Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3). 80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes. This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group. These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults. EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257 . The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).

Antibodies to Contactin-1 and Neurofascin 155 (Nfasc155) have recently been associated with subsets of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Contactin-1 and Nfasc155 are cell adhesion molecules that constitute the septate-like junctions observed by electron microscopy in the paranodes of myelinated axons. Antibodies to Contactin-1 have been shown to affect the localization of paranodal proteins both in patient nerve biopsies and in animal models after passive transfer. However, it is unclear whether these antibodies alter the paranodal ultrastructure. We examined by electron microscopy sural nerve biopsies from two patients presenting with anti-Nfasc155 antibodies, and also four patients lacking antibodies, three normal controls, and five patients with other neuropathies. We found that patients with anti-Nfasc155 antibodies presented a selective loss of the septate-like junctions at all paranodes examined. Further, cellular processes penetrated into the expanded spaces between the paranodal myelin loops and the axolemma in these patients. These patients presented with important nerve conduction slowing and demyelination. Also, the reactivity of anti-Nfasc155 antibodies from these patients was abolished in neurofascin-deficient mice, confirming that the antibodies specifically target paranodal proteins. Our data indicate that anti-Nfasc155 destabilizes the paranodal axo-glial junctions and may participate in conduction deterioration.

Neuropathologic abnormalities can be sufficiently characteristic to suggest the genetic basis of some hereditary neuropathies such as those associated with mutations in MPZ , GJB1 , GDAP1 , MTMR2 , SH3TC2 , PRX , FGD4 , and LMNA . We analyzed the morphologic features of 9 sural nerve biopsies from 6 patients with mutations of mitofusin 2 . All patients presented in early childhood with axonal neuropathies designated as mild or severe motor and sensory neuropathy. In all cases, there was a marked decrease in density of myelinated fibers, mainly of large diameter fibers. These changes were more marked in the second biopsies of 3 patients that were performed from 7 to 19 years after the first biopsies. Neurophysiologic findings were most suggestive of axonal degeneration, but some onion bulbs were present in all cases. Axonal mitochondria were smaller than normal, were round, and were abnormally aggregated. These changes may result from abnormal mitochondrial fusion and fission. The results suggest that these clinical and pathological features may be sufficiently characteristic to suggest the diagnosis of mitofusin 2 -related neuropathy.

Polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (MAG) antibodies is an immune-mediated demyelinating neuropathy. The pathophysiology of this condition is likely to involve anti-MAG antibody deposition on myelin sheaths of the peripheral nerves and it is supposed to be distinct from chronic inflammatory demyelinating neuropathy (CIDP), another immune-mediated demyelinating peripheral neuropathy. In this series, we have retrospectively reviewed clinical and laboratory findings from 60 patients with polyneuropathy, IgM gammopathy, and anti-MAG antibodies. We found that the clinical picture in these patients is highly variable suggesting a direct link between the monoclonal gammopathy and the neuropathy. Conversely, one-third of patients had a CIDP-like phenotype on electrodiagnostic testing and this was correlated with a low titer of anti-MAG antibodies and the absence of widening of myelin lamellae. Our data suggest that polyneuropathy associated with anti-MAG antibodies is less homogeneous than previously said and that the pathophysiology of the condition is likely to be heterogeneous as well with the self-antigen being MAG in most of the patients but possibly being another component of myelin in the others.

This review focuses on recent advances in the diagnostic approaches and the underlying pathophysiological mechanisms of Charcot-Marie-Tooth (CMT) disease. We also discuss the emerging therapies for this hereditary neuropathy. To date, numerous genes are implicated in CMT, and new genes have recently been found to be associated with this neuropathy (INF2, FBLN5, etc.). Some specific or evocative clinical signs of CMT subtypes (proteinuria with INF2 mutations, etc.) have been identified. Characteristic pathological findings, which may suggest gene mutations, are also recognized by nerve biopsy (mainly ultrastructural lesions). CMT disease is the most common inherited neuromuscular disorder, with a fairly homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed tendon reflexes). With more than 40 genes implicated, an update of the present and rather confusing classification of CMT is needed. Over the last few years, new mutated genes have been discovered. Although nerve biopsy is not routinely carried out in CMT neuropathies, it may show characteristic features, which can orientate the search for the mutated gene. There are currently no effective medications for CMT, but clinical trials are ongoing or planned.