Original Article

The Central Nervous System Phenotype
of X-Linked Charcot-Marie-Tooth Disease:
A Transient Disorder of Children
and Young Adults

Journal of Child Neurology
2014, Vol. 29(3) 342-348
ª The Author(s) 2013
Reprints and permission:
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DOI: 10.1177/0883073812474343
jcn.sagepub.com

Majeed Al-Mateen, MD1,2,3, Alexa Kanwit Craig, MD3,
and Phillip F. Chance, MD4

Abstract
We describe 2 patients with X-linked Charcot-Marie-Tooth disease, type 1 (CMTX1) disease and central nervous system manifestations and review 19 cases from the literature. Our first case had not been previously diagnosed with Charcot-Marie-Tooth
disease, and the second case, although known to have Charcot-Marie-Tooth disease, was suspected of having CMTX1 after presentation with central nervous system manifestations. The most common central nervous system manifestations were transient
and included dysarthria, ataxia, hemiparesis, and tetraparesis resembling periodic paralysis. Of the 21 patients, 19 presented at 21
years of age or younger, implicating CMTX1 with transient central nervous system manifestations as a disorder that predominantly affects children and adolescents. CMTX1 should be included in the differential diagnosis of patients who present with transient central nervous system phenomena, including stroke-like episodes, tetraparesis suggestive of periodic paralysis, dysarthria,
ataxia, or combinations of these deficits. Reversible, bilateral, nonenhancing white matter lesions and restricted diffusion on magnetic resonance imaging are characteristic features of the central nervous system phenotype of CMTX1.
Keywords
Charcot-Marie-Tooth disease, connexin 32, GJB1 gene, white matter lesions, transient central nervous system symptoms
Received November 3, 2012. Received revised December 11, 2012. Accepted for publication December 17, 2012.

Charcot-Marie-Tooth disease is the eponym for a group of
inherited disorders affecting the motor and sensory nerves of
the peripheral nervous system. It is one of the most common
neurogenetic disorders with an overall prevalence of approximately 1 in 2500 people.1 Charcot-Marie-Tooth disease is classically characterized by slowly progressive distal muscle
weakness and atrophy, initially affecting the lower extremities,
sensory impairment, and foot deformities (pes cavus and
hammer toes). In a recent clinical study of 787 patients with
Charcot-Marie-Tooth disease, autosomal dominant CharcotMarie-Tooth disease type 1A caused by a duplication or point
mutation of the peripheral myelin protein (PMP-22) gene
accounted for 55% of the genetically defined cases.2
X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) was
the second most common form and accounted for 15.2% of the
genetically defined cases in that study. The gene responsible
for X-linked Charcot-Marie-Tooth disease was discovered in
1993 by direct sequencing of the connexin 32 (Cx32) gene that
is normally expressed in myelinated peripheral nerve.3 Mutations in affected persons from the 8 CMTX families studied,
identified the gap junction beta 1 (GJB1) gene located on the
X chromosome. To date, over 400 distinct Cx32 mutations

have been identified (http://www.molgen.ua.ac.be/CMTMutations/). Transient central nervous system deficits associated
with white matter abnormalities on magnetic resonance imaging (MRI) have been reported in patients with CMTX1.4-18
We describe the cases of 2 unrelated boys with CMTX1 who
presented with transient neurological deficits and white matter
lesions on MRI. In 1 case a stroke-like episode preceded the
diagnosis of CMTX1, and in the other case known to have
Charcot-Marie-Tooth disease, recurrent stroke-like episodes,
transient generalized weakness, and lesions on MRI prompted

1

Mary Bridge Children’s Hospital and Health Center, Tacoma, WA, USA
Department of Neurology, University of Washington School of Medicine,
Seattle, WA, USA
3
Division of Neurology, Seattle Children’s Hospital, Seattle, WA, USA
4
Department of Pediatrics (Genetics), University of Washington school of
Medicine, Seattle, WA, USA
2

Corresponding Author:
Majeed Al-Mateen, MD, Mary Bridge Children’s Hospital and Health Center,
2 West Neurology, 311 South L Street, Tacoma, WA 98415, USA.
Email: majeed.al-mateen@multicare.org

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Figure 1a. Magnetic resonance imaging case 1: Left and right centrum
semiovale T2 hyperintensities.

Figure 1b. Magnetic resonance imaging case 1: Two months later there
is decrease in size in both the left and right centrum semiovale lesions.

suspicion of CMTX1. Description of these patients and comparison with previously described cases from the literature may
alert others to suspect CMTX1 in children and young adults
who present with acute neurological dysfunction associated
with white matter lesions on MRI.

(FLAIR) hyperintensities and restricted diffusion (see
Figure 1a). There was no contrast enhancement and no mass
effect. MRI of the whole spine and magnetic resonance angiography were normal. He was admitted and treated with highdose intravenous corticosteroids for 3 days and recovered
completely. While recovering from a viral upper respiratory
infection 2 months later, he complained of right hand tingling.
MRI of the brain showed interval decrease in size of both centrum semiovale T2 lesions (see Figure 1b) and no restricted
diffusion. The examination was normal except for impaired
walking on heels, pes cavus, hammertoes, and diminished
muscle stretch reflexes prompting referral for electrodiagnostic
studies. The results were abnormal because of severe lengthdependent demyelinating sensorimotor neuropathy with evidence of active denervation and chronic reinnervation in the
left tibialis anterior muscle. DNA analysis showed a cytosine
to guanidine transition sequence alteration at nucleotide position 260 in the Cx32 allele of the GJB1 gene, causing an
amino acids change from proline to leucine at codon position
87 (Athena Diagnostics, Worcester, Massachusetts).

Case Reports
Case 1
A 14-year-old right-handed male presented to the emergency
department with a 2-day history of episodic numbness and
weakness in the right hand. His symptoms were present on the
first day for about 6 hours, but resolved. On the second day, the
symptoms recurred in the right hand and then progressed to
include a right facial droop and right leg weakness. He was
an athlete and had no fever and no recent illness. He had been
vacationing in Moab, Utah (elevation of 4,025 feet) just prior to
presentation. On examination there was a slight pronator drift
on the right, slight right facial weakness, and mild weakness
of the right upper extremity. Muscle stretch reflexes were 1þ
and symmetric in the upper extremities, trace at the quadriceps,
and absent at the gastrocnemius bilaterally. Sensation to touch
and sharp object were intact. Serum electrolytes, renal function, liver function tests, complete blood count with differential, erythrocyte sedimentation rate, and C-reactive protein
were all normal. Cerebrospinal fluid glucose, protein, and cell
counts were normal. Cerebrospinal fluid culture and oligoclonal bands were negative. MRI of the brain performed on admission showed left and right centrum semiovale and splenium of the
corpus callosum T2 and fluid-attenuated inversion recovery

Case 2
A 17-year-old male with Charcot-Marie-Tooth disease was
admitted for progressive paralysis of all 4 extremities. The day
before admission he complained of weakness of both arms followed by progressive weakness of both legs. On the morning of
admission weakness of all 4 extremities and difficulty swallowing and speaking persisted without alteration in his level of
consciousness. These features were felt to be compatible with
periodic paralysis. The serum potassium was 3.8 mmol/L. The

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Figure 2a. Magnetic resonance imaging case 2: Bilaterally nearly symmetric white matter increased T2 signal abnormality with posterior
predominance.

Figure 2b. Magnetic resonance imaging case 2: Two months later
there is significantly decreased but persistent bilateral deep white matter increased T2 signal.

patient’s mother had Charcot-Marie-Tooth disease and the
diagnosis was suspected in our patient because of weakness
of dorsiflexors of both feet and pes cavus. The first episode
of unilateral weakness between 9 and 10 years of age involved
only an upper extremity and lasted several minutes. He was
evaluated at a hospital in another state after an episode of unilateral upper and lower extremity weakness that lasted about 90
minutes. MRI was not available for review. The episodes of
unilateral weakness recurred about once a year, usually 2
weeks after a febrile illness. He always recovered within an
hour. On examination, 12 hours after admission for tetraparesis, he had regained his baseline level of function; he was
alert, his speech was fluent, and his cranial nerves were normal.
There was mild weakness and atrophy of the muscles of the
hands, moderate atrophy of distal leg muscles, bilateral pes
cavus, and weakness of both foot dorsiflexors. Muscle stretch
reflexes were trace at the biceps and absent at the both quadriceps and gastrocnemius. Sensory examination was normal and
he had a steppage gait. An hour after this examination he had a
second episode of weakness of all 4 extremities and inability to
speak. He was alert and followed directions. Facial movement
was weak, gag was absent and tongue movement was limited.
There was slight antigravity movement and areflexia in all
extremities. Plantar responses were mute. Nerve conduction
studies performed during this event showed marked slowing
of the left median motor conduction velocity and absent
median sensory nerve action potentials consistent with a

demyelinating motor and sensory neuropathy. The weakness,
dysarthria, hypophonia, and dysphagia resolved over 12 hours,
and he was walking without assistance within 24 hours. A third
event occurred 38 hours after admission and persisted only several hours. Brain MRI (see Figure 2a) the day after admission
showed bilateral nearly symmetric white matter signal abnormality with a posterior predominance and involving the posterior
body of the splenium of the corpus callosum with associated
marked abnormally restricted diffusion. There was no contrast
enhancement and no mass effect. DNA analysis that was not
available on the day of admission but obtained 7 years earlier
showed a guanidine to adenine transition sequence alteration
in the Cx32 allele of the GJB1 gene in nucleotide position
477 predicting a valine to methionine amino acid substitution
at codon position 139 (Athena Diagnostics, Worcester, Massachusetts). Brain MRI performed 8 weeks after presentation (see
Figure 2b) showed significantly decreased but persistent relatively symmetric bilateral deep white matter and corticospinal
tract increase in T2/FLAIR signal, with resolution of diffusion
restriction.

Results
Clinical, MRI, and DNA data of 19 cases from the literature
and our 2 cases were reviewed (see Tables 1-3). The age range
was 7 to 44 years. All patients were male. One 43-year-old
female patient included in the family reported by Hanemann

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Table 1. Clinical Features of 21 Patients With CMTX1 and Central Nervous System Phenotype.
Motor
Impairment

Reference

Age(y)/Sex

4
4
5
6
6
7

10/male
12/male
14/male
16/male
26/male
10/male

7
8
9
10
11
11
12
13

19/male
12/male
44/male
10/male
13/male
16/male
10/male
14/male

LH, RH
LH, T
RH
T
T

14
15
16
17
18
Case 1
Case 2

7/male
21/male
15/male
11/male
14/male
14/male
10/male

LH
LH
LH
RH
RH, T, M
RH
H, T, M

T
T
RH
T
SW
T
H

Ataxia

A
A

A
RH, M
A
A

A
A

Dysarthria/
Dysphagia
DA/DP
DA
DA/DP
DA
DA
DA/DP

Other

Predisposing Factor(s)

Dyspnea
Dyspnea

Exp Aphasia

DA/DP
DA/DP
DA/DP
DA
DA
DA

CNIII, VII(B)
Exp Aphasia

DA

L: CN V, VII, XII
Confusion

5 h to 3 d
5 h to 3 d
6h
8 to 10 h
2w
3h

Fever
High altitude
High altitude
Exercise
High altitude
Mononucleosis
Exercise

Fever

1h
4h
NR
< 80 m
8h
4h
3h
12 to 24 h

Upper respiratory infection
Exercise
Vomiting, diarrhea
Fever
Fever
High altitude
Fever

36 h
5h
several h
2.5 h
5-7 h
6 h to 3 d
1 to 12 h

Hyperventilation
Concussion
Pneumonia

DA
DP
DA

Exp aphasia
Exp aphasia, dizziness
Diplopia

DA/DP

Vertigo

Duration to
Recovery

Abbreviations: A, ataxia; B, bilateral; CN, cranial nerves; d, days; DA, dysarthria; DP, dysphagia; Exp, expressive; H, hemiparesis; h, hours; L, left; m, minutes;
M, monoparesis; NR, not recorded in case report; R, right; SW, symmetrical weakness (mild); T, tetraparesis; y, years old.

Table 2. MRI in 21 Patients With CMTX1 and Central Nervous System Phenotype.
MRI (presentation)
Reference

Age(y)/Sex

Abnormal Bilateral
White Matter T2/FLAIR

4
4
5
6
6
7
7
8
9
10
11
11
12
13
14
15
16
17
18
Case 1
Case 2

10/male
12/male
14/male
16/male
26/male
10/male
19/male
12/male
44/male
10/male
13/male
16/male
10/male
14/male
7/male
21/male
15/male
11/male
14/male
14/male
10/male

PV
PV
PO
PC
Post, SCC
P
P
CS
PV, SCC, pons
Diffuse
No MRI
O, CC
post CS
P
PV, post, CC
FPCR, GSCC
post CS
post, CS
PO, GSCC
CS
post

Restricted
Diffusion

SCC, CS

SCC
CS
O, CC
SCC

Deep white matter
SCC
CC
PO, GSCC
SCC
SCC

MRI (follow-up)
Result

Interval

NR
NR
N
N
I
I
I
I, ND
NR
I, ND

2 months
2 months
1 year
3 months
6 months
11 weeks

N
N
I
I
N
I, ND
I, ND
I
I, ND
I, ND

3 months
3 months
6 months
6 weeks
2 years
11 days
3 months
3 months
2 months
2 months

Abbreviations: CC, corpus callosum; CS, centrum semiovale; FLAIR, fluid-attenuated inversion recovery; FPCR, frontoparietal corona radiata; G, genu;
I, improved; MRI, magnetic resonance imaging; N, normal (all modalities); ND, normal diffusion weighted imaging; P, parietal; PC, pericallosal; PO, parietooccipital;
post, posterior; PV, periventricular; S, splenium; y, years.

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Table 3. Mutations in Cx32 Allele of GJB1 Gene in 21 Patients With
CMTX1 and Central Nervous System Phenotype.
Mutation
Age(y)/
Reference Sex
4
4
5
6
6
7
7
8
9
10
11
11
12
13
14
15
16

17
18
Case 1
Case 2

10/male
12/male
14/male
16/male
26/male
10/male
19/male
12/male
44/male
10/male
13/male
16/male
10/male
14/male
7/male
21/male
15/male

Nucleotide
Transition
(position)
C > T (164)
C > T (164)
C > T (?)
G > A (565)

C > T (235)
C > T (?)
G > A (65)
G > A (477)
G > A (477)

T > C (530)
G > T (556)
? > ? (397)
Frameshift
mutation
11/male G > A (196)
14/male
14/male C > G (260)
10/male G > A (477)

Amino Acid Substitution
(codon)
Threonine > isoleucine (55)
Threonine > isoleucine (55)
Arginine > tryptophan (164)
Cysteine > tyrosine (168)
Arginine > tryptophan (132)
Glutamic acid > ? (102)
Glutaic acid > ? (102)
Arginine > tryptophan (75)
Arginine > glutamine (?)
Valine > methionine (139)
Valine > methionine (139)
Arginine > glutamine (22)
Glutamine > arginine (164)
Valine > alanine (177)

Demographics
1. Male
2. Seven to 26 years of age (mean: 13 years)
Transient neurological deficits
1. Limb weakness
a. Hemiparesis
b. Tetraparesis/complete paralysis
c. Monoparesis
2. Dysarthria, dysphagia
3. Ataxia
Brain MRI
1. MRI at presentation:
a. Abnormal diffusion weighted images (DWI)
b. Non-enhancing T2 and FLAIR lesions:
i. Bilateral deep white matter
ii. Predominantly posterior
iii. Corpus callosum (splenium)
2. MRI at follow-up:
a. Abnormal DWI at presentation are normal at follow-up
b. Abnormal T2 and FLAIR lesions at presentation are
normal or significantly improved at follow-up
Figure 3. Charcot-Marie-Tooth X1 with central nervous system phenotype: Characteristic features.
Abbreviations: FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging case.

Aspartic acid > asparagine (66)
Asparagine > serine (54)
Proline > leucine (87)
Valine > methionine (139)

Abbreviations: A, Adenine; C, Cytosine; G, Guanine; T, Thymine; y, years;
?, information not included in case report.

was not included in this review because she was not examined
by the authors when she was symptomatic between 7 and 17
years of age and she was symptomatic during an era in which
MRIs were not available.7 In all, 17 patients had dysarthria,
dysphagia, or both (81%); 13 patients had hemiparesis
(62%); 9 patients had tetraparesis/complete paralysis (43%);
and 7 patients had ataxia (33%). Other symptoms reported in
less than 20% of the cases included expressive aphasia, vertigo,
cranial nerve deficits, and dyspnea. The central nervous system
symptoms followed a fever in 5 patients (24%), travel to high
altitude in 4 patients (19%), exercise in 3 patients (14%), and
a concussion in 1.11 In 1 patient hemiparesis, ataxia, and dysarthria followed hyperventilation associated with emotional distress.10 In all but the eldest, a 44-year-old patient, the central
nervous system deficits resolved in 1 hour to 2 weeks. All 20
patients who had MRI at presentation had bilateral abnormal
T2/FLAIR signal in the white matter. The abnormal white matter signal was posterior in 9 (45%) and periventricular in 4
(20%). The corpus callosum was involved (abnormal T2,
restricted diffusion, or both) in 12 (60%) and the splenium only
in 8 (40%). Restricted diffusion was reported in 11 (55%).
Follow-up MRI results were reported in 17 patients, and all
showed improvement or were normal. All follow-up reports
of restricted diffusion weighted abnormalities were normal. The

1 patient who did not have an MRI at presentation had a normal
CT.11 In comparison to our first case, our second case had
more severe symptoms and more extensive lesions on MRI (see
Figures 1 and 2). Qualitative review of the published MRI
reproductions4-18 did not allow correlation between severity of
symptoms reported and the extent of lesions on MRI. The GJB1
gene mutation in our second patient matched that reported in 2
brothers11 and represents the first report of the same mutation
in the GJB1 gene from 2 different kindreds with CMTX1 associated with central nervous system involvement. The mutation in
the GJB1 gene in our first case has not been previously reported
in CMTX1 associated with central nervous system involvement
and transient nonenhancing white matter lesions on MRI. Our
first case and 4 other patients7,8,9,15 received Intravenous immunoglobulin (IVIg), corticosteroids, or plasma exchange, alone or
in various combinations prior to considering the diagnosis of
CMTX1 with central nervous system phenotype.

Discussion
Central nervous system involvement has been reported in
patients with CMTX1 including abnormal brainstem auditory
evoked responses19 and somatosensory evoked potentials
without cerebral abnormalities on MRI.20 Our 2 case reports
combined with others from the literature demonstrate that
CMTX1 with reversible central nervous system involvement
predominantly affects children, adolescents, and young adults
and has characteristic features (see Figure 3). Of the 2 cases
presenting with central nervous system involvement after 21
years of age, 1 showed features characteristic of the other 19
cases reviewed. He was 26 years of age when he presented with

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transient central nervous system symptoms.6 He was atypical,
however, in that his symptoms persisted for 2 weeks and all
of the younger 19 patients recovered in 3 days or less. The other
case presenting after 21 years of age was that of a 44-year-old
man who was atypical in that central nervous system symptoms
persisted and MRI showed abnormal T2 signal in the pons,
gadolinium enhancing lesions, and CSF findings more suggestive of inflammation and an autoimmune response.9
Onset of CMTX1 in males and carrier females is most often
in early childhood.21 Typical features of Charcot-Marie-Tooth
disease may not be recognized until after presentation with central nervous system manifestations, as in our first case. It is therefore important to consider CMTX1 in previously healthy
children who present with symptoms suggestive of transient central nervous system dysfunction and conducting a thorough
examination for features of Charcot-Marie-Tooth disease including pes cavus, hammertoes, distal atrophy, areflexia, impaired
sensory examination, and eliciting a family history of features
of Charcot-Marie-Tooth disease, which may be milder, in the
mother. Documentation of the acute clinical course of our second case demonstrates the variety of transient neurological deficits an individual with CMX1 may display over the course of
several hours and several days. This patient also had recurrent
episodes of transient hemiparesis that began at 10 years of age,
7 years before presentation with transient neurological deficits
that included dysarthria, dysphagia, and generalized weakness
(tetraparesis). Panas et al also reported 2 boys who had repeated
episodes of generalized weakness suggestive of periodic paralysis; however, no mutations of the genes responsible for periodic
paralysis were found. The MRIs of both boys showed bilateral
hyperintensities of the periventricular white matter on T2
weighted images.4 We also considered periodic paralysis prior
to obtaining MRI results in case 2 and would include CMTX1
in the differential diagnosis of children who present with tetraparesis resembling periodic paralysis.
Transient paralysis in children may also represent a feature of
familial hemiplegic migraine, alternating hemiplegia, Todd’s
paralysis, moyamoya disease, and mitochondrial encephalopathy
with lactic acidosis and stroke-like episodes (MELAS). A more
refined differential diagnosis, based largely on white matter
lesions on MRI includes toxic, inherited metabolic disease such
as adrenoleukodystrophy, infectious, and inflammatory causes
such as acute disseminated encephalomyelitis. Simultaneous
Guillain-Barré syndrome and acute disseminated encephalomyelitis has been reported.22 Paralysis in cases of Guillain-Barré
syndrome plus acute disseminated encephalomyelitis is sustained over weeks and electrodiagnostic abnormalities are usually not apparent until days after the onset of weakness. In
contradistinction, only 1 patient with transient central nervous
system symptoms and CMTX1 in our review had symptoms
longer than 3 days. Electrodiagnostic abnormalities noted on
presentation with the central nervous system phenotype of
CMTX1 are those expected in a chronic hereditary motor and
sensory neuropathy, as documented in both of our cases.
CMTX1 is unique among the most common hereditary motor
and sensory neuropathies in that the mutated GJB1 gene product,

the gap junction protein, Cx32 is expressed in both peripheral
nerves (Schwann cells) and brain (oligodendrocytes). Most
GJB1 mutations cause neuropathy by loss of normal Cx32 function leading to disability with increasing age.23 It is the younger
patients with CMTX1, however, who appear to be more susceptible to the transient central nervous system abnormalities
described in our 2 cases and other case reports with mutations
involving Cx32. Connexins are critical for normal myelination
in the central nervous system. One of the other connexins coexpressed in oligodendrocytes is connexin 47 (Cx47). A loss-offunction mutation in the GJA12 gene, which encodes the gap
junction protein Cx47 in humans, causes PelizaeusMerzbacher-like hypomyelinating leukoencephalopathy in children.24,25 Unlike Pelizaeus-Merzbacher-like hypomyelinating
leukoencephalopathy, the cellular mechanism by which GJB1
mutations cause the reversible central nervous system events
in CMTX1 is not well understood but may involve disruption
of gap junction communication between oligodendrocytes and
astrocytes leading to inability of these cells to regulate fluid
exchange.8 Indeed, restricted diffusion was documented on brain
MRIs during attacks in more than half of the patients in this
review. Our second case and the 2 brothers reported by Halbrich
et al11 are the only cases with CMTX1 and central nervous system phenotype from different pedigrees that are reported to share
the same missense mutation in the Cx32 gene. Thus far, however, there does not appear to be a ‘‘hotspot’’ for Cx32 mutations
associated with transient central nervous system symptoms and
MRI abnormalities. Moreover, a GJB1 frameshift mutation
caused a central nervous system phenotype similar to those
caused by missense mutations suggesting that central nervous
system phenotypes in CMTX1 lack a consistent genotypephenotype correlation.15 Expression of the central nervous system phenotype in patients with CMTX1 may be influenced by
other factors. The transient central nervous system deficits in
CMTX1 patients have been associated with intercurrent febrile
illness5,17,18 as in our second case. Exposure to high altitude
prior to presentation, as noted in our first case, has also been
reported.6,7 In 3 cases the events occurred after exercise7,8,15 and
suggested that under normal circumstances, the other connexins
compensate for the Cx32 deficit in the central nervous system,
which only presents clinically at times of metabolic stress.15
Children and young adults with CMTX1 may present with
stroke-like episodes, generalized weakness resembling periodic
paralysis, ataxia, dysarthria, or combinations of these deficits.
The fluctuation in these neurological disturbances and MRI findings should prompt suspicion of the diagnosis. The central nervous system phenotype of CMTX1 disease has a favorable
prognosis with respect to central nervous system function and recognition will avoid unnecessary investigations and potentially
harmful therapeutic intervention. Dedicated reporting of Cx32
mutations associated with the central nervous system phenotype
for genotype-phenotype correlation, predisposing factors (high
altitude, exercise, or fever), and MRI findings will help further our
understanding of the role of connexins in leukoencephalopathies
and why children with CMTX1 are at higher risk for developing
the central nervous system phenotype.

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Author Contributions
MA wrote the initial draft of case 2, drafted the initial manuscript, and
reviewed and revised the manuscript. AKC wrote the initial draft of
case 1 and reviewed and revised the manuscript. PFC reviewed and
revised the manuscript.

Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article:
PFC served on the speakers’ bureau of Athena Diagnostics. He has not
participated for 4 years.

Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.

References
1. Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth
disease. Clin Genet. 1974;6:98-118.
2. Saporta ASD, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth
subtypes and genetic testing strategies. Ann Neurol. 2011;69:22-33.
3. Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations
in X-linked Charcot-Marie-Tooth disease. Science. 1993;262:
2039-2042.
4. Panas M, Kalfakis N, Karadimas C, Vassilopoulos D. Episodes of
generalized weakness in two siblings with the C164 T mutation of
the connexin 32 gene. Neurology. 2001;57:1906-1908.
5. Schelhaas H, van Engelen B, Gabreels-Festen A, et al. Transient
white matter lesions in a patient with connexin 32 missense mutation. Neurology. 2002;59:2007-2008.
6. Paulson H, Garbern J, Hoban T, et al. Transient central nervous
system white matter abnormality in X-linked Charcot-MarieTooth disease. Ann Neurology. 2002;52:429-434.
7. Hanemann C, Bergmann C, Senderek J, et al. Transient recurrent,
white matter lesions in X-linked Charcot-Marie-Tooth disease
with novel connexin 32 mutation. Arch Neurol. 2003;60:605-609.
8. Taylor R, Simom E, Marks H, Scherer S. The CNS phenotype of
X-linked Charcot-Marie-Tooth disease: more than a peripheral
problem. Neurology. 2003;61:1475-1478.
9. Isoardo G, Di Vito N, Nobile M, Benetton G, Fassio F. X-linked
Charcot-Marie–Tooth disease and progressive relapsing central
demyelinating disease. Neurology. 2005;65:1672-1673.
10. Srinivasan J, Leventer RJ, Kornberg AJ, et al. Central nervous
system signs in X-linked Charcot-Marie-Tooth disease after
hyperventilation. Pediatr Neurol. 2008;38:293-295.

11. Halbrich M, Barnes J, Bunge M, et al. A V139M mutation also
causes the reversible CNS phenotype in CMTX. Can J Neurol Sci.
2008;35:372-374.
12. Rosser T, Muir J, Panigrahy A, et al. Transient leukoencephalopathy associated with X-linked Charcot-Marie-Tooth disease.
J Child Neurol. 2010;25:1013-1016.
13. Fusco C, Frattini D, Pisani F, et al. Coexistent central and peripheral nervous system involvement in a Charcot-Marie-Tooth syndrome X-linked patient. J Child Neurol. 2010;25:759-763.
14. Anad G, Maheshwari N, Roberts D, et al. X-linked hereditary
motor sensory neuropathy (type 1) presenting with stroke-like
episode. Dev Med Child Neurol. 2010;52:677-679.
15. Basu A, Horvath R, Esisi B, et al. Recurrent stroke-like episodes
in X-linked Charcot-Marie-Tooth disease. Neurology. 2011;77:
1205-1206.
16. Sakaguchi H, Yamashita S, Miura A, et al. A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked
Charcot-Marie-Tooth disease. J Neurol. 2011;25:284-290.
17. U-King-Im JM, Yiu E, Donner EJ, et al. MRI findings in X-linked
Charcot–Marie-Tooth disease associated with a novel connexin
mutation. Clin Radiol. 2011;66:471-474.
18. Zhong L, Yan K, Liu C, et al. Clinical reasoning: a young man
with reversible paralysis, cerebral white matter lesions, and peripheral neuropathy. Neurology. 2012;79:e70-e72.
19. Nicholson G, Corbett A. Slowing of central conduction in
X-linked Charcot-Marie-Tooth neuropathy shown by brainstem
auditory evoked responses. J Neurol Neurosurg Psychiatry.
1996;61:43-46.
20. Kawakami H, InoueSakakihara I, et al. Novel mutation in
Charcot-Marie-Tooth disease associated with CNS impairment.
Neurology. 2002;59:923-926.
21. Yiu EM, Geevasinga N, Nicholson GA, et al. A retrospective
review of X-linked Charcot-Marie-Tooth disease in childhood.
Neurology. 2011;76:461-466.
22. Bernard G, Riou E, Rosenblatt B, et al. Simultaneous GuillainBarre syndrome and acute disseminated encephalomyelitis in the
pediatric population. J Child Neurol. 2008;23:752-757.
23. Shy ME, Siskind C, Swan RE, et al. CMT1X phenotypes represent loss of GJB1 gene function. Neurology. 2007;68:849-855.
24. Kleopa KA, Zamba-Papanicolaou E, Alevra X, et al. Phenotypic
and cellular expression of two novel connexin 32 mutations causing CMT1X. Neurology. 2006;66:396-402.
25. Bugiani M, Al Shahwan MD, Lamantea E, et al. GJA12 mutations
in children with recessive hypomyelinating leukoencephalopathy.
Neurology. 2006;67:273-279.

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