Quantitative deep motor phenotyping of 102 people with SCN2A, KCNQ2, CSNK2A1, CACNA1A or SCN8A-related disorders
- 1UTHealth Houston
Abstract
Background and Objectives: Motor dysfunction is a major contributor to disability in pediatric-onset monogenic neurodevelopmental disorders (NDDs), yet systematic quantifications of motor phenotypes across development using validated clinical scales remain underdeveloped. Existing studies have classified motor phenotypes rather than quantified domain-specific severity, limiting their use as outcome measures in clinical trials. Here, we systematically quantify motor dysfunction using established clinical rating scales to explore their utility as motor endpoints. Methods: In this cross-sectional observational study, 102 individuals with NDDs (0.5-38 years) secondary to pathogenic or likely pathogenic variants in five genes (SCN2A, KCNQ2, CSNK2A1, CACNA1A, SCN8A) and 31 unaffected sibling controls underwent standardized motor assessments using the Scale for Assessment and Rating of Ataxia, Burke-Fahn-Marsden Dystonia Scale, and the Modified Ashworth Scale. Regional and functional categorization of parameters enabled differentiated interpretation. Gene-specific patterns were evaluated using z-score standardization across the pooled affected cohort, with gene-level averaging and nonparametric bootstrap-derived 95% confidence intervals. Results: Dysfunction was present in individuals with NDDs across speech (90%), coordination (87%), dystonia (83.3%), gross motor (82.4%) and spasticity (42.2%), with minimal impairment in controls (0-12.9%). We observed substantial heterogeneity across motor domains and subdomains; ataxic dysarthria had the highest score distribution (median 0.83 [IQR, 0.17-1.0]), whereas spasticity showed near-floor scores. Individuals with SCN2A variants demonstrated higher mean z-scores across multiple subdomains than other genes, with more consistent deviations observed in coordination and speech domains (Coordination: mean z = 0.29, 95% CI 0.03-0.54; Speech: mean z = 0.3, 95% CI 0.03-0.57), whereas domain-specific or less pronounced patterns were observed in other genes. The ataxia and dystonia scales demonstrated low floor and ceiling effects. Discussion: Using three clinical scales across a broad developmental and functional range, our study moves motor phenotyping in monogenic NDDs from categorical description toward quantitative, domain-resolved severity assessment. Exploratory analysis indicates marked heterogeneity in severity profiles across genes, most notably in SCN2A, suggesting potential selective motor vulnerability. These findings provide evidence for the feasibility of motor phenotyping and provide preliminary, cross-sectional benchmark severity distributions. Subsequent longitudinal validation and validation in larger, longitudinal, and variant-stratified cohorts will enable natural history studies and future therapeutic trials alongside seizure outcomes.
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BibTeX
@misc{bajaj2026quantitative,
title = {{Quantitative deep motor phenotyping of 102 people with SCN2A, KCNQ2, CSNK2A1, CACNA1A or SCN8A-related disorders}},
author = {S. Bajaj and T. Bruenger and M. Fauteux and R. G. Francisco and M. Ochoa-Urrea and C. T. Sargent and A. Merket and A. Cherukara and E. Moura Coelho da Silva and A. R. Smith and L. Montanucci and S. Kim and C. Leu and C. Hsu and G. Taylor and V. Kasto and W. Fazeli and J. Lim and S. Perry and S. M. L. Wilson and S. E. McMahan and S. S. Varnado and S. D. Lhatoo and G. Von Allmen and L. Schust Myers and S. Egan and B. Babineaux and S. Simms and K. Craig and L. Manaster and S. Johnson and P. Fox and J. Sills and G. Rushing and I. E. Scheffer and N. Thakur and D. Lal},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.26365785},
url = {https://www.medrxiv.org/content/10.64898/2026.11.03.26365785v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Quantitative deep motor phenotyping of 102 people with SCN2A, KCNQ2, CSNK2A1, CACNA1A or SCN8A-related disorders
AU - S. Bajaj
AU - T. Bruenger
AU - M. Fauteux
AU - R. G. Francisco
AU - M. Ochoa-Urrea
AU - C. T. Sargent
AU - A. Merket
AU - A. Cherukara
AU - E. Moura Coelho da Silva
AU - A. R. Smith
AU - L. Montanucci
AU - S. Kim
AU - C. Leu
AU - C. Hsu
AU - G. Taylor
AU - V. Kasto
AU - W. Fazeli
AU - J. Lim
AU - S. Perry
AU - S. M. L. Wilson
AU - S. E. McMahan
AU - S. S. Varnado
AU - S. D. Lhatoo
AU - G. Von Allmen
AU - L. Schust Myers
AU - S. Egan
AU - B. Babineaux
AU - S. Simms
AU - K. Craig
AU - L. Manaster
AU - S. Johnson
AU - P. Fox
AU - J. Sills
AU - G. Rushing
AU - I. E. Scheffer
AU - N. Thakur
AU - D. Lal
PY - 2026
DA - 2026/11/03
PB - medRxiv
DO - 10.64898/2026.11.03.26365785
UR - https://www.medrxiv.org/content/10.64898/2026.11.03.26365785v1
AB - Background and Objectives: Motor dysfunction is a major contributor to disability in pediatric-onset monogenic neurodevelopmental disorders (NDDs), yet systematic quantifications of motor phenotypes across development using validated clinical scales remain underdeveloped. Existing studies have classified motor phenotypes rather than quantified domain-specific severity, limiting their use as outcome measures in clinical trials. Here, we systematically quantify motor dysfunction using established clinical rating scales to explore their utility as motor endpoints. Methods: In this cross-sectional observational study, 102 individuals with NDDs (0.5-38 years) secondary to pathogenic or likely pathogenic variants in five genes (SCN2A, KCNQ2, CSNK2A1, CACNA1A, SCN8A) and 31 unaffected sibling controls underwent standardized motor assessments using the Scale for Assessment and Rating of Ataxia, Burke-Fahn-Marsden Dystonia Scale, and the Modified Ashworth Scale. Regional and functional categorization of parameters enabled differentiated interpretation. Gene-specific patterns were evaluated using z-score standardization across the pooled affected cohort, with gene-level averaging and nonparametric bootstrap-derived 95% confidence intervals. Results: Dysfunction was present in individuals with NDDs across speech (90%), coordination (87%), dystonia (83.3%), gross motor (82.4%) and spasticity (42.2%), with minimal impairment in controls (0-12.9%). We observed substantial heterogeneity across motor domains and subdomains; ataxic dysarthria had the highest score distribution (median 0.83 [IQR, 0.17-1.0]), whereas spasticity showed near-floor scores. Individuals with SCN2A variants demonstrated higher mean z-scores across multiple subdomains than other genes, with more consistent deviations observed in coordination and speech domains (Coordination: mean z = 0.29, 95% CI 0.03-0.54; Speech: mean z = 0.3, 95% CI 0.03-0.57), whereas domain-specific or less pronounced patterns were observed in other genes. The ataxia and dystonia scales demonstrated low floor and ceiling effects. Discussion: Using three clinical scales across a broad developmental and functional range, our study moves motor phenotyping in monogenic NDDs from categorical description toward quantitative, domain-resolved severity assessment. Exploratory analysis indicates marked heterogeneity in severity profiles across genes, most notably in SCN2A, suggesting potential selective motor vulnerability. These findings provide evidence for the feasibility of motor phenotyping and provide preliminary, cross-sectional benchmark severity distributions. Subsequent longitudinal validation and validation in larger, longitudinal, and variant-stratified cohorts will enable natural history studies and future therapeutic trials alongside seizure outcomes.
ER -