Parental mosaicism of a novel PMP22 mutation with a minimal neuropathic phenotype

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth disease (CMT) encompasses a group of inherited peripheral nervous system disorders.
• Dominant mutations in genes like PMP22 are known causes of CMT, particularly CMT type 1E (CMT1E).
• Germline and somatic mosaicism, where different cell populations have distinct genetic makeups, are recognized but rarely reported in dominant CMT.

Observation:

• A novel heterozygous missense mutation (p.Trp39Cys) in the PMP22 gene was identified in two siblings with early-onset demyelinating CMT1E.
• The mutation was found in the extracellular domain of the peripheral myelin protein 22.
• The mother, a source of the mutation, presented with mild distal polyneuropathy and had approximately 20% of the mutant PMP22 allele in her blood, indicating somatic mosaicism.

Findings:

• The identified PMP22 mutation is associated with a mild phenotype of CMT1E, even in the presence of significant somatic mosaicism.
• The mother's asymptomatic status despite carrying the mutation highlights the variable expressivity and potential for mosaicism to result in subtle clinical presentations.
• Sural nerve action potentials (SNAPs) were slightly reduced in the mother, correlating with minor neurological signs.

Implications:

• This case suggests that post-zygotic mutations in CMT-related genes can lead to peripheral neuropathy phenotypes.
• Recognizing genetic mosaicism is crucial for accurate diagnosis and genetic counseling in families with CMT.
• Further research into the mechanisms and clinical impact of somatic mosaicism in CMT is warranted.