Challenges in modelling the Charcot-Marie-Tooth neuropathies for therapy development

Abstract

Much has been achieved in terms of understanding the complex clinical and genetic heterogeneity of Charcot-Marie-Tooth neuropathy (CMT). Since the identification of mutations in the first CMT associated gene, , the technological advancement in molecular genetics and gene technology has allowed scientists to generate diverse animal models expressing monogenetic mutations that closely resemble the CMT phenotype. Additionally, one can now culture patient-derived neurons in a dish using cellular reprogramming and differentiation techniques. Nevertheless, despite the fact that finding a disease-causing mutation offers a precise diagnosis, there is no cure for CMT at present. This review will shed light on the exciting advancement in CMT disease modelling, the breakthroughs, pitfalls, current challenges for scientists and key considerations to move the field forward towards successful therapies.

A novel family with axonal Charcot‐Marie‐Tooth disease caused by a mutation in the EGR2 gene

“…Otherwise, in the last years it is growing up the idea that pathogenic mutations may act synergistically with other unknown genetic and epigenetic modifiers that could influence the clinical phenotype and the electrophysiological pattern as well.…”

Insights into the pathogenesis of ATP1A1‐related CMT disease using patient‐specific iPSCs

“…In the last years, iPSC‐derived neurons or glial cells have been developed from CMT patients suffering from axonal or demyelinating forms of the disease . Notably, the iPSC‐derived neurons developed from axonal CMT patients, carrying MFN2 , NEFL , or HSPB1 mutations, have shown morphological and functional abnormalities that significantly contribute to the understanding of molecular mechanisms underlying the defects observed in the various families.…”

“…Notably, the iPSC‐derived neurons developed from axonal CMT patients, carrying MFN2 , NEFL , or HSPB1 mutations, have shown morphological and functional abnormalities that significantly contribute to the understanding of molecular mechanisms underlying the defects observed in the various families. In CMT2A, where mutations of MFN2 gene were detected, motor neurons derived from iPSCs were found to be hyperexcitable, probably due to an increased sodium current density and an impaired inactivation of voltage dependent calcium channels . Similarly, in CMT2E, bearing mutations in NEFL gene, iPSC‐derived neurons were hyperexcitable, although no change in sodium current density was described .…”

“…In the last years, iPSC-derived neurons or glial cells have been developed from CMT patients suffering from axonal or demyelinating forms of the disease. 19 Notably, the iPSC-derived neurons developed from axonal CMT patients, carrying MFN2, NEFL, or HSPB1 mutations, have shown morphological and functional abnormalities that significantly contribute to the understanding of molecular mechanisms underlying the defects observed in the various families. In CMT2A, where mutations of MFN2 gene were detected, motor neurons derived from iPSCs were found to be hyperexcitable, probably due to an increased sodium current density and an impaired inactivation of voltage dependent calcium channels.…”

“…5,19 Similarly, in CMT2E, bearing mutations in NEFL gene, iPSC-derived neurons were hyperexcitable, although no change in sodium current density was described. 5,19 The authors suggested that the increased neuronal firing observed in motor neurons from CMT2A and CMT2E patients might lead to axonal degeneration, possibly due to Na + /K + pump failure and Ca 2+ influx. Therefore, altered function of Na + /K + ATPase appears to be one of the key players in the development of several forms of the disease.…”