Views & Reviews CME The CNS phenotype of X-linked Charcot-Marie-Tooth disease More than a peripheral problem Robert A. Taylor, MD; Erin M. Simon, MD; Harold G. Marks, MD; and Steven S. Scherer, MD, PhD X-linked Charcot-Marie-Tooth disease (CMTX) is the lasting 4 hours. The following day, he developed the second most common form of inherited demyelinat- same symptoms, and mild right leg weakness, last- ing neuropathy, next to CMT type 1A, which is ing 10 hours. On day 3, he developed a complete caused by duplication of the PMP22 gene.1 CMTX is motor aphasia, right arm weakness, dysphagia, and caused by mutations in GJB1, the gene encoding loss of gag reflex, lasting 4 hours. MRI (on day 3) connexin32 (Cx32), which belongs to a highly con- showed abnormally increased T2 signal and reduced served family of proteins that form gap junctions in diffusion in the posterior portion of the centrum vertebrates. Myelinating Schwann cells express semiovale bilaterally (figure 1, A and B), as well as Cx32, which likely forms gap junctions between the in the splenium of the corpus callosum (figure 1, C layers of the myelin sheath, thereby providing a and D). These lesions spared the subcortical U fibers shorter pathway for the diffusion of small molecules and did not enhance (not shown). Three-dimensional and ions directly across the myelin sheath.2 Oligo- time-of-flight MR angiography of the intracranial dendrocytes also express Cx32, which participates in vessels, electroencephalography, and CSF were nor- the gap junction coupling of oligodendrocytes and mal, including a normal lactate level (1.1 mmol/L) astrocytes.3 and no oligoclonal bands. Laboratory tests, including More than 240 different GJB1 mutations have complete blood count, electrolytes, renal function, co- been described (http://molgen-www.uia.ac.be/CMT- agulation parameters, urinalysis, and urine toxicol- Mutations/DataSource/MutByGene.cfm). Most pa- ogy screen, were negative. A Lyme antibody titer tients with CMTX, including those with a deletion of was normal. Varicella zoster and Epstein-Barr anti- the GJB1 gene, have a similar degree of neuropathy, body titers were consistent with prior infections. indicating that most mutations probably cause a loss Very long chain fatty acid levels were normal. A of function.1 In agreement, many Cx32 mutants do diagnosis of probable ADEM was made and he was not form functional gap junctions,4 often related to treated with high-dose IV corticosteroids for 3 days. their aberrant trafficking to the cell membrane.5 In A subsequent outpatient evaluation revealed high- addition to their peripheral neuropathy, many pa- arched feet, hyporeflexia at the ankles, and minimal tients have asymptomatic evidence of brain involve- weakness in ankle dorsiflexion. There was a family ment, such as abnormal brainstem auditory evoked history of CMT—in his mother, two maternal uncles, responses (BAER).6,7 Patients have also been found a maternal aunt and her son, the maternal grand- to have abnormal brain MRI results in association mother, and the maternal great-grandmother. None with transient CNS symptoms.8-11 Here, we report a of these family members reported similar transient patient who had two episodes resembling acute de- neurologic episodes. The patient’s mother had nor- myelinating encephalomyelitis (ADEM), the first ep- mal results on brain MRI; the other affected family isode preceding the diagnosis of CMTX. members did not have brain MRI performed. Se- quencing GJB1 (performed by Athena Diagnostics, Case report. A 12-year-old boy presented in Janu- Worchester, MA) from the patient revealedaCtoT ary 1999 with three consecutive episodes of transient mutation at nucleotide position 285, predicted to re- neurologic dysfunction, over the course of 3 days, sult in an amino acid change from arginine to trypto- with complete recovery between each episode. Ini- phan at codon 75 (R75W). Other family members tially, he had numbness of the right face and arm, were presumed to have the same mutation. paresis of the right arm and face, and dysarthria, In November 2002, at age 15, he presented again From the Department of Neurology (Drs. Taylor and Scherer), Hospital of the University of Pennsylvania, Philadelphia; and Departments of Radiology (Dr. Simon) and Pediatric Neurology (Dr. Marks), Children’s Hospital of Philadelphia, PA. Received May 19, 2003. Accepted in final form July 21, 2003. Address correspondence and reprint requests to Dr. Robert Taylor, Department of Neurology, The University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104; e-mail: [email protected] Copyright © 2003 by AAN Enterprises, Inc. 1475 Figure 1. Episode 1: Axial fat-suppressed fluid attenuated inversion recovery (FLAIR) (A) (repetition time/echo time/in- version time 9,000/119/2,200 msec) through the centrum semiovale shows the bilaterally symmetric regions of abnormal T2 hyperintensity. Calculated apparent diffusion coefficient map (ADC) (4,000/100) (B) demonstrates the reduced diffu- sion as hypointensity in the same regions. Axial fat-suppressed FLAIR (C) shows the abnormal hyperintensity in the sple- nium with corresponding reduction in diffusion shown on ADC (D). Episode 2: Axial fat-suppressed FLAIR (E) shows the recurrent T2 signal abnormality in similar regions to episode 1. ADC (F) reveals reduction in diffusion in the affected ar- eas. Eleven-week follow-up: Axial fat-suppressed FLAIR (G) shows mild residual T2 signal abnormality with resolution of the lesions on ADC (H). with 2 days of mild right arm weakness and worsen- tions, including T55I, E102deleted, R142W, and ing handwriting. After wrestling with his brother on R164W, C168Y.8-11 These patients had various combi- the second day, he developed a severe hemiparesis of nations of dysarthria; dysphagia; expressive aphasia; the left face and arm, dysarthria, and dysphagia, mono-, para-, hemi-, and quadriparesis; disorienta- lasting about 8 hours, which then resolved com- tion; ataxia; incoordination; and cranial neuropa- pletely over several hours. MR performed 2 days thies. Episodes began suddenly or progressed over later again showed symmetric abnormally increased days, typically lasting hours to days, sometimes fluc- T2 signal and diffusion reduction in the posterior tuating or recurring multiple times during a period frontal and parietal white matter bilaterally, in ap- of several weeks. Patients seem to recover com- proximately the same distribution as the MR 4 years pletely without any specific therapy. Individual at- earlier (figure 1, E and F), again with no abnormal tacks seem to be provoked by travel to high enhancement. Routine laboratory studies and CSF altitudes, respiratory distress, or fever/infection, but were normal, and oligoclonal bands were absent. He can be unprovoked. The CSF is normal, suggestive was not treated with corticosteroids and had recov- that inflammation is not a primary etiology. There- ered completely without any specific therapy. Repeat fore, high dose corticosteroids may not be beneficial. brain MRI performed 11 weeks later showed a re- The diagnosis of CMTX should be considered in a turn to normal diffusion and improvement in the patient who has a family history of CMT and an abnormal T2 signal with some mild areas of persis- unusual ADEM-like illness, especially with white tently increased T2 signal in the white matter (fig- matter findings on MRI. ure 1, G and H). MRI obtained acutely shows increased T2- weighted signal, sometimes associated with reduc- Discussion. This patient initially presented with tion in diffusion but no abnormal enhancement, an unusual ADEM-like attack, was subsequently predominantly in the posterior centrum semiovale, found to have CMTX, and then presented again with splenium of the corpus callosum, and sometimes the another ADEM-like attack. ADEM-like attacks have middle cerebellar peduncles.8-11 The MRI lesions are been described in individuals with other GJB1 muta- largely confluent in the deep white matter and spare 1476 NEUROLOGY 61 December (1 of 2) 2003 Table Summary of CNS mutants, their phenotypes, and the ers were not reported to have had an MRI.15,16 An- localization of the mutant protein (if known) in transfected cells other patient with CMTX had hypoperfusion of the Mutation Phenotype Localization5,18 cerebellum shown on SPECT (iodine-123-N- isopropyl-p-iodoamphetamine), but reportedly had W24C EPR12 ND normal results on brain MRI.17 Thus, subclinical in- M34V EPR* Golgi & GJP volvement is common, but is not necessarily associ- A39V EPR26 ER ated with abnormal MRI findings. The disruption of gap junction communication be- T55I Abnormal MRI8 ER tween oligodendrocytes and astrocytes may be the D66N EPR† ND cellular mechanism by which GJB1 mutations cause R75W Abnormal MRI Golgi a “CNS phenotype.” Certain Cx32 mutants may have M93V EPR27 Golgi & GJP dominant-negative effects on other connexins ex- pressed in oligodendrocytes—Cx29 and Cx4718-20— E102 deleted Abnormal MRI11 ND thereby decreasing their expression. Astrocytes 12 E109 stop Abnormal MRI ND express different connexins than do oligodendro- R142W Abnormal MRI9 Golgi cytes, so that Cx32 and/or Cx47 would likely interact R164Q Abnormal MRI13 Golgi with Cx26, Cx30, and/or Cx43 on the astrocytic cell 21 R164W Abnormal MRI10 Golgi membrane. Interestingly, dominant mutations of GJA1/Cx43 are also associated with abnormal white C168Y Abnormal MRI9 ND matter signal on MRI.22 The physiologic conse- R183H Abnormal MRI14 Golgi & GJP quences of disrupting the gap junction–mediated T191 frameshift EPR12 ND coupling between oligodendrocytes and astrocytes likely lead to an inability of these cells to regulate * Dr. Steven Scherer, unpublished. † Dr. Richard Sater, personal communication. fluid exchange. This could explain the restricted dif- EPR ϭ extensor plantar responses; ER ϭ endoplasmic reticulum; ND ϭ not determined; GJP ϭ gap junction plaques. the subcortical U fibers. These abnormalities have been reported to persist for months, even after the patient is asymptomatic, and may or may not resolve completely.9,11 Abnormal MRI have also been re- ported in patients with CMTX who were not reported to have had an ADEM-like illness.