Data for this review were identified by searches of PubMed with the search terms “Charcot-Marie-Tooth” and “inherited neuropathies” and these terms were combined with “inflammation”, “lymphocytes”, “macrophages”, and “treatment”. First search strategies were done for previous original and review articles on the topic in 1999 and the search was updated monthly until March 2004. All publications, including those older than 20 years, were considered. Articles were also taken from searches of
ReviewImmune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients
Section snippets
Culprit genes and animal models of the most common CMT1 neuropathies
Peripheral myelin protein 22 (PMP22), myelin protein zero (P0, MPZ) and connexin 32 (CX32) are the genes most commonly implicated in demyelinating inherited neuropathies.2, 3, 4 Other Schwann-cell-related genes cause much rarer demyelinating inherited neuropathies including the integral membrane protein periaxin, the transcription factor EGR2, and myotubularin-related protein 2. These are not considered further in this review.
PMP22
More than 50% of all CMT1 neuropathies are caused by a 1·5 megabase DNA duplication of chromosome 17p11·2 comprising the gene of the Schwann cell-related integral membrane protein PMP22.5 The resulting disorder is designated CMT1A. Although the role of PMP22 is not completely understood, promotion of myelin formation and maintenance are considered to be important functions.3, 6 Transgenic mice and rats have been generated to mimic the raised gene dose of PMP22 as the underlying gene defect in
P0
Another glial gene, located on chromosome 1q22, encodes the myelin-adhesion molecule P0, which plays a pivotal role in myelin compaction.4, 6 This glycoprotein is a 30 kD adhesion molecule with a single immunoglobulin domain and interacts with PMP22.12 On the basis of in vitro studies, P0 seems to mediate compaction of myelin owing to its homophilic adhesion properties that are crucial for the close apposition of the extracellular surface of the spiralling Schwann-cell membrane when forming the
CX32
Mutations in the gene for the gap-junction protein CX32 (gap-junction protein beta 1, GJB1) cause the X chromosomal dominant form of CMT (CMT1X). The discovery that CX32 is a component of peripheral nerve myelin originated from the observed linkage of CMT1X to mutations in CX32.22 More than 400 mutations have been described in human beings that all cause a clinical and pathological phenotype of moderate severity in hemizygous males. Detailed immuncytological investigations and the finding of
Evidence for a pathogenetic role of immune cells in animal models
We and others have previously shown that in mice heterozygously deficient for P0 (P01/−), numbers of CD8 lymphocytes and macrophages are elevated in peripheral nerves.31, 32 The lymphocytes are few in number, are not arranged in clusters, but are almost uniformly dispersed in the endoneurium without the preference to perivascular, perineurial, or epineurial compartments typically seen in primary immune-mediated neuropathies.29 Macrophages outnumber the T-lymphocytes by a factor of about 20 and,
Concluding remarks: a hypothesis on the immune component in CMT 1
On the basis of the unequivocal finding that immune cells (macrophages and T lymphocytes) are definitively involved in primarily genetically mediated demyelination in myelin mutant mice, we aimed to find evidence that the immune system may operate in a similar way in patients with CMT1.
The observation that a few patients respond to anti-inflammatory treatment was taken as evidence that this type of autoimmune disorder may be common to CMT1 in general. However, considering various clinical,
Search strategy and selection criteria
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2013, Experimental NeurologyProlonged high frequency electrical stimulation is lethal to motor axons of mice heterozygously deficient for the myelin protein P<inf>0</inf> gene
2013, Experimental NeurologyCitation Excerpt :Early pathogenic studies in dysmyelinating CMT were focused on the abnormal axon-Schwann cell interaction (Kamholz et al., 2000; Maier et al., 2002; Sahenk, 1999) as some P0 mutations were found to cause loss of axons in the absence of dysmyelination (Li et al., 2006; Marrosu et al., 1998). More recently, studies in P0 deficient mice (Carenini et al., 2001; Martini and Toyka, 2004; Martini et al., 2008; Schmid et al., 2000; Wang et al., 2006) as well as other CMT models (Kobsar et al., 2005) revealed a substantial increase of inflammatory cells within the dysmyelinated nerves. This raised the possibility that neurotoxic immunological mediators such as nitric oxide (NO) may play a role in the neurodegenerative process.