Critical Functional Domains in Pediatric Onset TUBB₄A-Related Leukodystrophy: A Clinical and Caregiver's Perspective

Pediatric-onset TUBB4A-related leukodystrophy (TUBB4A-LD) is a rare, progressive genetic disorder affecting white matter, caused by gain-of-function mutations in TUBB4A. It leads to severe neurological disabilities across cognitive and functional dimensions and exhibits broad phenotypic heterogeneity. To date, no study has examined the impact of TUBB4A-LD on the lives of affected individuals and their caregivers. The administration of the Vineland Adaptive Behavior Scales 3 edition (VABS-3) and quality of life questionnaires was conducted in a cohort of caregivers of children diagnosed with TUBB4A-LD. The questionnaires comprised the Pediatric Quality of Life-Generic Core and Pediatric Quality of Life-Family Impact (PedsQL-FI) modules, the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD), and the Caregiver Traumatic Brain Injury-Care Quality of Life. Overall, 58 caregivers participated in the study. The VABS-3 (n = 58) demonstrated a lesser impact on the Communication and Socialization Domains compared to Activities of Daily Living and Motor Domains (mixed effect analysis with multiple comparisons with Bonferroni's correction, Communication: Activity of Daily Living P = 0.003, other comparisons P < 0.0001). The CPCHILD (n = 56), Pediatric Quality of Life-Generic Core (n = 47), Care Quality of Life (n = 54), and PedsQL-FI (n = 47) showed relevant impairment in motor abilities and daily living activities, aligning closely with the VABS-3 profile. The CPCHILD and PedsQL-FI demonstrated superior performance in our cohort. Through standardized surveys and outcome assessments, we demonstrate the severe impact of TUBB4A-LD on the quality of life of affected subjects and their caregivers, who experience impairments in motor and expressive language abilities. These results will inform the design of future patient-centric clinical trials.