A rare association between multiple sclerosis and Charcot‐Marie‐Tooth type 1B

The association between multiple sclerosis (MS) and hereditary and sporadic demyelinating disorders of the peripheral nervous system is extremely rare. We herein report a case of Charcot‐Marie‐Tooth disease type 1B with p.Val102fs mutation in the MPZ gene that developed relapsing remitting MS.

Herein we describe a case of Charcot-Marie-Tooth disease type 1B (CMT1B) who developed relapsing MS.
A 40-years-old woman was admitted to our hospital complaining of a 10 years history of bilateral progressive weakness and numbness of the lower limbs, followed by loss of strength and difficulty with fine motor skills from a few months before the observation.
She also referred a history of bulimic alimentary disturbance when she was 34, fully recovered after 3-year treatment with paroxetine (20 mg/daily). Because of this disorder the patient underwent a brain MRI that showed two T2 hyperintense, nongadolinium-enhancing lesions of right semiovale center and corona radiata, initially interpreted as gliosis.
On admission, the neurological examination revealed ataxic gait, impossible on toes and heels, horizontal exhaustible nystagmus, mild distal muscle weakness (MRC = 4) of the four limbs more prominent on the right side, where the deep tendon reflexes were increased, with Hoffman and Babinski sign. There was also a moderate reduction in the vibration sensation in the four limbs, bilateral pes cavus, and urinary incontinence. Disability score on Expanded Disability Status Scale  studies revealed diffuse reduction in motor and sensory conduction.
The mutation p.Val 102fs has been also identified in the proband's brother and daughter.
The patient was diagnosed with MS and CMT 1B disease and she was then started on treatment with glatiramer acetate.
In the following 2 years the patient develop one clinical relapse, whereas MRI remained stable compared with the previous one.
In the case presented here, clinical history, imaging, and cerebrospinal fluid findings supported the diagnosis of MS. In particular, conventional MRI showed the dissemination in space and in time typical of MS, and spectroscopy revealed abnormal lower NAA (indicating that neuronal damage had already occurred) and higher Cho (suggestive of active membrane turnover, most likely due to de-and remyelination; Belinda et al., 2003).
However, neurophysiological analysis and family history suggested the co-occurrence of an autosomal inherited demyelinating neuropathy confirmed by the evidence of a point mutation in the P0 gene compatible with a diagnosis of CMT1B.
Few cases with a mutation in the MPZ gene and MS have been described until now and, to the best of our knowledge, this is the first case with a p.Val 102fs mutation (Table 1; Rajabally & Abbott, 2005). The p.Val102fs mutation in the MPZ gene has been reported previously, but no patient with this mutation showed a concomitant central nervous system involvement (Pareyson et al., 1999;Warner et al., 1996).
Given the very high prevalence of MS and the rarity of inflammatory and hereditary demyelinating neuropathy, the sporadic concomitant peripheral and central demyelination has been usually related to the chance (Potulska-Chromik et al., 2012). However, a potential explanation of this association may be the presence of an autoimmune disorder involving both central and peripheral myelin (Kawamura et al., 2013;Potulska-Chromik et al., 2012), only in a single case report of this association antifascin antibodies have been detected (Sharma et al., 2008). In the case presented here, we did not perform antifascin antibodies detection.
Data from literature reported the association between CMT (particularly CMT1B) and inflammatory neuropathy, supported by pathological studies on CMT1B animal models showing a lymphocytic infiltration with macrophages on the onion bulbs (Shy et al., 1997).
The authors thereby hypothesized a proinflammatory potential role of mutated P0 protein involved in CMT1B pathogenesis due to molecular mimicry (Shy et al., 1997). Additionally, a genetic susceptibility to develop MS has been aimed in patients with CMT1C, in which mutations in LITAF gene would lead to a TNF-α overexpression. A role of TNF-α in the pathogenesis and outcome of MS has been widely demonstrated, thus supporting the hypothesis that a possible link between these conditions may be tied to a proinflammatory role of mutated myelin proteins involved in the pathogenesis of CMT diseases (Potulska-Chromik et al., 2012).
Even if the association reported here is probably due to chance, the evidence of the increasing number of cases with CMT and MS may require larger prospective studies to clarify such a proinflammatory role.