To summarise, we report a kindred with a novel mutation in the MPZ gene, which results in a mild form of CMT disease (in relation to motor dysfunction and sensory loss), but debilitating neuropathic pain.
MPZ is an integral membrane glycoprotein synthesised by Schwann cells; it is the major glycoprotein of peripheral nerve myelin and possesses an intracellular and extracellular domain. Homotypic interactions between the extracellular domains of MPZ mediate the compaction of myelin lamellae [6,16,18]
. A large number of different MPZ mutations have been reported in association with CMT (Inherited Peripheral Neuropathies Mutation Database: Mutations in MPZ [P0] http://www.molgen.ua.ac.be/CMTMutations/Mutations/Mutations.cfm?Context=2
). These display striking phenotypic variability and include axonal, demyelinating, and intermediate forms of CMT, with differing levels of severity from mild to severe neuropathies 
. These can be broadly split into 2 groups: a severe early-onset demyelinating neuropathy and a late-onset neuropathy with predominantly axonal loss. Certain mutations associated with the former have gain of function-dominant negative effects and mutations associated with the latter partial loss of function 
. The Trp101X mutation is predicted to result in premature termination of translation and a truncated protein lacking the transmembrane domain required for membrane anchorage. This may, therefore, be predicted to lead to less MPZ protein insertion into the myelin membrane. The level of MPZ within myelin membranes was found to be normal in another mutation that causes premature truncation: the heterozygous Val102 frame shift mutation 
. This indicates that there may be potential compensatory mechanisms, although such compensation for gene dosage must be incomplete, as individuals with these mutations develop a mild neuropathy.
CMT is increasingly recognised as a cause of both nociceptive and neuropathic pain [3,7]
, and there is some evidence that neuropathic pain may be more common in the axonal rather than demyelinating forms of CMT. The distribution and nature of the pain experienced by patients with the Trp101X MPZ mutation was neuropathic in nature, and these patients would fulfil recent criteria for definite neuropathic pain 
. There have been occasional reports of neuropathic pain associated with MPZ mutations. Burns et al. reported a patient who developed an acute neuropathy with pain as a prominent feature, evidence of demyelination on neurophysiology, who was found to have an Arg36Trp mutation in MPZ 
. Schneider-Golf et al. report a German kindred with an Asp234Tyr missense mutation resulting in a neuropathy with features of intermediate conduction, the predominant symptom being burning sensations in the arms and legs as well as muscle cramps 
. Such reports are, however, the exception rather than the rule.
A number of other frame shift or premature stop MPZ mutations leading to a nonfunctional truncated MPZ protein in the heterozygous state (ie, those mutations likely to share the same pathophysiological mechanisms as the Trp101x mutation) have been described as causing a mild neuropathy with intermediate conduction. The symptoms are often predominantly sensory rather than motor, including paraesthesia and muscle cramps; and the index case carrying the Glu71stop mutation described by Lagueny et al. complained of burning pain of the extremities [15,20,21,35]
. It should be noted that some subjects carrying such mutations have, however, been reported to be asymptomatic, indicating potential modifying factors.
Extensive preclinical literature exists regarding the aetiology of neuropathic pain following traumatic nerve injury or in the context of axonal neuropathies 
. Less is known regarding the pathophysiology of neuropathic pain in demyelinating neuropathies. Primary demyelination has been shown to induce neuropathic pain-related hypersensitivity that was associated with ectopic activity in primary afferents 
. Mice that lack the myelin constituent periaxin have been shown to develop ectopic activity in primary afferents and pain-related hypersensitivity 
associated with demyelination. The generation of neuropathic pain by demyelination may relate to a number of potential mechanisms, including the redistribution of ion channels in demyelinated axolemma 
, Schwann cell proliferation 
, the release of cytokines and chemokines 
, and the recruitment of inflammatory cells such as macrophages 
. The neuropathic pain reported in relation to the MPZ mutations described by Burns et al. and Schneider-Gold et al. was thought to partially have an immune aetiology, given the acute onset, and in one case, the patient’s pain responded to treatment with intravenous immunoglobulin [2,26]
The majority of our patients with the Trp101X mutation had evidence of distal, symmetrical sensory impairment on bedside testing. Only 2 patients agreed to detailed quantitative sensory testing, making it difficult to draw definitive conclusions about the pattern of sensory dysfunction in these patients. Both patients had a tendency to raised detection thresholds to cooling, which is likely to relate to impaired function in thin myelinated fibres 
. In relation to the function of large myelinated sensory fibres, one patient had raised mechanical-detection threshold in response to the application of von Frey filaments and impaired vibration detection. There were also some signs of hypersensitivity to sensory stimuli applied to the foot, including a unilateral enhanced wind-up ratio and lowered pressure pain threshold. In one patient who consented to a skin biopsy, there was no evidence of loss of C fibres within the epidermis of the lower leg (a region that was symptomatic in relation to pain). We had hoped to assess whether there was evidence of demyelination and altered ion channel distribution in myelinated dermal fibres. Myelinated internodes have previously been reported in skin biopsy samples 
and were reliably observed in our control samples. We could not, however, visualise any myelinated internodes in the patient with the Trp101X MPZ mutation despite immunostaining of sections throughout the sample. This may be indicative of distal demyelination; however, we cannot exclude the possibility that this could be a sampling issue. It is likely that dysfunction in sensory axons that would normally be myelinated is responsible for the neuropathic pain in these patients.
These cases emphasise the heterogeneity of the phenotype of MPZ mutations, the fact that mutations in myelin proteins can result in disabling neuropathic pain and that there is no simple relationship between overall neuropathy severity and the degree of neuropathic pain.