Mechanisms and Treatments in Demyelinating CMT

Abstract

Demyelinating forms of Charcot-Marie-Tooth disease (CMT) are genetically and phenotypically heterogeneous and result from highly diverse biological mechanisms including gain of function (including dominant negative effects) and loss of function. While no definitive treatment is currently available, rapid advances in defining the pathomechanisms of demyelinating CMT have led to promising pre-clinical studies, as well as emerging clinical trials. Especially promising are the recently completed pre-clinical genetic therapy studies in PMP-22, GJB1, and SH3TC2-associated neuropathies, particularly given the success of similar approaches in humans with spinal muscular atrophy and transthyretin familial polyneuropathy. This article focuses on neuropathies related to mutations in PMP-22, MPZ, and GJB1, which together comprise the most common forms of demyelinating CMT, as well as on select rarer forms for which promising treatment targets have been identified. Clinical characteristics and pathomechanisms are reviewed in detail, with emphasis on therapeutically targetable biological pathways. Also discussed are the challenges facing the CMT research community in its efforts to advance the rapidly evolving biological insights to effective clinical trials. These considerations include the limitations of currently available animal models, the need for personalized medicine approaches/allele-specific interventions for select forms of demyelinating CMT, and the increasing demand for optimal clinical outcome assessments and objective biomarkers.

Endoplasmic Reticulum Stress in Chemotherapy-Induced Peripheral Neuropathy: Emerging Role of Phytochemicals

“…A known neuroprotective agent and has been recently associated with inhibition of ER stress regulatory factors in several nervous system-associated disorders [ 149 , 150 ]. The CMTD [CMT1 (CMT1A and CMT1B)] is associated with unregulated activation of ER stress-mediated UPR leading to cellular damage [ 151 ]. In the course of treatment, curcumin is found to impair calcium-dependent chaperones (calnexin, calreticulin), thus altering the ER Ca 2+ levels and subsequently decreasing the UPR/activation of the ERAD pathway [ 152 ].…”

Recent advances in the treatment of Charcot‐Marie‐Tooth neuropathies

“…Many progresses have been made in the last three decades in the identification of genes and mutations and in the elucidation of the disease pathogenesis, through the generation of animal and cellular models, that have been instrumental to study disease physiology. 5,6 However, therapies are not yet available for any CMT form. This can be due to several issues: CMTs are caused by more than 1500 mutations in at least 100 genes; the therapy should be delivered to the PNS (Peripheral Nervous System), that, as the CNS (Central Nervous System), is protected by the blood-nerve barrier; CMT models not always reproduce the severity of disease, particularly for axonal CMT2, and, finally, there is the need of natural history studies for many CMT forms with the identification of biomarkers and of informative outcome measures to adequately monitor disease progression that is often very slow.…”

High diagnostic yield with algorithmic molecular approach on hereditary neuropathies

“…Genetic heterogeneity of CMT has been revealed by the common use of next-generation sequencing (NGS). Until now, more than 100 genes have been described as having causative mutations for CMT 5 . Especially, four genes are responsible for nearly 80% of genetically inherited CMTs: PMP22, GJB1, MFN2, and MPZ 6 .…”