charcot - marie - tooth ( cmt ) disease encompasses a group of inherited disorders affecting the motor and sensory nerves of the peripheral nervous system .
it is characterized by progressive weakness and atrophy of distal muscles , high arched feet ( pes cavus ) , and loss of deep tendon reflexes .
five main types of cmt , with multiple subtypes , are described in most classification systems , and more than 60 causative genes are currently known .
x - linked charcot - marie - tooth disease type 1 ( cmtx1 ) is an x - linked , semidominant form of cmt .
this second most common form of cmt , accounting for 10 - 15% of cases , is caused by mutations in the gap junction protein beta 1 ( gjb1 ) gene located on chromosome xq13.1 , encoding connexin 32 ( cx32 ) .
cx32 is normally expressed in schwann cells , oligodendrocytes , and astrocytes , where it is thought to provide a pathway for the diffusion of small molecules and ions directly across the myelin sheath .
in addition to the common peripheral presentation of cmt , cmtx1 has been reported to have transient central nervous system manifestations . here
, we describe a cmtx1 patient who has experienced multiple episodes of transient central nervous system ( cns ) dysfunction associated with white matter abnormalities on magnetic resonance imaging ( mri ) of the brain , and demonstrate the temporal progression of his radiological abnormalities over the course of several years .
type 1 and a known personal history of cmtx1 presented to our emergency department with acute - onset dysarthria , tongue deviation , left facial weakness , and left hand numbness developing over the course of about 3 h. he described poor sleep , slight nausea , and mildly elevated blood glucose ( 183 mg / dl on home testing ) in the hours prior to symptom onset .
he noted no recent fevers , travel , or strenuous physical exercise . by the time of presentation
physical exam findings included a lingual dysarthria and subtle left facial weakness in an upper motor neuron pattern .
there was normal strength in all extremities except for ankle dorsiflexion graded at 4-/5 , which appeared to be his baseline .
there was subjectively decreased sensation in the left upper extremity , primarily in the medial forearm , but not in any specific peripheral nerve distribution .
the intrinsic muscles of the feet appeared atrophic , with hammer toes and high arches .
serum electrolytes , renal function , liver function tests , complete blood count with differential , erythrocyte sedimentation rate , and c - reactive protein were all normal .
mri of the brain showed symmetric , nonenhancing areas of restricted diffusion in the corona radiata bilaterally , also seen on t2/fluid - attenuated inversion recovery ( flair ) sequences ( fig .
intracranial mr angiography was normal . a review of the patient 's pediatric records revealed that he had experienced two prior episodes of unilateral weakness at ages 13 and 14 years , separated by 10 months .
both were of sudden onset but gradual evolution over the course of hours to their peak severity , and each resolved completely over the course of several days .
at the time of the first episode , the patient was admitted to the hospital and evaluated with cerebrospinal fluid ( csf ) studies and brain mri .
his csf showed no evidence of infection and was negative for oligoclonal bands , intrathecal immunoglobulin synthesis , and other markers of inflammation .
mri of the brain at that time demonstrated abnormalities in t2/flair and diffusion - weighted mri sequences in the bilateral centrum semiovale , right parietal lobe , and splenium of the corpus callosum without gadolinium enhancement ( fig .
he was initially diagnosed with acute disseminated encephalomyelitis ( adem ) and treated with methylprednisolone . a follow - up mri 3 months after the initial presentation had demonstrated nearly complete resolution of the lesions ( fig .
1b ) , and mr spectroscopy obtained 9 months after the initial event was unremarkable .
the second episode consisted of right - sided weakness and ataxia and resulted in another hospital admission with repeated imaging .
mri of the brain at this time demonstrated large , nonenhancing t2/flair hyperintensities in the bilateral centrum semiovale , the splenium of the corpus callosum , the left greater than right corticospinal tracts , and the left greater than right cerebellar peduncle ( fig .
a tentative diagnosis of recurrent adem was made , and treatment with steroids was provided .
the patient again improved quickly and had recovered to his baseline at a 6-month outpatient follow - up .
further evaluation continued in the outpatient setting , with symptoms of peripheral neuropathy becoming apparent .
nerve conduction studies and electromyography demonstrated low amplitude sensory and motor responses with sensory conduction velocities in the 38- to 46-m / s range and motor conduction velocities in the 37- to 54-m / s range .
the findings were suggestive of a mild - to - moderate sensorimotor polyneuropathy with mixed axonal and demyelinating features .
a detailed pedigree of other affected family members revealed that the patient 's mother , maternal grandfather , maternal aunt , and a male first cousin ( son of the affected aunt ) also have neuropathy , although none reported stroke - like episodes .
about 2 years after his initial presentation , genetic testing confirmed a t467 g ( leu156arg ) hemizygous disease - associated mutation in the gene for cx2 ( gjb1 ) .
four years after his initial presentation , after about 3 years free of episodes , a fourth brain mri was obtained to evaluate the progression of the extensive white matter lesions seen at the time of the second event ( fig .
this study showed a small nonenhancing area of t2/flair hyperintensity in the left cerebellar peduncle , with the previously seen signal in the right cerebellar peduncle , centrum semiovale , and splenium of the corpus callosum all resolved .
three years later , at the time of his most recent episode , the t2/flair hyperintensity in the left cerebellar peduncle had also resolved ( fig .
the clinical features of cmtx1 , an x - linked semidominant disorder , are characteristic of most dominant cmt forms .
patients have slowly progressive weakness and atrophy with onset in distal leg muscles , usually manifesting first as difficulty running and frequently sprained ankles .
however , they may develop mild clinical manifestations at an older age ( as with this patient 's mother ) , or have subclinical evidence of peripheral neuropathy on electrophysiological studies .
nerve conduction studies in cmtx1 show variable results , but typically , there is an intermediate ( 30 - 40 m / s ) or even mild ( > 40 m / s ) slowing of motor conduction velocities .
axon loss occurs even in early disease stages , suggesting an underlying mixed axonal and demyelinating pathology ; this distinguishes cmtx1 from most other cmt forms associated with mutations in myelin - related genes .
in addition to peripheral neuropathy , cmtx1 patients often have subclinical cns involvement that can be detected by brainstem auditory evoked potentials .
overt cns manifestations tend to be episodic and of acute to subacute onset , frequently described as stroke - like as in this case .
brain mri obtained during the acute phase of a stroke - like event usually shows an increased t2/flair - weighted signal , sometimes associated with restricted diffusion but without contrast enhancement .
involvement has been described most frequently in the posterior centrum semiovale , splenium of the corpus callosum , and sometimes the middle cerebellar peduncle .
these abnormalities have variously been described both as resolving completely or persisting even once patients are asymptomatic .
disruption of the gap junction - mediated coupling between oligodendrocytes and astrocytes likely leads to an inability of these cells to properly regulate ion and fluid exchange , which may explain the restricted diffusion seen on mri of the patient with cmtx1 in the acute phase of their illness .
such dysregulation may at least in part explain why stressors like high altitude , intense exercise , febrile illness , hyperventilation , and concussion have been found to precipitate the acute events .
although no clear precipitating events were found for any of this patient 's episodes , it is worth noting that he also has diabetes , and it is tempting to speculate that metabolic stress related to this condition could have been a contributor .
this case serves as a reminder that exacerbation of central cmtx1 disease is a consideration in the differential diagnosis of stroke - like acute - onset neurological deficit with diffusion - weighted positive mri , or an unusual adem - like illness .
the prognosis of the cns phenotype of cmtx1 is usually spontaneous resolution without permanent deficit ; therefore , promptly identifying the disease is vital to avoid unnecessary investigation and potentially harmful therapeutic intervention .
the central white matter lesions on mri in cmtx1 have been described previously as either fully or partly reversible . in the patient
reported here , some white matter signal changes persisted for 3 years but were found to fully resolve ( at least at the level of 1.5-tesla resolution ) by 6 years .
we believe this report , spanning 7 years in total , represents the longest period of serial cns imaging in a single cmtx1 patient yet described in the english language literature .
the findings described herein suggest that the central lesions of cmtx1 are likely to be fully reversible but may persist for several years after an event .
written informed consent was obtained from the patient for publication of this case report and any accompanying images .
a copy of the written consent is available for review by the editor of this journal .
 charcot - marie - tooth disease ( cmt ) , also known as hereditary motor sensory neuropathy , is a heterogeneous group of disorders best known for causing inherited forms of peripheral neuropathy . 
 the x - linked form , cmtx1 , is caused by mutations in the gap junction protein beta 1 ( gjb1 ) gene , expressed both by peripheral schwann cells and central oligodendrocytes . 
 central manifestations are known but are rare , and there are few case reports of leukoencephalopathy with transient or persistent neurological deficits in patients with this cmt subtype . here , 
 we report the case of a man with multiple male and female family members affected by neuropathy who carries a pathologic mutation in gjb1 . 
 he has experienced three transient episodes with variable neurological deficits over the course of 7 years with corresponding changes on magnetic resonance imaging ( mri ) . 
 this case illustrates cmt1x as a rare cause of transient neurological deficit and demonstrates the evolution of associated reversible abnormalities on mri over time . to the best of our knowledge , 
 this report provides the longest period of serial imaging in a single patient with this condition in the english language literature . 
Introduction
Case Presentation
Discussion
Statement of Ethics
Disclosure Statement