What is the pathophysiology of Charcot-Marie-Tooth (CMT) disease?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Traditionally, CMT pathophysiology has been categorized into 2 processes: a predominant demyelinating process resulting in low conduction velocities (CMT1) and a predominant axonal process resulting in low potential amplitudes (CMT2). However, even for CMT1 a heated debate has focused on the relative contribution of axonal versus demyelinative damage to the disease manifestations and progression.

In some hereditary neuropathies discussed below, focal asymmetric features (eg, hereditary neuropathy with liability to pressure palsy [HNPP]) predominate; in others (eg, certain cases of Charcot-Marie-Tooth disease type 1A (CMT1A) and inherited brachial plexus neuropathy [IBPN]/hereditary neuralgic amyotrophy [HNA]), proximal weakness predominates. Typically, a predilection exists for distal limbs as the site of disease onset and more severe symptoms and signs. Furthermore, while significant variation in nerve conduction velocities exists between and within families, this parameter does not predict severity, with the exception of the very low (ie, < 5 m/s) velocities observed in Dejerine-Sottas syndrome (DSS) and congenital hypomyelination neuropathy (CHN).

Axonal degeneration is a prediction of disability. This suggests that, in most cases, axonal damage is the root cause of the neuropathy, not demyelination. [6] However, the gene mutations responsible for the different forms of CMT1 are clearly myelin genes. Through mechanisms that at present can only be speculated about, myelin disturbances result in axonal damage. This is not surprising given the strong evidence for interaction between myelin and axon gene expression in development and after experimental nerve lesions. On the other hand, axonal damage can result in secondary demyelination.

Myelinating Schwann cells form a myelin sheath around a single axon and express high levels of myelin-related proteins and messenger RNA (mRNA). Axonal degeneration leads to Wallerian degeneration, in which myelin sheaths are phagocytosed, previously myelinating Schwann cells dedifferentiate, and mRNA expression is down-regulated. When Schwann cells re-ensheathe axons, levels of proteins or mRNA, or both, increase. Myelin genes and products affected in this manner include myelin protein zero (MPZ, P0), peripheral myelin protein 22 (PMP22), connexin 32 (CX32, Cx32), myelin-associated glycoprotein (MAG, Mag), myelin basic protein (MBP, Mbp), early growth response gene 2 (EGR2), periaxin (PRX), and others.

Whether Schwann cells differentiate into myelinating or nonmyelinating (a misnomer because such Schwann cells myelinate > 1 axon) phenotypes depends on axonal characteristics, which are determined at least in part by transcription factors such as Oct-6 (POU domain family) and EGR2.

Mutations in structural myelin genes or the transcription factors responsible for their expression lead to demyelination (ie, PMP22, P0, CX32, EGR2). P0, linked to Charcot-Marie-Tooth disease type 1B (CMT1B), is the most abundant protein in compact myelin and is a cell adhesion molecule (CAM). PMP22, linked to CMT1A, is a protein of unclear function that has features of both a channel protein and a CAM. Schwann cells also express Cx32, linked to X-linked Charcot-Marie-Tooth Disease type 1 (CMTX1), which belongs to the connexin family. EGR2 is a transcription factor linked to Charcot-Marie-Tooth disease type 1D (CMT1D).

More recently, mutations in the LITAF (lipopolysaccharide-induced tumor necrosis factor-alpha) complex were found to account for CMT1C; these mutations are involved in the proliferation and apoptosis in Schwann cells carrying PMP22 alterations. [7]

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