Abstract
Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.
In a cohort of 74 subjects, the Peabody Developmental Motor Scales–2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales–2 scores within a genotype was assessed by interquartile ranges (IQRs).
Peabody Developmental Motor Scales–2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).
This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales–2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.
Aicardi-Goutières syndrome (AGS) is a rare genetic disorder resulting in a broad spectrum of neurologic dysfunction.1–3 Aicardi-Goutières syndrome results from pathogenic variants in 9 genes involved in nucleic acid sensing/metabolism or histone pre–messenger RNA processing.4,5 Children with Aicardi-Goutières syndrome demonstrate atypical neurologic development, with delayed acquisition of motor and cognitive developmental skills and psychomotor regression.2,3 Although the spectrum of gross motor dysfunction has been well characterized,6,7 there is a lack of understanding surrounding the fine motor and visual-motor abilities of this population. These fine motor and visual skills are critical for developmental milestones, play, academic success, activities of daily living, and access to adaptive technology.8–11 In general pediatric populations, fine motor and visuomotor skills correlate with academic success and predicting language and cognitive function.8,9,12
The AGS Severity Scale, a validated disease-specific tool, captures therapeutic response and overall neurologic progression. 6 This scale, however, largely neglects fine motor skills, allocating 1 point out of a maximum of 11 for the ability to self-feed or execute pincer grasp. 6 Although the AGS Severity Scale successfully captures overall function, there is an unmet need for additional validated sensitive outcome measures able to better measure fine motor and visual motor function. A tool with robust construct validity, internal consistency, and reproducibility 13 is needed in this population to guide services, therapies, and equipment selection. 14
The Peabody Developmental Motor Scales–Second Edition (PDMS-2) is a tool developed to describe the gross motor and fine motor skills of a pediatric population up to the age of 6 years. 15 It has proven to be a reliable tool,16,17 able to show concurrent validity with other pediatric psychometric assessments, such as the Bayley-III. 18 Rehabilitative and early intervention therapists often use this tool for assessment of function in a pediatric population, as well as to determine potential appropriate interventions. 19 The Peabody Developmental Motor Scales–2 has been successfully applied to individuals with cerebral palsy, 20 trisomy 21, 21 autistic spectrum disorder, 22 and Pompe Disease. 23
The main objective of our study is to characterize the fine and visual motor functional abilities of individuals with a diagnosis of Aicardi-Goutières syndrome through the administration of the Peabody Developmental Motor Scales–2 grasping and visual-motor integration subtests. The secondary aim of this study is to determine the association between fine and visual motor function along with overall severity.
Methodology
Cohort
Subjects were recruited, and they provided consent/assent as appropriate, as part of a leukodystrophy registry, the IRB-approved Myelin Disorders Biorepository Project (MDBP). All subjects had a confirmed diagnosis of Aicardi-Goutières syndrome, both by genetic testing and clinical testing, were included in the statistical analysis. Inclusion criteria for enrollment were as follows: clinically and molecularly confirmed diagnosis of Aicardi-Goutières syndrome, completion of the Peabody Developmental Motor Scales–2 and availability of a research encounter scorable for or including an Aicardi-Goutières syndrome Severity Scale score. All individuals enrolled under MDBP qualifying for this study were included in this study.
Data Extraction and Collection
Peabody Developmental Motor Scales–2 case report forms were collected from all participants. Peabody Developmental Motor Scales–2 individual item responses were extracted from scoring booklets and verified by a second provider. Two trained pediatric neurologists determined the AGS Severity Scale scores. Information including sex, age at evaluation, genotype, and AGS Severity Scale Scores were derived from concurrent medical notes for the entire cohort. Age at disease onset was calculated as previously described 2 and study data were managed using REDCap tools hosted at Children's Hospital of Philadelphia.24,25
Outcome Measures
The Peabody Developmental Motor Scales–2 was administered by licensed occupational therapists. All providers underwent a training process provided by the Institution and successfully completed an interrater reliability process prior to participation to this research project. The Peabody Developmental Motor Scales–2 is an assessment designed to explore motor function in the pediatric population. 26 Normative data are available within the 0-72 months age range. The Fine Motor Quotient 26 of the Peabody Developmental Motor Scales–2 is composed of grasping and visual-motor integration subdomains. The grasping subtest is composed of 26 items, whereas the visual-motor integration is composed of 72 items. Each item can be scored within a range of 0-2 (grasping raw scores range 0-52, visual-motor integration raw scores range 0-144). Scores of 0 represent inability to attempt item completion, scores of 1 represent a clear resemblance to the item mastery criteria without fully meeting the criteria, whereas scores of 2 represent mastery of the item. 26 The raw score was calculated per the standardized administration protocol. The assessment was administered to all enrolled individuals, independently of their age. Because of the large proportion of subjects outside the normative age range (N = 28, 37.84% of the cohort), fine motor performance of the population was captured by the use of raw scores only rather than the age-based normative data. Raw scores are associated with age equivalents. As there is no current agreement on the definition of floor and ceiling effect at the Peabody Developmental Motor Scales–2 raw scores, floor and ceiling effects were respectively determined as scores lower than 10% of maximum raw scores, and higher than 90% of maximum raw scores, respectively (grasping: floor <6, ceiling >46; visual motor integration: floor <15, ceiling >129). Administration time of the Peabody Developmental Motor Scales–2 varied from 15 to 45 minutes.
Two pediatric neurologists trained in using the tool determined the AGS Severity Scale scores. The AGS Severity Scale is a disease-specific tool (range 0-11) that captures postural control, mobility, fine motor function, communication, social smile, and presence or absence of microcephaly. 6 The AGS score extracted from the medical documentation most recent to the Peabody Developmental Motor Scales–2 administration was used for comparison. The average time elapsed between Peabody Developmental Motor Scales–2 and AGS Severity Scale score was 1.05 days (median 0, range 0-29 days). As previously described, the Aicardi-Goutières syndrome population was divided into cohorts by severity: severe (range 0-3), moderate (range 4-8), and attenuated (range 9-11). 6
Statistical Analysis
SAS 9.4 was used for analysis with 2-sided tests and an alpha level of 0.05 as the criterion for statistical significance. 27 Descriptive and correlative statistics were used to compare Peabody Developmental Motor Scales–2 grasping and visual-motor integration subtest, with the AGS Severity Scale scores. Descriptive statistics included frequency and percentages for categorical variables and computation of means, standard deviations (SDs), medians, ranges (minimum to maximum values), and IQR of continuous variables. Spearman rank correlation coefficient was used to analyze correlations with AGS Severity Scale scores. 28 Genotypes with fewer than 2 individuals were excluded from genotype-specific analysis because of the limited cohort size (RNU7-1). Disease severity categories were defined by AGS Severity Scale scores 0 to 3 as severe, 4 to 8 as moderate, and 9 to 11 as attenuated. Kruskal-Wallis test with Dunn test for multiple comparisons was used for comparisons across genotype groups and severity categories. The RNASEH2A, -2B, and -2C genotypes were grouped in the RNASEH2- group because of common mechanism.
Results
Demographics
Overall, 74 individuals (42 males, 56.76%) were included in the study (Table 1). Eight genotypes associated with Aicardi-Goutières syndrome were represented in the study cohort: 14 TREX1 (18.92%), 25 RNASEH2A/2B/2C (33.78%), 13 SAMHD1 (17.57%), 13 ADAR1 (17.57%), 8 IFIH1 (10.81%), and 1 RNU7-1 (1.35%). The mean chronologic age at assessment date was 6.41 years (SD 5.88, range 0.18-22.72, IQR 5.61). The average age at disease onset was 0.56 years (median 0.25, SD 0.73, range 0.00-3.02, IQR 0.90). When considering the stratification of the population by clinical severity, the severe group had a mean chronologic age at assessment of 5.28 years (SD 5.75, range 0.18-22.37, IQR 5.3), the moderate group had a mean chronologic age at assessment of 4.47 years (SD 3.84, range 0.43-18.85, IQR 2.68), whereas the attenuated group had a mean chronologic age at assessment of 11.22 years (SD 5.95, range 2.77-22.72, IQR 10.41).
Cohort Demographic Description.
Abbreviations: IQR, interquartile range; PDMS-2, Peabody Developmental Motor Scales–2nd Edition; SD, standard deviation.
Fine Motor Skills in Aicardi-Goutières syndrome
All 74 individuals underwent the administration of the Peabody Developmental Motor Scales–2 grasping and visual-motor integration subtests. Overall, the performance of the population was representative of a broad spectrum of functional abilities. The average overall performance by the grasping subtest was 21.41 points (median 11.50, SD 20.37, IQR 41), with TREX1 and RNASEH subgroups showing the lowest performance (median 4.5, 7 points respectively). The TREX1 cohort showed the least variability in grasping performance, with the largest being SAMHD1 (IQR: 10.00, 51.00 points respectively) (Figure 1A, Table 2). Performance by age equivalent is represented in Table 2.
Assessment of fine motor function in Aicardi-Goutières syndrome by Peabody Developmental Motor Scales–2. Each individual is represented by a single dot.
Cohort Performance at the PDMS-2 Grasping and VMI Subtests (Raw Scores and AE).
Abbreviations: AE, age equivalents; PDMS-2, Peabody Developmental Motor Scales–2nd Edition; VMI, visual-motor integration.
The average overall performance at the visual-motor integration subtest was 51.36 points (median 17, SD 55.20, IQR 93), with TREX1 and RNASEH- subgroups showing the lowest performance (median 0.5 and 10, respectively). Variability of performance was then explored by genotype: TREX1 cohort showed the smallest IQR, with the largest being SAMHD1 and IFIH1 (12 vs 132 and 134, respectively) (Figure 1B, Table 2). Performance by age equivalent is represented in Table 2.
To assess the correlation of captured fine motor skills with overall severity, AGS Severity Scale scores were compared with the Peabody Developmental Motor Scales–2 performance. The average AGS Severity Scale score was 5 (median 4, SD 3.58, IQR 6), with TREX1 and RNASEH groups showing the lowest performance (median 2.5 and 3, respectively). Variability of scores was explored by genotype: the TREX1 cohort showed the smallest IQR, with the largest being SAMHD1 and IFIH1 (1.75 vs 8 and 8.25, respectively) (Table 3).
AGS Severity Scale Performance.
Abbreviations: AGS, Aicardi-Goutières syndrome; IQR, interquartile range; SD, standard deviation.
Peabody Developmental Motor Scales–2 and AGS Severity Scale Score Correlation
Next, the fine motor and visual motor skills were compared to overall severity. Peabody Developmental Motor Scales–2 grasping and visual motor integration raw scores strongly correlated with the AGS Severity Scale (Spearman correlation: r = 0.87, P < .0001; r = 0.91, P < .0001 respectively). When considering genotypes, the lowest correlation was observed within the TREX1 cohort (grasping r = 0.56, visual-motor integration r = 0.73), whereas the other genotypes showed comparable correlations (r range: grasping 0.83-0.92; visual-motor integration 0.86-0.97; Table 4).
Spearman Correlation (r) Between PDMS-2 Subtests and AGS Severity Scale.
Abbreviations: AGS, Aicardi-Goutières syndrome; PDMS-2, Peabody Developmental Motor Scales–2nd Edition; VMI, visual-motor integration.
The cohort was then subdivided into 3 groups by AGS Severity Scale score: Severe (score 0-3, n = 35; 47.30%), Moderate (score 4-8, n = 22; 29.73%), and Attenuated (score 9-11, n = 17; 22.97%). Mean rank Peabody Developmental Motor Scales–2 grasping score varied by severity (Kruskal-Wallis test with Dunn test for multiple comparisons, P < .0001: severe/moderate P < .0001, moderate/attenuated P = .0071, severe/attenuated P < .0001). Floor effect was observed within the severe cohort, with 80.00% (n = 28/35) of subjects performing below the floor. A ceiling effect was observed in the attenuated cohort, with 76.47% (n = 13/17) of the cohort performing within the top 10% of potential scores (Figure 2A).
Performance at the Peabody Developmental Motor Scales–2 by disease severity. Disease severity is defined by AGS Severity Scale scores, with the generation of 3 severity categories (severe for AGS Severity Scale scores range 0-3, moderate for AGS Severity Scale scores range 4-8, and attenuated for AGS Severity Scale scores range 9-11).
Mean rank Peabody Developmental Motor Scales–2 visual-motor integration score was significantly different between the 3 severity categories (Kruskal-Wallis test with Dunn test for multiple comparisons, P < .0001: severe/moderate P < .0001, moderate/attenuated P = .0123, severe/attenuated P < .0001). Floor effect was observed within the severe cohort, with 91.43% (n = 32/35) of subjects performing within the lowest 10% of possible scores. Ceiling effect was observed in the attenuated cohort, with 76.47% (n = 13/17) of the cohort performing in the top testing range (Figure 2B).
Discussion
Aicardi-Goutières syndrome (AGS) is a rare genetic leukodystrophy characterized by a broad spectrum of neurologic impairments.1–3 Although the daily relevance of fine and visual motor skills is well established,10,11,29,30 limited information is available about the fine motor function in leukodystrophies. In this study, we characterized the fine motor and visual-motor integration performance of a cohort of individuals with Aicardi-Goutières syndrome using the Peabody Developmental Motor Scales–2 and the AGS Severity Scale.
Overall, there was a broad range of fine motor function in patients with Aicardi-Goutières syndrome as captured by the Peabody Developmental Motor Scales–2 grasping and visual-motor integration subtest scores. When considering performance within disease severity cohorts, the Peabody Developmental Motor Scales–2 was capable in discriminating between individuals across severity domains as well as within the moderate cohort. Both floor and ceiling effects were noted in the extreme ends of severity.
Within the attenuated phenotype group, the majority of the items in both subtests were completed, demonstrating the presence of fine motor function at least comparable to a pediatric population 6 years of age. Examples of skills from this group are grasping a marker with a tripod grasp, snipping with scissors, and folding paper. As the attenuated cohort included a prevalence of individuals older than 6 years of age, our findings suggest that the Peabody Developmental Motor Scales–2 can be considered an appropriate tool for the assessment of individuals with attenuated Aicardi-Goutières syndrome phenotypes within the normative data age range. Older individuals may need to be assessed with age-appropriate fine motor and visual motor outcome measures, such as the Bruininks-Oseretsky Test of Motor Proficiency–Second Edition (BOT-2) 31 or the Nine Hole Peg Test. 32
Individuals presenting a moderate phenotype (as characterized by the AGS Severity Scale) demonstrated minimal floor and ceiling effects, indicating the suitability of the Peabody Developmental Motor Scales–2 to assess this population. Individuals within the moderate cohort showed fine motor abilities ranging from a limited ability to grasp objects with high affordance (such as a rattle or a cloth) to individuals able to proficiently manipulate a marker to mark paper. Visual motor abilities varied from a limited ability to visually follow a moving object to proficiency in cutting paper with scissors. Because of the nonneurotypical acquisition of developmental milestones in Aicardi-Goutières syndrome, raw scores were used rather than scores derived from age-based normative data. The application across a broader age range may have exacerbated the ceiling effect as the attenuated population was also the oldest.
Individuals within the severe cohort demonstrated the most limitations in fine motor skills, which is an expected finding. Both sustained primitive grasping reflex and cortical visual impairment are common findings in the severe Aicardi-Goutières syndrome cohort. 33 Skills like gross grasp and visual tracking were seen to be the most easily achievable, whereas grasping a cube while upright or reaching to midline while supine were unable to be achieved, with 1 exception. Further studies will need to focus on exploring the performance of different tools in this population, moving toward the identification of more appropriate fine motor and visual assessments in individuals with a more severe phenotype.
Our results demonstrate the association of fine motor skills with overall neurologic severity. Moreover, the measures were strongly correlated across genotypes, with the exclusion of TREX1. We hypothesize that this is likely due to the severe motor impairment observed within this subgroup, as previously described in the literature.2,31 These subtests were developed with a focus on capturing fine and visual motor functional performance, whereas the AGS Severity Scale classifies patients based on a wider breadth of neurologic function, including gross motor, social, and cognitive skills. Individuals with SAMHD1 and IFIH1-related Aicardi-Goutières syndrome showed the highest performance heterogeneity, with some individuals presenting extremely severe fine motor impairment and others showing functional abilities aligned with what is expected in a neurotypical child of 6 years of age. The range of performance observed within the SAMHD1 and IFIH1 cohorts is also consistent with the broad clinical spectrum that these genotypes are known to represent. 34
This study was conducted at a single site through in-person Peabody Developmental Motor Scales–2 administration, and thus reflects a population that was able to travel to participate in the study. Other limitations include the relatively small sample size of the cohort analyzed, as expected for a rare disease. The Peabody Developmental Motor Scales–2 assessment is scored through the identification of a basal and a ceiling level. In individuals with non-neurotypical development, such as the Aicardi-Goutières syndrome population, this approach might limit the complete understanding of motor function if skills are gained non-sequentially.
In conclusion, Peabody Developmental Motor Scales–2 can be considered an appropriate tool to explore fine motor function in individuals with moderate and attenuated Aicardi-Goutières syndrome phenotypes. Skills explored on the Peabody Developmental Motor Scales–2 are anticipated to be obtained by the age of 6 years in a child with typical development. Individuals with attenuated Aicardi-Goutières syndrome should be assessed within the PDSM–2 age range, whereas subjects with moderate phenotype can be assessed with the Peabody Developmental Motor Scales–2 independently of their age. There is a need for further outcome measures to capture fine motor function at either extreme of severity. In addition, the AGS Severity Scale has shown a strong correlation with the Peabody Developmental Motor Scales–2, suggesting its use for an easy stratification of individuals to select appropriate outcome measures to appropriately describe the fine motor function of individuals with a diagnosis of Aicardi-Goutières syndrome.
Footnotes
Author Contributions
SVC contributed to study design, contributed to data acquisition, analysis, and interpretation, drafted the manuscript, and gave final approval for submission. FG contributed to study design, contributed to data acquisition, analysis, and interpretation, drafted the manuscript, and gave final approval for submission. IPB contributed to data acquisition and interpretation and critically revised the manuscript, and gave final approval for submission. NBM contributed to data acquisition and interpretation and critically revised the manuscript, and gave final approval for submission. SW contributed to data analysis and interpretation and critically revised the manuscript, and gave final approval for submission. BF contributed to data analysis and interpretation and critically revised the manuscript, and gave final approval for submission. SAL contributed to conception of the study, contributed to data interpretation, critically revised the manuscript, and gave final approval for submission. SBD contributed to conception of the study, contributed to data interpretation, critically revised the manuscript, and gave final approval for submission. ArV contributed to data acquisition and critically revised the manuscript. AJ contributed to study design, contributed to data analysis and interpretation, critically revised the manuscript, and gave final approval for submission. TE contributed to data acquisition, analysis, and interpretation, critically revised the manuscript, and gave final approval for submission. AMG contributed to study design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript, and gave final approval for submission. AdV contributed to study conception and design, contributed to data analysis and interpretation, critically revised the manuscript, and gave final approval for submission. LAA contributed to study conception and design, contributed to data analysis and interpretation, critically revised the manuscript, and gave final approval for submission.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AV receives grants and in-kind support for research from Eli Lilly, Gilead, Takeda, Illumina, Biogen, Homology, Ionis, Passage Bio, and Orchard Therapeutics and serves on the scientific advisory boards of the European Leukodystrophy Association and the United Leukodystrophy Foundation, as well as in an unpaid capacity for Takeda, Ionis, Biogen, and Illumina. LAA is a consultant for Takeda, Biogen, and Orchard Therapeutics.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: SC, FG, AV, LAA, SL, and SDM are supported by grants U01 NS106845 and U54TR002823 from the National Institutes of Health (NIH), National Institute of Neurological Diseases ad Stroke (NINDS), and the National Center for Advancing Translational Sciences (NCATS). LAA is supported by NINDS grant K23NS114113. IPB is supported by NINDS grant 5K23NS114113-04. Research reported in this publication was supported by CURE Pennsylvania grant, Clinical Center (grant numbers K23NS114113, U01 NS106845, and U54TR002823).
