The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy

Francesco Gavazzi; Brittany Charsar; Eline Hamilton; Jacqueline A. Erler; Virali Patel; Sarah Woidill; Anjana Sevagamoorthy; Guy Helman; Johanna Schmidt; Amy Pizzino; Kayla Muirhead; Asako Takanohashi; Joshua L. Bonkowsky; Kelsee Meyerhoffer; Cas Simons; Hiroshi Doi; Miyatake Satoko; Naomichi Matsumoto; Mauricio R. Delgado; Meredith Sanchez-Castillo; Jingming Wang; Daniel Rocha de Carvalho; Ivailo Tournev; Teodora Chamova; Albena Jordanova; Nancy J. Clegg; Francesco Nicita; Enrico Bertini; Michelle Teng; Dan Williams; Davide Tonduti; Henry Houlden; Menno Stellingwerff; Evangeline Wassmer; Angeles Garcia-Cazorla; Geneviève Bernard; Amytice Mirchi; Helia Toutounchi; Nicole I. Wolf; Marjo S. van der Knaap; Justine Shults; Laura A. Adang; Adeline L. Vanderver

doi:10.1016/j.ymgme.2025.109048

The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy

Francesco Gavazzi^*
, Brittany Charsar
, Eline Hamilton
, Jacqueline A. Erler
, Virali Patel
, Sarah Woidill
, Anjana Sevagamoorthy
, Guy Helman
, Johanna Schmidt
, Amy Pizzino
, Kayla Muirhead
, Asako Takanohashi
, Joshua L. Bonkowsky
, Kelsee Meyerhoffer
, Cas Simons
, Hiroshi Doi
, Miyatake Satoko
, Naomichi Matsumoto
, Mauricio R. Delgado
, Meredith Sanchez-Castillo

Jingming Wang, Daniel Rocha de Carvalho, Ivailo Tournev, Teodora Chamova, Albena Jordanova, Nancy J. Clegg, Francesco Nicita, Enrico Bertini, Michelle Teng, Dan Williams, Davide Tonduti, Henry Houlden, Menno Stellingwerff, Evangeline Wassmer, Angeles Garcia-Cazorla, Geneviève Bernard, Amytice Mirchi, Helia Toutounchi, Nicole I. Wolf, Marjo S. van der Knaap, Justine Shults, Laura A. Adang, Adeline L. Vanderver

^*Corresponding author for this work

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

Abstract

We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function – Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late-infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 % and n = 77, 43.0 %). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of G-tube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.

Original language	English
Article number	109048
Pages (from-to)	1-14
Number of pages	14
Journal	Molecular Genetics and Metabolism
Volume	144
Issue number	3
Early online date	1 Feb 2025
DOIs	https://doi.org/10.1016/j.ymgme.2025.109048
Publication status	Published - Mar 2025

Bibliographical note

Publisher Copyright:
© 2024

Funding

AV, LA, JLB and FG were supported by U54NS115052 from the NIH, NINDS and NCATS. They have also received funding from the UK H-ABC Foundation and Fight H-ABC as well as SynaptixBio.LA is supported by the NIH under Award Number K23NS114113.GB has received a Clinical Research Scholar Junior 1 award from the Fonds de Recherche du Quebec – Santé (FRQS) (2012–2016), New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022) and Senior Clinical Research Scholar award from the FRQS (2022–2025).MSvdK, NIW, FN, and EB are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510.IT, TCH, AJ were funded in part by the Bulgarian National Science Fund and the Bulgarian National Plan for Recovery and Resilience (grant BG-RRP-2.004-0004-C01 to AJ and IT). AJ was funded in part by the Fund for Scientific Research (FWO-Flanders) (research grants G048220N and G0A2122N to AJ) and the Association Belge contre les Maladies Neuromusculaires' (ABMM-Telethon) (research grant to AJ). GB has received a Clinical Research Scholar Junior 1 award from the Fonds de Recherche du Quebec – Santé (FRQS) (2012–2016), New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022) and Senior Clinical Research Scholar award from the FRQS (2022–2025). IT, TCH, AJ were funded in part by the Bulgarian National Science Fund and the Bulgarian National Plan for Recovery and Resilience (grant BG-RRP-2.004-0004-C01 to AJ and IT). AJ was funded in part by the Fund for Scientific Research ( FWO-Flanders ) (research grants G048220N and G0A2122N to AJ) and the Association Belge contre les Maladies Neuromusculaires' (ABMM-Telethon) (research grant to AJ). LA is supported by the NIH under Award Number K23NS114113 .

Funders	Funder number
NIW
Association Belge contre les Maladies Neuro-Musculaires
Santé
National Institute of Neurological Disorders and Stroke
ABMM-Telethon
UK H-ABC Foundation
Bulgarian National Science Fund
Fight H-ABC
Fonds De La Recherche Scientifique - FNRS
National Center for Advancing Translational Sciences
Canadian Institutes of Health Research	2022–2025, 2017–2022
Bulgarian National Plan for Recovery and Resilience	BG-RRP-2.004-0004-C01
National Institutes of Health	K23NS114113
ERN-RND	739510
Fonds Wetenschappelijk Onderzoek	G0A2122N, G048220N

Keywords

Disease stratification
Leukodystrophy
Neurology
Pediatric
TUBB4A

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10.1016/j.ymgme.2025.109048

https://pmc.ncbi.nlm.nih.gov/articles/PMC11875891/

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Gavazzi, F., Charsar, B., Hamilton, E., Erler, J. A., Patel, V., Woidill, S., Sevagamoorthy, A., Helman, G., Schmidt, J., Pizzino, A., Muirhead, K., Takanohashi, A., Bonkowsky, J. L., Meyerhoffer, K., Simons, C., Doi, H., Satoko, M., Matsumoto, N., Delgado, M. R., ... Vanderver, A. L. (2025). The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy. Molecular Genetics and Metabolism, 144(3), 1-14. Article 109048. https://doi.org/10.1016/j.ymgme.2025.109048

@article{982ee63ffe41436c835f808536b3e0d4,

title = "The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy",

abstract = "We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function – Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late-infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 \% and n = 77, 43.0 \%). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of G-tube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.",

keywords = "Disease stratification, Leukodystrophy, Neurology, Pediatric, TUBB4A",

author = "Francesco Gavazzi and Brittany Charsar and Eline Hamilton and Erler, \{Jacqueline A.\} and Virali Patel and Sarah Woidill and Anjana Sevagamoorthy and Guy Helman and Johanna Schmidt and Amy Pizzino and Kayla Muirhead and Asako Takanohashi and Bonkowsky, \{Joshua L.\} and Kelsee Meyerhoffer and Cas Simons and Hiroshi Doi and Miyatake Satoko and Naomichi Matsumoto and Delgado, \{Mauricio R.\} and Meredith Sanchez-Castillo and Jingming Wang and \{de Carvalho\}, \{Daniel Rocha\} and Ivailo Tournev and Teodora Chamova and Albena Jordanova and Clegg, \{Nancy J.\} and Francesco Nicita and Enrico Bertini and Michelle Teng and Dan Williams and Davide Tonduti and Henry Houlden and Menno Stellingwerff and Evangeline Wassmer and Angeles Garcia-Cazorla and Genevi{\`e}ve Bernard and Amytice Mirchi and Helia Toutounchi and Wolf, \{Nicole I.\} and \{van der Knaap\}, \{Marjo S.\} and Justine Shults and Adang, \{Laura A.\} and Vanderver, \{Adeline L.\}",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2025",

month = mar,

doi = "10.1016/j.ymgme.2025.109048",

language = "English",

volume = "144",

pages = "1--14",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

publisher = "Academic Press Inc.",

number = "3",

}

Gavazzi, F, Charsar, B, Hamilton, E, Erler, JA, Patel, V, Woidill, S, Sevagamoorthy, A, Helman, G, Schmidt, J, Pizzino, A, Muirhead, K, Takanohashi, A, Bonkowsky, JL, Meyerhoffer, K, Simons, C, Doi, H, Satoko, M, Matsumoto, N, Delgado, MR, Sanchez-Castillo, M, Wang, J, de Carvalho, DR, Tournev, I, Chamova, T, Jordanova, A, Clegg, NJ, Nicita, F, Bertini, E, Teng, M, Williams, D, Tonduti, D, Houlden, H, Stellingwerff, M, Wassmer, E, Garcia-Cazorla, A, Bernard, G, Mirchi, A, Toutounchi, H, Wolf, NI, van der Knaap, MS, Shults, J, Adang, LA & Vanderver, AL 2025, 'The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy', Molecular Genetics and Metabolism, vol. 144, no. 3, 109048, pp. 1-14. https://doi.org/10.1016/j.ymgme.2025.109048

TY - JOUR

T1 - The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy

AU - Gavazzi, Francesco

AU - Charsar, Brittany

AU - Hamilton, Eline

AU - Erler, Jacqueline A.

AU - Patel, Virali

AU - Woidill, Sarah

AU - Sevagamoorthy, Anjana

AU - Helman, Guy

AU - Schmidt, Johanna

AU - Pizzino, Amy

AU - Muirhead, Kayla

AU - Takanohashi, Asako

AU - Bonkowsky, Joshua L.

AU - Meyerhoffer, Kelsee

AU - Simons, Cas

AU - Doi, Hiroshi

AU - Satoko, Miyatake

AU - Matsumoto, Naomichi

AU - Delgado, Mauricio R.

AU - Sanchez-Castillo, Meredith

AU - Wang, Jingming

AU - de Carvalho, Daniel Rocha

AU - Tournev, Ivailo

AU - Chamova, Teodora

AU - Jordanova, Albena

AU - Clegg, Nancy J.

AU - Nicita, Francesco

AU - Bertini, Enrico

AU - Teng, Michelle

AU - Williams, Dan

AU - Tonduti, Davide

AU - Houlden, Henry

AU - Stellingwerff, Menno

AU - Wassmer, Evangeline

AU - Garcia-Cazorla, Angeles

AU - Bernard, Geneviève

AU - Mirchi, Amytice

AU - Toutounchi, Helia

AU - Wolf, Nicole I.

AU - van der Knaap, Marjo S.

AU - Shults, Justine

AU - Adang, Laura A.

AU - Vanderver, Adeline L.

PY - 2025/3

Y1 - 2025/3

N2 - We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function – Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late-infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 % and n = 77, 43.0 %). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of G-tube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.

AB - We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function – Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late-infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 % and n = 77, 43.0 %). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of G-tube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.

KW - Disease stratification

KW - Leukodystrophy

KW - Neurology

KW - Pediatric

KW - TUBB4A

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UR - https://www.scopus.com/pages/publications/85217686288#tab=citedBy

U2 - 10.1016/j.ymgme.2025.109048

DO - 10.1016/j.ymgme.2025.109048

M3 - Article

AN - SCOPUS:85217686288

SN - 1096-7192

VL - 144

SP - 1

EP - 14

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 3

M1 - 109048

ER -

The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy

Abstract

Bibliographical note

Funding

Keywords

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