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

Francesco Gavazzi; Virali Patel; Jacqueline A. Erler; Brittany Charsar; Ylenia Vaia; Anjana Sevagamoorthy; Ariel Vincent; Sarah Woidill; Evangeline Wassmer; Henry Houlden; Angeles Garcia-Cazorla; Davide Tonduti; Nicole I. Wolf; Marjo Van der Knaap; Geneviève Bernard; Laura A. Adang; Adeline Vanderver

doi:10.1016/j.pediatrneurol.2025.09.019

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

Francesco Gavazzi^*
, Virali Patel
, Jacqueline A. Erler
, Brittany Charsar
, Ylenia Vaia
, Anjana Sevagamoorthy
, Ariel Vincent
, Sarah Woidill
, Evangeline Wassmer
, Henry Houlden
, Angeles Garcia-Cazorla
, Davide Tonduti
, Nicole I. Wolf
, Marjo Van der Knaap
, Geneviève Bernard
, Laura A. Adang
, Adeline Vanderver

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: 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. Methods: The administration of the Vineland Adaptive Behavior Scales 3^rd 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. Results: 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. Conclusions: 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.

Original language	English
Pages (from-to)	156-165
Number of pages	10
Journal	Pediatric Neurology
Volume	173
Early online date	3 Oct 2025
DOIs	https://doi.org/10.1016/j.pediatrneurol.2025.09.019
Publication status	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© 2025 Elsevier Inc.

Keywords

Caregivers
Impact of disease
Leukodystrophy
Pediatric
Quality of life
Rare disorders

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10.1016/j.pediatrneurol.2025.09.019

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Gavazzi, F., Patel, V., Erler, J. A., Charsar, B., Vaia, Y., Sevagamoorthy, A., Vincent, A., Woidill, S., Wassmer, E., Houlden, H., Garcia-Cazorla, A., Tonduti, D., Wolf, N. I., Van der Knaap, M., Bernard, G., Adang, L. A., & Vanderver, A. (2025). Critical Functional Domains in Pediatric Onset TUBB4A-Related Leukodystrophy: A Clinical and Caregiver's Perspective. Pediatric Neurology, 173, 156-165. https://doi.org/10.1016/j.pediatrneurol.2025.09.019

@article{3e17426ac0cd4b869859f5850dc89340,

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

abstract = "Background: 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. Methods: The administration of the Vineland Adaptive Behavior Scales 3rd 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. Results: 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. Conclusions: 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.",

keywords = "Caregivers, Impact of disease, Leukodystrophy, Pediatric, Quality of life, Rare disorders",

author = "Francesco Gavazzi and Virali Patel and Erler, \{Jacqueline A.\} and Brittany Charsar and Ylenia Vaia and Anjana Sevagamoorthy and Ariel Vincent and Sarah Woidill and Evangeline Wassmer and Henry Houlden and Angeles Garcia-Cazorla and Davide Tonduti and Wolf, \{Nicole I.\} and \{Van der Knaap\}, Marjo and Genevi{\`e}ve Bernard and Adang, \{Laura A.\} and Adeline Vanderver",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = dec,

doi = "10.1016/j.pediatrneurol.2025.09.019",

language = "English",

volume = "173",

pages = "156--165",

journal = "Pediatric Neurology",

issn = "0887-8994",

publisher = "Elsevier Inc.",

}

Gavazzi, F, Patel, V, Erler, JA, Charsar, B, Vaia, Y, Sevagamoorthy, A, Vincent, A, Woidill, S, Wassmer, E, Houlden, H, Garcia-Cazorla, A, Tonduti, D, Wolf, NI, Van der Knaap, M, Bernard, G, Adang, LA & Vanderver, A 2025, 'Critical Functional Domains in Pediatric Onset TUBB4A-Related Leukodystrophy: A Clinical and Caregiver's Perspective', Pediatric Neurology, vol. 173, pp. 156-165. https://doi.org/10.1016/j.pediatrneurol.2025.09.019

TY - JOUR

T1 - Critical Functional Domains in Pediatric Onset TUBB4A-Related Leukodystrophy

T2 - A Clinical and Caregiver's Perspective

AU - Gavazzi, Francesco

AU - Patel, Virali

AU - Erler, Jacqueline A.

AU - Charsar, Brittany

AU - Vaia, Ylenia

AU - Sevagamoorthy, Anjana

AU - Vincent, Ariel

AU - Woidill, Sarah

AU - Wassmer, Evangeline

AU - Houlden, Henry

AU - Garcia-Cazorla, Angeles

AU - Tonduti, Davide

AU - Wolf, Nicole I.

AU - Van der Knaap, Marjo

AU - Bernard, Geneviève

AU - Adang, Laura A.

AU - Vanderver, Adeline

PY - 2025/12

Y1 - 2025/12

N2 - Background: 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. Methods: The administration of the Vineland Adaptive Behavior Scales 3rd 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: The administration of the Vineland Adaptive Behavior Scales 3rd 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. Results: 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. Conclusions: 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.

KW - Caregivers

KW - Impact of disease

KW - Leukodystrophy

KW - Pediatric

KW - Quality of life

KW - Rare disorders

UR - https://www.scopus.com/pages/publications/105019259335

UR - https://www.scopus.com/pages/publications/105019259335#tab=citedBy

U2 - 10.1016/j.pediatrneurol.2025.09.019

DO - 10.1016/j.pediatrneurol.2025.09.019

M3 - Article

AN - SCOPUS:105019259335

SN - 0887-8994

VL - 173

SP - 156

EP - 165

JO - Pediatric Neurology

JF - Pediatric Neurology

ER -

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

Abstract

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Keywords

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