Objective X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS.
Methods Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS. Additionally, 18 patients with CMTX without CNS symptoms and 18 matched controls underwent brain MRI to investigate incidental findings. Serum from patients with CMTX and MS was tested for CNS immunoreactivity.
Results We identified three patients with CMTX who developed clinical features suggestive of inflammatory CNS demyelination fulfilling MS diagnostic criteria. The resulting 20-year MS incidence (4.3%) differed significantly from the highest background 20-year MS incidence ever reported from Greece (p=0.00039). The search for incidental brain MRI findings identified two CMTX cases (11%) with lesions suggestive of focal demyelination compared with 0 control. Moreover, 10 cases in the CMTX cohort had hyperintensity in the splenium of the corpus callosum compared with 0 control (p=0.0002). No specific CNS-reactive humoral factors were identified in patients with CMTX and MS.
Conclusions We have demonstrated a higher than expected frequency of MS in patients with CMTX and identified incidental focal demyelinating lesions on brain MRI in patients with CMTX without CNS symptoms. This provides circumstantial evidence for GJB1 mutations acting as a possible MS risk factor.
- multiple sclerosis
- CNS demyelination
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Contributors GKou conceived and designed the study, examined the patients clinically, reviewed the imaging findings, analysed the data and wrote the manuscript. MB contributed to study design, examined the patients clinically, analysed the data and revised the manuscript. GV contributed to study design, interpreted the imaging findings, analysed the data and revised the manuscript. JT contributed to the study design, performed and interpreted the immunological analysis, and revised the manuscript. CKar performed the genetic testing and revised the manuscript. EK designed and performed the imaging analysis, and revised the manuscript. DT, MA, EA, ME and CKil examined the patients clinically and revised the manuscript. DK contributed to the study design, performed and interpreted the neuropsychological testing, and revised the manuscript. CP contributed to the study design, interpreted the neuropsychological testing and revised the manuscript. MP conceived the study, contributed to the study design, examined the patients clinically and revised the manuscript. GKar conceived the study, contributed to the study design, performed the genetic testing and revised the manuscript.
Funding This work was partly supported by a grant from Teva Pharmaceuticals (grant number 12846, special account for research grants, National and Kapodistrian University of Athens).
Competing interests GK reports grants from Teva Pharmaceuticals and Genesis Pharma; personal fees from Novartis, Genesis Pharma, Sanofi-Genzyme and Teva Pharmaceuticals; non-financial support from Merck, Sanofi-Genzyme and Genesis Pharma; MB reports no disclosures; GV reports no disclosures; JT reports shares in a diagnostic laboratory (Tzartos Neurodiagnostics) in Athens; DK reports no disclosures; CK reports no disclosures; EK reports no disclosures; DT reports no disclosures; MA reports research grants from Biogen, Merck-Serono, Novartis, Teva, Bayer and Genzyme, as well as lecture-fees from Novartis, Teva, Biogen and Genzyme; EA reports research grants from Biogen, Merck-Serono, Novartis, and Sanofi-Aventis, as well as lecture-fees from Teva; M-EE reports consultation services and honoraria from Novartis, Biogen and Teva; CK reports research grants from Biogen, Novartis, Teva, and Merck-Serono; CP reports no disclosures; MP reports no disclosures; GK reports no disclosures.
Patient consent Obtained.
Ethics approval Eginition Hospital Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Anonymised data will be shared on request by any qualified investigator.
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