Inflammatory demyelinating CNS disorder in a case of X-linked Charcot–Marie–Tooth disease: positive response to natalizumab

Abstract

Charcot–Marie–Tooth (CMT) is an inherited peripheral neuropathy affecting approximately 1 in 2,500–3,000 [1]. X-linked CMT (CMTX) is caused by mutations in the gene encoding connexin 32 (Cx32) [2, 3]. Cx32 is a gap junction protein expressed in many cell types including both Schwann cells and oligodendrocytes [4]. The latter is probably responsible for the subclinical, and rarely transient clinical, CNS involvement that has been documented in CMTX [5–9]. Here we report the case of a 22-year-old man with known CMTX who presented with a rapidly relapsing inflammatory central demyelinating disorder, which fully responded to natalizumab treatment. The patient’s Cx32 (S26L) mutation in the first transmembrane domain of the Cx32 gene is a de novo base exchange (c77t), as the patient’s mother did not carry the gene alteration. His hereditary neuropathy had been diagnosed 2 years before he was referred to us with subacute complaints of vertigo, vision disturbances, and diplopia. On clinical examination, saccadic eye movements and decreased vision were noted. Moreover, distal palsy of the lower limbs more than the upper limbs with distal muscular atrophy was noted as sequelae of the peripheral neuropathy. Feet extension was highly paretic resulting in a marked stepper gait. Light touch sensation was distally reduced in both upper and lower limbs, with mild to moderately reduced pallesthesia. Gait was atactic and a dysmetric finger–nose test as well as a feeling of vertigo while standing and sitting were found. Achilles’ reflexes were absent with otherwise symmetric, normal muscular reflexes. Muscle tension was normal to hypotonic, and no pyramidal signs were noticed. Due to the new and subacute symptoms suggesting CNS involvement, an MRI was performed which showed several focal both gadolinium (Gd)-uptaking and non-Gd-uptaking lesions with MS-typical distribution including ‘‘black holes’’ infraas well as supratentorially (see Fig. 1a, c, e). Electrophysiology showed sensory-evoked afferent conduction slowing from upper and lower limbs, as well as bilaterally delayed visual-evoked potentials on the right side more than on the left side. Neurography was consistent with the known sensomotory, demyelinating, and axonal polyneuropathy. Further investigation revealed an inflammatory CSF constellation with 22 cells/ll, intrathecal oligoclonal IgG production including an elevated varizella zoster virus antibody index as well as minor blood–brain barrier impairment. Partial optic nerve atrophy was observed funduscopically and decreased vision (right eye 40%; left eye 60%) was found on both sides sustaining the diagnosis of optic neuritis. These findings based on the clinical and MRI results were disseminated in space and time and suggest that the patient had an inflammatory CNS disorder fulfilling the criteria for multiple sclerosis. Consequently, the patient was treated with two cycles of high-dose methylprednisolone (1 g i.v. daily for 3 days), which resulted in a partial remission and improved vision J. H. Weishaupt M. Bahr DFG-Research Center for Molecular Physiology of the Brain (CMPB), Humboldtallee 23, Gottingen, Germany