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

Area of Science:

• Neurology
• Genetics
• Molecular Biology

Background:

• Myelin protein zero (MPZ)-related neuropathies encompass demyelinating CMT1B and axonal CMT2I/J.
• Pathogenic MPZ variants can cause disease through gain-of-function (destabilizing MPZ, activating UPR) or loss-of-function (disrupting myelin interactions).

Purpose of the Study:

• Investigate early-onset (<18 years) MPZ-related neuropathies in a large Italian cohort.
• Analyze clinical progression and genotype-phenotype correlations for MPZ variants.
• Assess the relevance of findings for emerging unfolded protein response (UPR)-targeted therapies.

Main Methods:

• Analyzed clinical and genetic data from 75 patients across 7 Italian centers.
• Categorized MPZ variants as destabilizing or non-destabilizing.
• Evaluated missense variant stability using the DUET online tool (∆∆G values) and assessed statistical correlations.

Main Results:

• Early-onset MPZ neuropathies show disease progression (CMTES correlated with age).
• Destabilizing MPZ variants correlated with earlier onset, upper limb involvement, impaired ambulation, scoliosis, and faster progression.
• Protein destabilization (∆∆G) correlated with age at onset, clinical severity (CMTES), and progression rate.

Conclusions:

• Stratifying MPZ variants into destabilizing and non-destabilizing categories is vital for predicting disease severity and prognosis.
• This stratification is crucial for tailoring therapeutic strategies, particularly for upcoming UPR-modulating treatments.
• Integrating molecular and clinical insights is essential for optimizing patient care in MPZ-related neuropathies.