PMP22 variants that cause CMT1E: Natural History and Disease Mechanism

Paper

Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of PMP22 variants

Kailee S Ward , Christopher P Ptak , Natalya Pashkova , Tiffany Grider , Tabitha A Peterson , Davide Pareyson , Chiara Pisciotta , Paola Saveri , Isabella Moroni , Matilde Laura , Joshua Burns , Manoj P Menezes , Kayla Cornett , Richard Finkel , Bipasha Mukherjee-Clavin , Charlotte J Sumner , Maxwell Greene , Omer Abdul Hamid , David Herrmann , Reza Sadjadi , David Walk , Stephan Züchner , Mary M Reilly , Steven S Scherer , Inherited Neuropathy Consortium , Robert C Piper , Michael E Shy

Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare inherited nerve disorder caused by changes in the PMP22 gene. Symptoms vary widely, from mild weakness to severe childhood-onset disease, and how the condition progresses is not well defined.

We studied patients with CMT1E seen at specialized neuropathy clinics, using standard exams and scoring systems to track disease severity over time. Different PMP22 variants were also tested in cells to see how they affect the protein.

Fifty patients from 35 families carried 24 disease-causing PMP22 variants. Many had delayed walking, and some had hearing or skeletal problems. More severe disease was most often linked to variants located in the membrane-spanning regions of the PMP22 protein.

Overall, disease severity tracks with where the mutation occurs and how well PMP22 reaches the cell surface. Variants in transmembrane regions disrupt protein trafficking, leading to early-onset, more severe neuropathy, while variants outside these regions tend to cause milder disease.