TY - JOUR
T1 - Axonal Charcot-Marie-Tooth Disease
T2 - from Common Pathogenic Mechanisms to Emerging Treatment Opportunities
AU - McCray, Brett A.
AU - Scherer, Steven S.
N1 - Funding Information:
This work was supported by NIH/NINDS K08 NS102509 (B.A.M.), the American Academy of Neurology Neuroscience Research Training Fellowship 0078966/129168 (B.A.M.), the Judy Seltzer Levenson Memorial Fund for CMT Research, the INC (U54NS065712), which is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the NINDS (S.S.S). We thank Natalia Nedelsky for graphical assistance.
Publisher Copyright:
© 2021, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.
AB - Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.
KW - Axonal neuropathy
KW - Charcot-Marie-Tooth disease
KW - Pathogenesis
KW - Peripheral neuropathy
KW - Treatment
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U2 - 10.1007/s13311-021-01099-2
DO - 10.1007/s13311-021-01099-2
M3 - Review article
C2 - 34606075
AN - SCOPUS:85116926195
SN - 1933-7213
VL - 18
SP - 2269
EP - 2285
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 4
ER -