Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients
Andrea Gangfuß, Vykuntaraju K. Gowda, Daniel Natera‐de Benito, Pinki Munot, Maria Vanegas, Alejandra Darling, Constanze Reutlinger, Laura Carrera‐Garcia, Gilbert Wunderlich, Heike Kölbel, Burkhard Stüve, David Muhmann, Lucía Monfort Belenguer, Diana‐Gabriela Barca, Viveka Santhosh Reddy C, Varunvenkat M. Srinivasan, Cristina Molina Anguita, Heinz Jungbluth, Hormos Salimi Dafsari, Thomas Rossor, Johann Böhm, Ulrike Schara‐Schmidt, Andreas RoosABSTRACT
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.