Abstract
There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the PMP22 gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second-phase III trial is ongoing. Gene therapy to substitute defective genes or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1.
Highlights
Charcot-Marie-Tooth disease collects a genetically heterogeneous group of inherited disorders sharing a common core phenotype of length-dependent progressive sensorymotor or motor neuropathy with foot deformities and altered deep tendon reflexes
Hereditary Neuropathy with liability to Pressure Palsies is an autosomal dominant disorder characterised by recurrent focal neuropathies, which are typically painless and transient, and it is associated with the deletion of the PMP22 gene, whereas the duplication of the same gene with PMP22 overexpression is associated with the most frequent Charcot-Marie-Tooth neuropathies (CMT) subtype, CMT1A
About 100 genes have been associated with CMT and related disorders, which code for proteins involved in many different functions relevant for the nerves, including myelin formation and maintenance, axonal transport, vesicular trafficking, mitochondrial homeostasis, Endoplasmic Reticulum (ER) stress, channels formation, etc. [1,2]
Summary
Charcot-Marie-Tooth disease collects a genetically heterogeneous group of inherited disorders sharing a common core phenotype of length-dependent progressive sensorymotor or motor neuropathy with foot deformities and altered deep tendon reflexes. Hereditary Neuropathy with liability to Pressure Palsies is an autosomal dominant disorder characterised by recurrent focal neuropathies, which are typically painless and transient, and it is associated with the deletion of the PMP22 gene, whereas the duplication of the same gene with PMP22 overexpression is associated with the most frequent CMT subtype, CMT1A. Overall, this group of inherited peripheral neuropathies is labelled as CMT and related neuropathies and is further classified according to the mutated gene. We will examine the current management of patients with CMT and related disorders and analyse the perspectives for potential future treatments
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