride width and decreased cadence which likely represent lack of stability, reduced strength, and overall motor dysfunction (Figure 1). Children with Dup15q syndrome show persistent abnormalities and delayed neuromotor maturation of gait. Children with greater motor dysfunction characterized by increased stride width and decreased cadence showed greater impairments in social communication. These findings not only establish feasibility of these motor measures, but they also emphasize their potential value as translational biomarkers in Dup15q syndrome. Use of this quantitative measure of motor function can aid in identifying biomarkers of clinical stratification, treatment targets, and meaningful outcome measures of clinical trials in ASD.