Expanding the Clinical Spectrum of -Associated Charcot-Marie-Tooth Disease.

Background And Objectives: Germline truncating variants in the gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined.

Methods: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with germline variants evaluated at 6 centers throughout Spain.

Results: We identified 7 Spanish families with 4 different likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections.

Discussion: Our findings support the causality of pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.