PMP22 sequence variants cause HNPP through protein loss or impaired folding and traffickingNew insights into the genetic causes of pressure palsy nerve damage

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant neuropathy classically caused by a heterozygous deletion of the 17p11.2-p12 region encompassing PMP22. However, PMP22 sequence variants can produce HNPP-like or overlapping phenotypes, complicating variant interpretation. This narrative review synthesizes clinical, genetic, functional, and experimental evidence relevant to PMP22 sequence variant-associated HNPP. PMP22 sequence variants may cause quantitative loss of functional protein or qualitative impairment through defective folding, trafficking, membrane localization, or MPZ/P0 interaction. We propose a descriptive two-dimensional framework that considers effective PMP22 functional activity and, where experimentally supported, variant-specific proteotoxic or dominant-negative burden; it complements rather than replaces established mechanistic terms such as haploinsufficiency. Clinically, sequence variants should be interpreted in relation to the pressure-palsy phenotype, the distribution of electrophysiological abnormalities, and variant-specific evidence. MLPA remains the first-line test for typical HNPP, whereas PMP22 sequencing and broader panels are relevant in deletion-negative or atypical cases. Current management remains preventive and supportive; molecular approaches remain preclinical. Future progress will require natural-history cohorts and variant-specific cellular and animal models.