Evidence map›Paper›PMID 39951964›Full record

ArticleMolecular genetics and metabolism2025

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 and 33 more

Abstract read
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Article in Molecular genetics and metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Genotypic and phenotypic heterogeneity in tubulinopathies: insights from a Turkish multicenter cohort.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Article
  2. Article
  3. The role of genetics and molecular mechanisms in early onset scoliosis.Journal of clinical orthopaedics and trauma · 2026
    Review
  4. Review
  5. Article
  6. Article
  7. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

43 authors.

Francesco GavazziNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: gavazzif@chop.edu.
Brittany CharsarNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Eline HamiltonDepartment of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Netherlands.
Jacqueline A ErlerNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Virali PatelNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sarah WoidillNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Anjana SevagamoorthyNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Guy HelmanNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Johanna SchmidtNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Amy PizzinoNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kayla MuirheadNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Asako TakanohashiNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Joshua L BonkowskyDivision of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA; Center for Personalized Medicine, Primary Children's Hospital, Salt Lake City, UT, USA.
Kelsee MeyerhofferDivision of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Cas SimonsMurdoch Childrens Research Institute, Melbourne, Australia.
Hiroshi DoiDepartment of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Miyatake SatokoDepartment of Human Genetics, Yokoama City University, Yokohama, Japan.
Naomichi MatsumotoDepartment of Human Genetics, Yokoama City University, Yokohama, Japan.
Mauricio R DelgadoDepartment of Neurology, University of Texas Southwestern Medical Center, USA.
Meredith Sanchez-CastilloTGen's Center for Rare Childhood Disorders, Phoenix, AZ, USA.
Jingming WangDepartment of Pediatrics, Peking University First Hospital, Beijing, China.
Daniel Rocha de CarvalhoGenetic Unit, SARAH Rehabilitation Hospital, Brasilia, Brazil.
Ivailo TournevClinic of Nervous Diseases, University Hospital Aleksandrovska, Department of Neurology, Medical University-Sofia, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Bulgaria.
Teodora ChamovaDepartment of Neurology, University Hospital Alexandrovska, Medical University Sofia, Sofia, Bulgaria.
Albena JordanovaMolecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University - Sofia, Sofia, Bulgaria; Molecular Neurogenomics Group, Center for Molecular Neurology, VIB, Antwerpen, Belgium; Molecular Neurogenomics Group, Center for Molecular Neurology, Department of Biomedical Sciences, University of Antwerp, Antwerpen, Belgium.
Nancy J CleggDivision of Clinical Research, Department of Research, Scottish Rite for Children, Dallas, TX, USA.
Francesco NicitaUnit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
Enrico BertiniResearch Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy.
Michelle TengSynaptixbio Ltd, Fermi Avenue, Harwell, UK.
Dan WilliamsSynaptixbio Ltd, Fermi Avenue, Harwell, UK.
Davide TondutiUnit of Pediatric Neurology, C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Milan, Italy; Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy.
Henry HouldenDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Menno StellingwerffDepartment of Pediatric Surgery, Vrije Universiteit, Amsterdam, Netherlands.
Evangeline WassmerNeurology Department, Birmingham Children's Hospital, Institute of Health and Neurodevelopment, Aston University, Birmingham, UK.
Angeles Garcia-CazorlaInstitut de Recerca Sant Joan de Déu, Barcelona, Spain; Neurology Department, Neurometabolic Unit and Synaptic Metabolism Lab, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, metabERN and CIBERER-ISCIII, Barcelona, Spain.
Geneviève BernardDepartments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
Amytice MirchiDepartments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
Helia ToutounchiDepartments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.
Nicole I WolfDepartment of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, Netherlands.
Marjo S van der KnaapDepartment of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, Netherlands.
Justine ShultsDepartment of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Laura A AdangNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Adeline L VanderverNeurology Department, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Funding

Validation of the GMFC-MLDU54NS115052 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI Laura Ann Adang · 2019 to 2026
$14.3M
Clinical measures in Aicardi Goutieres SyndromeK23NS114113 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI ADANG, LAURA ANN · 2019 to 2023
$947k
NINDS NIH HHS K23 NS114113NINDS NIH HHS U54 NS115052
6 · The paper itself

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.

Indexed as

Leukodystrophy, MetachromaticTubulinAdolescentAge of OnsetChildChild, PreschoolFemaleGenotypeHumansInfantLongitudinal StudiesMaleMutationRetrospective StudiesTUBB4A protein, humanTubulinDisease stratificationLeukodystrophyNeurologyPediatricTUBB4A

Identifiers

PMID39951964
PMCPMC11875891

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.