A novel PMP22 insertion mutation causing Charcot-Marie-Tooth disease type 3: A case report

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth disease (CMT) encompasses hereditary neuropathies characterized by muscle atrophy, sensory loss, and foot deformities.
• Mutations in the peripheral myelin protein 22 gene (PMP22) are a common cause of CMT, with missense, deletion, and duplication mutations frequently reported.
• Insertion mutations in PMP22 are rare in CMT patients, making their identification significant for understanding disease heterogeneity.

Observation:

• A 26-year-old male presented with general weakness, peroneal atrophy, and extremity deformities, including bilateral foot dystonia and delayed motor development since childhood.
• Electrophysiological tests revealed absent nerve conduction, consistent with severe neuropathy.
• Whole-exome sequencing identified a novel PMP22 insertion mutation (c.54_55insGTGCTG, p.(L19delinsVLL)).

Findings:

• The novel PMP22 insertion mutation (p.(L19delinsVLL)) was predicted as deleterious by PROVEAN analysis.
• Structural analysis indicated that the insertion disrupts the alpha-helix of the PMP22 protein, potentially explaining the CMT3 phenotype.
• The patient received symptomatic treatment and rehabilitation, showing some improvement but no cure.

Implications:

• This study establishes a link between a novel PMP22 insertion mutation and CMT3, expanding the known spectrum of PMP22-related neuropathies.
• Understanding the functional impact of this variant provides insights into PMP22 protein structure, function, and CMT pathogenesis.
• The findings underscore the importance of advanced sequencing technologies, like next-generation sequencing combined with Sanger sequencing, for comprehensive genetic diagnosis of CMT.