Charcot-Marie-Tooth Disease: Genetic and Neurological Implications

Charcot-Marie-Tooth disease (CMT) represents a spectrum of inherited peripheral neuropathies marked by progressive degeneration of motor and sensory nerves. Genetic heterogeneity underpins the condition, with more than 100 genes implicated in demyelinating, axonal or intermediate forms. Mutations in key genes—such as PMP22, MPZ, GJB1 and MFN2—disturb Schwann cell function, axonal transport and mitochondrial dynamics, leading to impaired myelination, axonal atrophy and altered nerve conduction. Clinically, patients present with distal muscle weakness, foot deformities and sensory loss, which progress over decades. Advances in high-throughput sequencing have improved diagnostic yield and revealed novel mutations, while growing insight into molecular pathomechanisms has enabled development of in vitro and in vivo models. The neurological implications extend beyond nerve fibre loss to include maladaptive immune responses and metabolic dysregulation. Understanding the interplay between genetic mutations, Schwann cell biology and axonal integrity is crucial for the design of targeted therapies and reliable biomarkers that can track disease activity and response to intervention.

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Technical terms

Peripheral neuropathy: A disorder affecting peripheral nerves, leading to sensory and motor dysfunction beyond the central nervous system.

Myelination: The process by which Schwann cells wrap axons in myelin sheaths to ensure rapid nerve impulse conduction.

Schwann cells: Glial cells of the peripheral nervous system responsible for myelin formation and nerve repair.

Induced pluripotent stem cells (iPSCs): Somatic cells reprogrammed to a pluripotent state, capable of differentiating into various cell types, including neurons and glia.

Neurofilament light chain: An axonal cytoskeletal protein released into biofluids upon nerve injury, serving as a quantitative biomarker of neurodegeneration.

References

1. Advances and challenges in modeling inherited peripheral neuropathies using iPSCs. Experimental & Molecular Medicine (2024).
2. Improvement of Charcot-Marie-Tooth Phenotype with a Nanocomplex Treatment in Two Transgenic Models of CMT1A. Biomaterials Research (2024).
3. Plasma neurofilament light chain concentration in the inherited peripheral neuropathies. Neurology (2018).
4. Charcot-Marie-Tooth: From Molecules to Therapy. International Journal of Molecular Sciences (2019).
5. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology (2019).