Severe phenotype with cis-acting heterozygous PMP22 mutations

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies.
• Mutations in the PMP22 gene are a common cause of CMT, particularly CMT type 1A.
• Understanding the genetic basis of CMT is crucial for diagnosis and potential therapeutic strategies.

Observation:

• A 20-year-old male presented with severe CMT symptoms, including early-onset polyneuropathy, muscle atrophy, distal paresis, hammer toes, and progressive scoliosis.
• Genetic analysis revealed a de novo deletion (c.281delG, p.G94AfsX17) on the paternal PMP22 allele.
• RNA analysis confirmed the presence of mutant transcripts and absence of nonsense-mediated decay in patient-derived lymphoblastoid cells.

Findings:

• The de novo PMP22 deletion (c.281delG) was identified as the sole cause of the severe CMT phenotype in this patient.
• The mutation was of paternal origin, representing a rare instance of a de novo single-base mutation in the PMP22 gene from the father.
• No neuropsychological alterations were observed, suggesting a specific impact on peripheral nerve function.

Implications:

• This case reinforces the PMP22 gene's critical role in peripheral nerve development and function.
• The findings suggest that this specific PMP22 deletion is sufficient to cause a severe CMT phenotype.
• This report contributes to the understanding of de novo mutations in PMP22 and their inheritance patterns in CMT.