Charcot–Marie–Tooth disease (CMT) is a peripheral nerve, single gene, inherited condition with defined clinical and genetic heterogeneity (El-Abassi et al., 2014). It has different incidence rates across various regions and subtypes (Barreto et al., 2016) and its diagnosis is based on a combination of family genetic history, electromyography (EMG), and clinical factors, such as chronic progressive lower extremity distal weakness and muscular atrophy, a reduction in reflexes, and multiple malformations (Pareyson et al., 2006; Barisic et al., 2008; Banchs et al., 2009). Magnetic resonance neuropathy (MRN) has allowed for the accurate, large-scale, three-dimensional display of the entire nerve tract and its branches, furthermore, providing noninvasive quantitative characteristics.

In this study, we reported a rare CMT genotype, a rare MPZ missense mutation, NC_000001.11 (NM_000530.6): c.308G > C that is detected by next-generation sequencing. Moreover, we described a typical presentation as two patterns of hypertrophy in the brachial and lumbosacral (LS) plexus, as well as enhancement in cauda equina and nerve roots, which could be helpful for identifying coexisting inflammation in hereditary sensory and motor neuropathy.

This study was approved by the institutional ethical review board, and a written informed consent was obtained from the patient. Clinical data were obtained from electronic medical records. The multimodal MRN examination was performed on a 3.0T MRI scanner (MAGNETOM Trio, Siemens Healthcare, Germany). The MRN protocol and post-processing procedures were as previously described (Su et al., 2019; Su et al., 2021). Specific sequences parameters are provided in the Supplementary Table.

In this study, we report a case of a rare MPZ mutation with an uncommon phenotype, that NC_000001.11 (NM_000530.6): c.308G > C was detected by next-generation sequencing. The SIFT and PolyPhen-2 databases were used to predict the variability in the heterozygote, and the incidence was very low in the population. In 2001, Fabrizi et al. (2001)first found the c.308G > A mutation in two CMT type I patients who were sisters, and verified that the mutation was not present in 50 unaffected individuals. The MPZ is located at locus 1q22 and belongs to the immunoglobulin superfamily and it is a type of adhesion molecule connecting sphingomyelin and plays a role in the formation of the myelin sheath. Most mutations lead to the formation of an abnormal extracellular structure of the protein (Warner et al., 1996; Shy et al., 2004).

MRN revealed hypertrophy of the nerve roots and their branches in the entire body, accompanied by increased T2 signal intensity, which was due to repeated demyelination and remyelination, consistent with previous findings (Chung et al., 2008; Chhabra et al., 2016; Khadilkar et al., 2017). Chhabra et al. (2016) reported that nerves in CMT show predominantly diffuse thickening, whereas those in chronic inflammatory demyelinating polyneuropathy (CIDP) are discontinuous, non-uniform, or patchily thickened. We found diffuse uniform hypertrophy of the brachial plexus, and multifocal fusiform hypertrophy of the LS plexus. The thickened pattern was similar to that of CIDP (Su et al., 2020). The inherent mechanism should be evaluated further.

As early as 1982, there were reports of the coexistence of hereditary and inflammatory neuropathy (Dyck et al., 1982). Gabriel et al. (2002) reported neuroinflammation in some CMT type I patients, confirmed by nerve biopsy , which is an invasive examination. In this case, EMG revealed severe diffuse sensorimotor polyneuropathy with demyelination and axonal loss, but failed to identify inflammation. When CMT is combined with certain types of acute and chronic peripheral nerve inflammation, clinical and electrophysiological examinations can be even more difficult to resolve, with potentially missed diagnoses (Trivedi et al., 2015; Zhan et al., 2015). However, enhancement was found in the cauda equina and nerve roots, implying coexistent inflammation, resulting from the increased permeability of the BNB. Moreover, the signal reductions, that is worm-eaten cavities, were detected in neural stems, which may be attributed to the effects of short T2 relaxation time by contrast agents, a feature that has been reported in CIDP patients (Su et al., 2020). Subsequent neuroinflammation, in this case, was confirmed by experimental immunotherapy and lumbar puncture.

DTI, a relatively powerful MR technology for nerve tracer imaging, provides quantitative assessment of peripheral nerve degeneration and changes in the tissue microstructure (Mukherjee et al., 2008; Tagliafico et al., 2011). It is generally believed that FA values are correlated with the density and diameter of axons as well as the density and thickness of myelin sheath, though the relation is thought to be much closer to the axons. When genetics lead to abnormal development of the myelin, long-term repeated loss and repair of the myelin sheath and axonal degeneration cause the cessation of diffusion of water molecules along the long axis of the nerve, and the FA value decreases (Carvalho et al., 2005). In this case, the site of fusiform hypertrophy in the LS plexus has close to the diffusion weighting of free water, indicating severe destruction of nerve tracts of the myelin sheath. This outcome is consistent with that of previous EMG studies; however, it is not consistent with mild clinical neurological signs after immunotherapy, which may probably be related to compensation due to slow progression of nerve injury over a long time period.

This study has some limitations. First, we failed to acquire the MRN characteristics of CMT type 1B with MPZ mutation while without neuroinflammation as a comparison. We have no more patients with CMT type IB disease associated with MPZ mutations, due to the incidence being very low in the population. Second, since there was only one case, we could not make a correlation analysis between the MRN pattern and disease duration. Therefore, a larger sample size might be required in future studies.

In conclusion, we reported a rare CMT genotype with atypical presentation complicated with neuroinflammation. MRN may be vital for identifying coexisting inflammation in hereditary sensory and motor neuropathy, especially for the patients with atypical symptoms or lack of a clear history. Furthermore, genotyping can provide scientific guidance for early intervention while prenatal DNA testing or pre-implantation genome diagnosis is important to protect future generations.