INTRODUCTION: Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. It primarily affects the peripheral nerves, leading to distal muscle weakness, sensory loss, gait abnormalities, and skeletal deformities.

AIM(S): The aim of this study was to describe the clinical presentation, genetic findings, and diagnostic evaluation of a paediatric patient with Charcot-Marie-Tooth disease caused by a pathogenic ORC2 gene mutation, and to emphasize the importance of early molecular diagnosis in improving clinical management and prognosis.

METHOD(S): A 9-year-old female presenting with painful progressive myopathy, lower limb weakness, and recurrent falls was clinically evaluated. Detailed medical and family history were obtained, followed by comprehensive neurological examination. Laboratory investigations and neuroimaging were performed to exclude acquired neuromuscular conditions. Genomic DNA was extracted from peripheral blood, and comprehensive genetic analysis was conducted using next-generation sequencing. Variants were prioritized based on pathogenicity predictions, allele frequency in population databases, inheritance pattern, and correlation with the patient’s phenotype. Functional relevance was assessed using published human and model organism data.

RESULTS: Genetic analysis identified a heterozygous pathogenic missense variant in the ORC2 gene: c.754C>T, resulting in the p.(Arg252Trp) amino acid substitution (rs864309503). This variant affects the ATPase domain of ORC2, which plays a critical role in chromatin modification, DNA repair, transcriptional regulation, and epigenetic silencing.

CONCLUSIONS: This case report highlights a rare pathogenic ORC2 gene mutation as the underlying cause of paediatric Charcot-Marie-Tooth disease, expanding the genetic landscape of inherited peripheral neuropathies.

FINANCIAL SUPPORT: N/A