Phenotype-Genotype Correlations in Early-Onset Myelin Protein Zero-Related Neuropathies.

BACKGROUND AND

OBJECTIVES

Myelin protein zero (MPZ)-related neuropathies include demyelinating CMT1B and later-onset axonal forms (CMT2I/J). CMT1B pathogenic variants act through gain-of-function, destabilizing MPZ and activating the unfolded protein response (UPR), or loss-of-function, disrupting MPZ homomeric interactions in myelin. This study investigates early-onset (<18 years) CMT1B due to MPZ variants in a large Italian cohort, shedding light on clinical progression and genotype-phenotype correlations, with relevance to emerging UPR-targeted therapies.

METHODS

We analyzed cross-sectional clinical and genetic data from 75 patients across 7 Italian centers. MPZ variants were categorized as destabilizing or non-destabilizing based on published data. To explore the relationship between the degree of protein destabilization and clinical severity, missense variants were evaluated for stability alterations using the DUET online tool, with negative ∆∆G values indicating greater destabilization. Statistical correlations between clinical and molecular features were assessed.

RESULTS

This study presents a comprehensive clinical characterization of one of the largest cohorts of early-onset MPZ-related neuropathies reported to date. The Charcot-Marie-Tooth Examination Score (CMTES) correlated with age at assessment (r s = 0.56; p < 0.001), suggesting disease progression in this cohort. Destabilizing variants were associated with earlier onset (p < 0.001), upper limb involvement (p < 0.001), impaired ambulation (p < 0.01), scoliosis (p < 0.01), and faster progression as measured by CMTES/age (0.24 vs 0.11 CMTES/year). After excluding the c.245A>C, p.Y82S outlier (highly destabilizing but not UPR-activating), ∆∆G values showed significant correlations with age at onset (r s = 0.54, p = 0.030), CMTES (r s = -0.82, p < 0.001), and progression (r s = -0.60, p = 0.032).

DISCUSSION: Stratification of MPZ variants into destabilizing and non-destabilizing is crucial for predicting severity and prognosis and tailoring therapeutic strategies. This approach has significant implications for upcoming UPR-modulating treatments and underscores the necessity of integrating molecular and clinical insights for optimal patient care.