Hereditary Polyneuropathies in the Era of Precision Medicine: Genetic Complexity and Emerging Strategies

TL;DR

This review discusses the genetic complexity of hereditary polyneuropathies and explores new therapeutic strategies in the era of precision medicine.

Contribution

The paper provides a comprehensive synthesis of mutations and evaluates emerging therapies for hereditary polyneuropathies.

Findings

Key causative genes like PMP22, MPZ, MFN2, TTR, EGR2, and CX32 (GJB1) are linked to various hereditary polyneuropathies.

Emerging therapies include adeno-associated virus mediated RNA interference, CRISPR-based gene editing, and antisense oligonucleotide therapy.

Precision diagnostics such as next-generation sequencing are highlighted for personalized disease management.

Abstract

Hereditary polyneuropathies represent a genetically and clinically heterogeneous group of disorders affecting the peripheral nervous system, characterized by progressive motor, sensory, and autonomic impairment. Advances in molecular genetics have identified key causative genes, including PMP22, MPZ, MFN2, TTR, EGR2, and CX32 (GJB1), which are implicated in Charcot–Marie–Tooth disease, Dejerine–Sottas syndrome, and related neuropathies. These conditions display substantial allelic and locus heterogeneity. Pathogenetically, mechanisms involve impaired myelin maintenance, disrupted axonal transport, mitochondrial dysfunction, and aberrant Schwann cell biology. Despite these insights, therapeutic options remain limited, and there is a pressing need to translate genetic findings into effective interventions. This review aims to provide a comprehensive synthesis of current knowledge compiling all known mutations resulting in hereditary polyneuropathies. In addition, it underscores the molecular pathomechanisms of hereditary polyneuropathies and evaluates emerging therapeutic strategies, including adeno-associated virus mediated RNA interference, CRISPR-based gene editing, antisense oligonucleotide therapy, and small-molecule modulators of axonal degeneration. Furthermore, the integration of precision diagnostics, such as next-generation sequencing and functional genomic approaches, is discussed in the context of personalized disease management. Collectively, this review underscores the need for patient-centered approaches in advancing care for individuals with hereditary polyneuropathies.

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