Genotypic and Phenotypic Characterization of Axonal Charcot-Marie-Tooth Disease in Childhood: Identification of One Novel and Four Known Mutations.

Charcot-Marie-Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the gene, consistent with CMT2S. Other variants were identified in the (CMT2CC), (CMT2O), and (CMT2EE) genes. Notably, a previously unreported co-occurrence of mutation and congenital heart disease was observed in one case. This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel variant and unique phenotypic associations provides new insights for future genotype-phenotype correlation studies.