Charcot Marie-Tooth disease

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. 

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. 

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. 

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.,... 

Dubouig O (2004) Charcot-Marie-Tooth disease from phenotype to genotype. Rev Neurol (Paris) 160 1221-1229... 

Hahn AF, Ainsworth PJ, Bolton CF, Bilbao JM, VaUat JM (2001) Pathological findings in the x-finked form of Charcot-Marie-Tooth disease a morphometric and ultrastructural analysis. Acta Neuropathol (Berl) 101 129-139... 

Sereda MW, Meyer zu Horste G, Suter U, Uzma N, Nave KA (2003) Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-IA). Nat Med 9 1533-1537... 

Shy ME (2004) Charcot-Marie-Tooth disease an update. Curr Opin Neurol 17 579-585 Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, LUien J, Garbem JY, Kamholz J (2004) Phenotypic clustering in MPZ mutations. Brain 127 371-384... 

C. Zhao, J. Takita, Y. Tanaka, M. Setou, T. Nakagawa, S. Takeda, H.W. Yang, S. Terada, T. Nakata, Y. Takei, M. Saito, S. Tsuji, Y. Hayashi, and N. Hirokawa. 2001. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIFlBbetaCe// 105 587-597. (PubMedl... 

---