The genetic architecture and pharmacogenetic landscape of Charcot-Marie-tooth disease type 1 A: a narrative review toward precision molecular therapeutics

Abstract

Charcot–Marie–Tooth disease (CMT) is the most common group of inherited peripheral neuropathies, and CMT1A is its most prevalent demyelinating subtype. It is most often caused by a recurrent ~ 1.4–1.5 Mb tandem duplication on chromosome 17p12 encompassing the PMP22 gene, resulting in increased PMP22 expression and a complex pathogenic cascade involving Schwann-cell proteostatic stress, impaired myelin and lipid homeostasis, metabolic dysfunction, and secondary axonal degeneration. Despite the relative genetic homogeneity of the primary defect, substantial inter- and intra-familial phenotypic variability is observed, suggesting contributions from genetic modifiers, regulatory elements, and epigenetic mechanisms. This narrative review synthesizes current evidence on the genetic, molecular, and regulatory architecture of CMT1A, with particular emphasis on distal regulatory elements controlling PMP22 expression, promoter-specific transcriptional regulation, and mechanisms contributing to phenotypic heterogeneity. We further examine the evolving therapeutic landscape, from symptomatic management toward disease-modifying and precision therapeutic strategies. Particular attention is given to approaches designed to reduce PMP22 expression, including synergistic pharmacological therapy, antisense oligonucleotides, RNA interference, AAV-mediated gene silencing, and experimental regulatory-element editing, as well as therapeutic strategies targeting downstream mechanisms such as axonal transport and neuromuscular function. Emerging biomarkers, particularly serum neurofilament light chain (NfL), may support exploratory treatment monitoring and patient stratification. However, their value as pharmacodynamic or surrogate endpoints for regulatory decision-making in CMT1A has not yet been established. We also discuss lessons from clinical trials, including the challenges posed by slow disease progression, placebo responses, and heterogeneous treatment effects. Finally, we propose a framework for future CMT1A trials incorporating appropriate patient stratification, extended follow-up, and multimodal clinical, biological, and digital outcome measures. Together, these developments support an increasingly individualized framework for CMT1A that integrates gene dosage, regulatory biology, genetic modifiers, biomarkers, and therapeutic response.