Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.
18 affiliations
- 1Department of Pediatric Neurology, University Duisburg-Essen, Essen, Germany.
- 2Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India.
- 3Neuromuscular Unit, Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
- 4Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, UK.
- 5Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' National Health Service Foundation Trust, London, UK.
- 6Metabolic Unit, Movement Disorders Unit, Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
- 7Department of Pediatric Neurology, DRK-Kinderklinik Siegen gGmbH, Siegen, Germany.
- 8Department of Neurology and Center for Rare Diseases, Faculty of Medicine, University Hospital Cologne, Cologne, Germany.
- 9Pediatric Neurology, Clínic Universitary Hospital of Valencia, Valencia, Spain.
- 10Pediatric Neurology Department, Center of Expertise for Rare Diseases in Pediatric Neurology, "Prof. Dr. Alexandru Obregia" Clinical Psychiatry Hospital, Bucharest, Romania.
- 11Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
- 12Pediatric Neurology, Consorci Sanitari de Terrassa, Barcelona, Spain.
- 13Faculty of Life Sciences and Medicine, Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK.
- 14Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- 15Max-Planck-Institute for Biology of Ageing, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany.
- 16Department of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM U1258, CNRS UMR7104, University of Strasbourg, Illkirch, France.
- 17Brain and Mind Research Institute, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
- 18Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Bochum, Germany.
Abstract
Background
Biallelic FIG4 variants classically cause distinct conditions characterized by peripheral neuropathy (Charcot-Marie-Tooth disease type 4J) or skeletal dysplasia (Yunis-Varón syndrome). However, central nervous system involvement is increasingly recognized. The prevalence and specific characteristics of movement disorders within FIG4-related disease remain poorly characterized, prompting a need to redefine its clinical continuum.Objective
To delineate the phenotypic spectrum of FIG4-related disorders beyond established entities (Yunis-Varón syndrome, Charcot-Marie-Tooth disease type 4J, bilateral temporooccipital polymicrogyria, and amyotrophic lateral sclerosis type 11) using an international multicentre cohort.Methods
We retrospectively analyzed clinical, genetic, and neurophysiological data from patients with biallelic FIG4 variants to redefine genotype-phenotype correlations, focusing on motor development, cognitive status, and movement disorders.Results
Evaluating 14 pediatric FIG4 patients revealed a continuous phenotypic spectrum rather than the clinical entities previously described in the literature. Instead of the typical peripheral neuropathy classically associated with pathogenic FIG4 variants, the predominant clinical picture in this age group was a severe neurodevelopmental disorder. Patients showed profound motor and cognitive delay, with a subset additionally displaying distinct movement abnormalities such as dystonia and bradykinesia.Conclusion
Loss of functional FIG4 causes a broader and more severe disease spectrum with central nervous system involvement, including intellectual disability and movement abnormalities such as dystonia and bradykinesia. Recognizing these features should prompt clinicians to consider FIG4-associated disorders, allowing for optimized patient care and tailored therapeutic strategies.
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BibTeX
@article{gangfuß2026clinical,
title = {{Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.}},
author = {Andrea Gangfuß and Vykuntaraju K Gowda and Daniel Natera-de Benito and Pinki Munot and Maria Vanegas and Alejandra Darling and Constanze Reutlinger and Laura Carrera-Garcia and Gilbert Wunderlich and Heike Kölbel and Burkhard Stüve and David Muhmann and Lucía Monfort Belenguer and Diana-Gabriela Barca and Viveka Santhosh Reddy C and Varunvenkat M Srinivasan and Cristina Molina Anguita and Heinz Jungbluth and Hormos Salimi Dafsari and Thomas Rossor and Johann Böhm and Ulrike Schara-Schmidt and Andreas Roos},
journal = {Annals of clinical and translational neurology},
year = {2026},
month = nov,
doi = {10.1002/acn3.70561},
url = {https://europepmc.org/article/MED/42974926},
note = {CC BY},
}
RIS
TY - JOUR
TI - Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.
AU - Andrea Gangfuß
AU - Vykuntaraju K Gowda
AU - Daniel Natera-de Benito
AU - Pinki Munot
AU - Maria Vanegas
AU - Alejandra Darling
AU - Constanze Reutlinger
AU - Laura Carrera-Garcia
AU - Gilbert Wunderlich
AU - Heike Kölbel
AU - Burkhard Stüve
AU - David Muhmann
AU - Lucía Monfort Belenguer
AU - Diana-Gabriela Barca
AU - Viveka Santhosh Reddy C
AU - Varunvenkat M Srinivasan
AU - Cristina Molina Anguita
AU - Heinz Jungbluth
AU - Hormos Salimi Dafsari
AU - Thomas Rossor
AU - Johann Böhm
AU - Ulrike Schara-Schmidt
AU - Andreas Roos
PY - 2026
DA - 2026/11/03
JO - Annals of clinical and translational neurology
DO - 10.1002/acn3.70561
UR - https://europepmc.org/article/MED/42974926
AB - Background Biallelic FIG4 variants classically cause distinct conditions characterized by peripheral neuropathy (Charcot-Marie-Tooth disease type 4J) or skeletal dysplasia (Yunis-Varón syndrome). However, central nervous system involvement is increasingly recognized. The prevalence and specific characteristics of movement disorders within FIG4-related disease remain poorly characterized, prompting a need to redefine its clinical continuum.Objective To delineate the phenotypic spectrum of FIG4-related disorders beyond established entities (Yunis-Varón syndrome, Charcot-Marie-Tooth disease type 4J, bilateral temporooccipital polymicrogyria, and amyotrophic lateral sclerosis type 11) using an international multicentre cohort.Methods We retrospectively analyzed clinical, genetic, and neurophysiological data from patients with biallelic FIG4 variants to redefine genotype-phenotype correlations, focusing on motor development, cognitive status, and movement disorders.Results Evaluating 14 pediatric FIG4 patients revealed a continuous phenotypic spectrum rather than the clinical entities previously described in the literature. Instead of the typical peripheral neuropathy classically associated with pathogenic FIG4 variants, the predominant clinical picture in this age group was a severe neurodevelopmental disorder. Patients showed profound motor and cognitive delay, with a subset additionally displaying distinct movement abnormalities such as dystonia and bradykinesia.Conclusion Loss of functional FIG4 causes a broader and more severe disease spectrum with central nervous system involvement, including intellectual disability and movement abnormalities such as dystonia and bradykinesia. Recognizing these features should prompt clinicians to consider FIG4-associated disorders, allowing for optimized patient care and tailored therapeutic strategies.
SN - 2328-9503
ER -