Advances in PMP22 sequence variant-associated hereditary neuropathy with liability to pressure palsies: from gene dosage effects to mechanism-informed variant interpretation

Abstract

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.