Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients

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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Publication Details

Journal
Annals of Clinical and Translational Neurology
Published
2026-11-03
DOI
https://doi.org/10.1002/acn3.70561
Primary Topic
Hereditary Neurological Disorders
Type
article
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article

Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients

Laura Carrera‐García, Gilbert Wunderlich, Pinki Munot, Lucía Monfort Belenguer et al.
Annals of Clinical and Translational Neurology
Hereditary Neurological Disorders
article

Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients

Laura Carrera‐García, Gilbert Wunderlich, Pinki Munot, Lucía Monfort Belenguer, Vykuntaraju K. Gowda, Heinz Jungbluth, Constanze Reutlinger, Andrea Gangfuß, Burkhard Stüve, Hormos Salimi Dafsari, Maria Vanegas, Andreas Roos, Varunvenkat M. Srinivasan, Alejandra Darling, Thomas E Rossor, Cristina Molina‐Anguita, Diana Bârcă, Heike Kölbel, Johann Böhm, Daniel Natera‐de Benito, Ulrike Schara, Viveka Santhosh Reddy C, David Muhmann
article en

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.

Annals of Clinical and Translational Neurology
National Health Service (GB), Centre National de la Recherche Scientifique (FR), Hospital Sant Joan de Déu Barcelona (ES), Inserm (FR), Carol Davila University of Medicine and Pharmacy (RO), University of Cologne (DE), King's College London (GB), Guy's and St Thomas' NHS Foundation Trust (GB), University of Siegen (DE), Children's Hospital of Eastern Ontario (CA), Great Ormond Street Hospital (GB), Folkwang University of the Arts (DE), Institut de génétique et de biologie moléculaire et cellulaire (FR), Hospital Clínico Universitario de Valencia (ES), Consorci Sanitari de Terrassa (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), BG University Hospital Bergmannsheil Bochum (DE), Evelina London Children's Healthcare (GB), Spitalul Clinic de Psihiatrie Alexandru Obregia (RO), University Hospital Cologne (DE), Indira Gandhi Institute of Child Health (IN), University College London (GB), University of Duisburg-Essen (DE)
Openalex Percentile: Top 22%
Hereditary Neurological Disorders
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