Central involvement in X-linked Charcot-Marie-Tooth disease

Nicholson PD, Pulst SM. Centrally involved X-linked Charcot-Marie-Tooth disease presenting as a stroke-mimic. Neurol Genet. 2017 Jan 5;3(1):e128.

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is the second most common hereditary motor sensory neuropathy (HMSN) representing an estimated 10%–15% of occurrences. CMTX1 arises from mutations in the gap-junction beta-1 gene (GJB1) on chromosome Xq13.1, which encodes the gap-junction protein connexin-32.1 Rather unique to CMTX1, among other forms of HMSN, is CNS involvement in a minority of patients with CMTX1.

We discuss the case of a 28-year-old man who presented with abrupt-onset severe dysarthria initially interpreted as being symptoms of stroke. In subsequent workup, his presentation was found to be due to previously undiagnosed CMTX1.

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From the article

Further history revealed that the patient had been admitted for 2 previous episodes of transient neurologic dysfunction at ages 10 and 14 years. Records from those admissions showed that on both presentations, MRI had shown similar findings. In each case, acute demyelinating encephalomyelitis had been suspected resulting in treatment with high-dose corticosteroids. Repeat MRI at 6-month follow-up in each case had shown complete resolution of the lesions…

CNS involvement of CMTX1 can cause transient neurologic dysfunction in men and more rarely in women carriers.  This is likely related to the presence of connexin-32 in oligodendrocytes as well as Schwann cells. Abnormal connexin-32 disrupts transport of ions through gap junctions, causing instability of the affected myelin and leading to central and peripheral nervous system manifestations of CMTX1…

This highlights that the CNS involvement in CMTX1, although rare, should be considered in the differential for acute stroke in young patients. Family history is important, and may aid in diagnosis, as it did in this case. Presentations can be clinically heterogeneous, with symptoms lasting hours to weeks and including relatively rapid onset of hemiparesis, sensory loss, dysarthria, aphasia, and even complete paralysis.

Despite clinical heterogeneity, imaging findings appear to be stereotyped with diffusion restriction in the posterior subcortical white matter (most often bilateral) and splenium of the corpus callosum on MRI.  It is interesting to note that in addition to predisposing factors of infection and physical exertion, change to high-altitude locations has been associated with development of white-matter lesions in CMTX1.3 MRI lesions in the splenium and posterior white matter are shared in patients with CMTX1 and individuals with high-altitude cerebral edema. Common to both is apparent diffusion coefficient hypointensity of the lesions indicating cytotoxic edema.