Charcot-Marie tooth

Peripheral neuropathy is degeneration of peripheral nerves. Because motor and sensory axons tun in the same nerves, usually both motor and sensory functions are affected in this disease. Neuropathies may be either acute (e.g., Charcot-Marie-Tooth disease) or chronic (e.g., Guillain-Barre syndrome) and are categorized as demyelinating or axonal. 

Wrabetz, L., Feltri, M. L. and Suter, U. Models of Charcot-Marie-Tooth disease. In R. A. Lazzarini (ed.), Myelin biology and disorders. San Diego, CA Elsevier Academic Press, 2004, 1143-1168. 

The importance of P0 in PNS myelin has been clearly demonstrated. In P0 gene knockout experiments in mice [40], severe hypomyelination and a virtual absence of compact myelin in the PNS is observed. In humans, there are two disease states associated with mutations in the P0 gene Charcot-Marie-Tooth type I disease (see Ch. 38) and Dejerine-Sottas disease, both dysmyelinating diseases that exhibit a spectrum of severity depending on the particular mutation. 

Other diseases with disruptions in neurofilament organization include diabetic neuropathy and Charcot-Marie-Tooth disease. For these diseases, the disruption of neuro filaments may be a secondary effect as in the case of trembler axons or a direct effect. For example, some forms of Charcot-Marie-Tooth peripheral neuropathy result from mutations in a neurofilament subunit [22, 43]. In most cases, neuronal degeneration is an eventual consequence, but neuronal function may be impaired prior to substantial loss of neurons. Generally, disruptions of neurofilaments have the most severe consequences in large motor neurons, which is consistent with the fact that the largest neurons have the highest levels of neurofilament expression. 

Brownlees, J., Ackerley, S., Grierson, A. J. et al. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum. Molec. Genet. 11 2837-2844, 2002. 

Neuropathies can result from mutations that alter the structure or level of expression of PNS myelin proteins (e.g. overexpression of PMP22 in Charcot-Marie-Tooth syndrome (CMT) type 1A), the metabolism of myelin lipids (e.g. metachromatic leukodystrophy), or the capacity of PNS neurons to support their axons in patients with CMT caused by mutations of KIF1B [4] or NF-L [5, 6]. Both acquired and inherited amyloid neuropathies can result from the deposition of poorly soluble proteins, for example cryoglobulins or mutant transthyretins, in and around endoneurial bloodvessels [7-9]. 

Zhao, C., Takita, J., Tanaka, Y. et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1B 3. Cell 105 587-597, 2001. 

Jordanova, A., De Jonghe, P., Boerkoel, C. F. et al. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain 126 590-597, 2003. 

Hattori, N., Yamamoto, M., Yoshihara, T. et al. Study Group for Hereditary Neuropathy in Japan. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32) a clinicopathological study of 205 Japanese patients. Brain 126 134-151,2003. 

Boerkoel, C. F., Takashima, H., Garcia, C. A. et al. Charcot-Marie-Tooth disease and related neuropathies. Mutation distribution and genotype-phenotype correlation. Ann. Neurol. 51 190-201,2002. 

Passage, E., Norreel, J. C., Noack-Fraissignes, P. etal. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat. Med. 10 396-405, 2004. 

Bergoffen, J., Scherer, S. S., Wang, S. et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262 2039-2042,1993. 

Birouk, N., Azzedine, H., Dubourg, O. et al. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene. Arch. Neurol. 60 598-604,2003. 

Charcot-Marie-Tooth disease and other inherited neuropathies AD, AR or X-linked PMP-22, P0, connexin-32 and other genes Variable degrees of myelin deficiency specific for the PNS see text 1,28-30... 

BCAA branched chain amino acids CMT Charcot-Marie-Tooth disease... 

Mutations in motor proteins or IFs themselves (which may alter their associations with IFAPs or motors) lead to accumulations of IFs in ALS, Charcot-Marie Tooth disease 2, and Parkinson s (Goldstein and Yang, 2000 Helfand et al., 2004). Impaired assembly and transport of NFs is a critical determinant of neurodegenerative disease. Consistent with a critical role for kinesin in vivo, mice lacking the neuronal-specific conventional kinesin heavy chain KIF5A were shown to have accumulations of NF-H, as well as NF-M and NF-L, in the cell bodies of peripheral sensory neurons. The presence of these accumulations was accompanied by a reduction in... 

Key words Motor neuron diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), peripheral neuropathies, Charcot-Marie-Tooth diseases, hereditary motor and/or sensory neuropathies (HSMNs), congenital myasthenic syndromes, neuromuscular junction, muscular dystrophies, Duchenne s disease. 

Seburn, K. L., Nangle, L. A., Cox, G. A., Schimmel, P. and Burgess, R. W. (2006) An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51, 715-726. 

Detmer, S. A., Vande Velde, C., Cleveland, D. W. and Chan, D. C. (2008) Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Hum Mol Genet 17, 367-375. 

Vigo T, Nobbio L, Hummelen PV, Abbruzzese M, Mancardi G, Verpoorten N, et al. Experimental charcot-marie-tooth type 1A A cDNA microarrays analysis. Mol Cell Neurosci 2005 28(4) 703-714. 

In part two, we review the role of Pis in human disease. Although Pis are not abundant in biological systems, they have displayed numerous important functions in multiple signal transduction pathways. A number of human diseases are characterized by dysfunctional PI pathways, including cancer, type 2 diabetes, Lowe syndrome, myotubular myopathy, and Charcot-Marie-Tooth disease. 

Berger, P., Bonneick, S., Willi, S., Wymann, M., and Suter, U., 2002, Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Hum. Mol. Genet. 11 1569-1579. 

Primary Demyelination and Hypomyelination in the PNS Charcot-Marie Tooth Diseases (CMT)... 

As noted in the preceding section, Cx32 is a ubiquitous protein that is also found in CNS myelin. Its presence in Schwann cells was discovered when Cx32 mutations were associated with Charcot-Marie-Tooth disease of the CMTX type. CMTX is an X-linked demyelinating neuropathy. The molecule is located in the paranodes. There are subtle anomalies of the myelin sheath and the Ranvier node (Hahn et al.,... 

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