Short Communication

X-linked Charcot–Marie–Tooth Disease Presenting
with Stuttering Stroke-like Symptoms
Duriel I. Hardy1

Daniel J. Licht1

Arastoo Vossough2

1 Division of Neurology, Department of Pediatrics, Children’s Hospital

of Philadelphia, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, Pennsylvania, United States
2 Department of Radiology, Children’s Hospital of Philadelphia,
Perelman School of Medicine at the University of Pennsylvania,
Philadelphia, Pennsylvania, United States
3 Department of Anesthesiology and Critical Care Medicine, Children’s
Hospital of Philadelphia, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew P. Kirschen1,3
Address for correspondence Dr. Duriel Hardy, MD, Division of
Neurology, Department of Pediatrics, Children’s Hospital of
Philadelphia, Perelman School of Medicine at the University of
Pennsylvania, 3401 Civic Center Blvd, Philadelphia, PA 19104,
United States (e-mail: Hardydi@email.chop.edu).

Abstract

Keywords

► X-linked Charcot–
Marie–Tooth disease
► gap junction β 1 gene
► neuropathy
► stroke-like symptoms

X-linked Charcot–Marie–Tooth disease (CMTX1) is the second most common form of
Charcot–Marie–Tooth disease (CMT). It is caused by a mutation in the gap junction β 1
(GJB1) gene, which encodes for connexin-32. In addition to the peripheral neuropathy
and foot deformities observed in classic CMT, central nervous system symptoms and
magnetic resonance imaging (MRI) signal abnormalities in the brain have been
reported in patients with CMTX1. Here we describe two cases of adolescent males
who presented with stuttering neurologic deficits that were initially suggestive of
acute ischemic stroke and were ultimately diagnosed with genetically confirmed
CMTX1. Both patients had evidence of T2 hyperintensity and decreased diffusion on
MRI in the centrum semiovale, posterior corona radiata, posterior periventricular white
matter, and corpus callosum. Though rare, these cases illustrate the importance of
comprehensive neurologic history, physical examination, and appropriate diagnostic
evaluation.

Introduction
X-linked Charcot–Marie–Tooth (CMTX1) disease is caused by
mutations in the gap junction β 1 (GJB1) gene (connexin-32),
which is present in both the central nervous system (CNS)
and peripheral nervous system.1 CMTX1’s clinical phenotype
consists of progressive muscle atrophy, weakness, areflexia,
variable sensory abnormalities, and, occasionally, CNS manifestations.2 The diagnosis is based on clinical presentation,
electromyography, and nerve conduction studies that
demonstrate slowed nerve conduction velocities with
demyelinating features. Sequencing of the GBJ1 gene detects
approximately 90% of cases.3 More than 400 different mutations in the GBJ1 gene have been identified, and transient
CNS deficits with associated white matter abnormalities on

received
March 4, 2019
accepted after revision
May 20, 2019

magnetic resonance imaging (MRI) have been reported in
patients with CMTX1.2,4,5
Here we report two previously healthy adolescent
patients who presented with stuttering stroke-like episodes
and were ultimately diagnosed with CMTX1 disease with
CNS features.

Case 1
A 13-year-old male presented with isolated right facial weakness and was diagnosed with Bell’s palsy and treated for Lyme
disease with doxycycline. His facial weakness improved temporarily, but he returned to the emergency department hours
later with recurrent facial weakness, dysarthria, and right
upper extremity weakness and numbness. He was admitted,

© Georg Thieme Verlag KG
Stuttgart · New York

DOI https://doi.org/
10.1055/s-0039-1692982.
ISSN 0174-304X.

Downloaded by: Universitätsbibliothek. Copyrighted material.

Neuropediatrics

Hardy et al.

placed on standard stroke precautions, and given aspirin. His
neurologic exam was notable for a mild, fluctuating right
upper and lower facial droop, decreased right-hand strength,
brisk right biceps and right patellar tendon reflexes, diminished ankle reflexes, pes cavus deformity of his feet, and mild
muscle wasting in his distal lower extremities. Additional
history revealed travel to the mountains in New York and
California the week prior to presentation.
Cerebrospinal fluid (CSF) analysis was normal. MRI showed
asymmetric restricted diffusion in the bilateral centrum semiovale, posterior corona radiata, and lateral aspects of the
splenium of the corpus callosum, with superior extension of
the left to the left precentral gyrus with associated T2 hyperintense signal corresponding to areas of restricted diffusion
(►Fig. 1A–C). Magnetic resonance (MR) angiography was
normal. Electromyography and nerve conduction studies
showed evidence of a mild-to-moderately severe and chronic
sensorimotor demyelinating neuropathy consistent with
CMTX1. Genetic testing demonstrated a hemizygous L76P
variant (c.227T > C (p.Leu76Pro (L76p)) of the GJB1 gene.

Case 2
A 14-year-old right-handed boy presented after 2 days of
stuttering symptoms of tongue tingling and right facial weakness while traveling to Bermuda on a cruise. He was treated
with diphenhydramine for a possible allergic reaction, with
resolution of symptoms. The following evening, the symptoms
returned prompting treatment with prednisone for possible
Bell’s palsy by the cruise physician. The next morning, he was
brought to an emergency room in Bermuda where he complained of right leg weakness. He was managed according to a
stroke protocol and transferred to our facility for further
diagnostics and management. His examination was notable
for ankle weakness, decreased vibration sense in lower extremities, absent lower extremity reflexes, and pes cavus deformity of his feet. Additional history revealed bilateral foot
weakness since childhood.
CSF showed an elevated protein of 139 mg/dL but was
otherwise unremarkable. MRI revealed symmetric foci of T2
and FLAIR (fluid-attenuated inversion recovery) hyperintensity of the centrum semiovale, posterior corona radiata, posterior periventricular white matter, and, to a lesser extent, the
splenium of the corpus callosum with marked decreased
diffusion in the areas of T2 prolongation (►Fig. 1D–F). MR
angiography was unremarkable. Electromyography and nerve
conduction studies revealed electrophysiological evidence of a
demyelinating neuropathy primarily in the arms and a mixed
demyelinating and axonal neuropathy in the legs with chronic
denervation throughout. A hemizygous mutation (c.425G > A
(p.Arg142Lgn)) was identified in the GJB1 gene.

Discussion
CNS manifestations of CMTX1 can include dysarthria, dysphagia, aphasia, extremity weakness, respiratory distress,
ataxia, paresthesias, and cranial neuropathies. These can be
stuttering, transient, or sustained. Stroke-like events have
Neuropediatrics

been described in individuals with CMTX1, and CNS involvement can precede clinical signs of peripheral neuropathy,
making the diagnosis challenging.6 In both cases described
here, the initial presenting symptoms were stuttering and
asymmetric, mimicking a vascular etiology, although signs of
peripheral neuropathy including pes cavus were present on
examination. Fluctuating episodes of Bell’s palsy were also
noted in both cases, which may have been secondary to
either bilateral white matter involvement or lower motor
neuron involvement, as CMTX1 is both a central and peripheral neurologic disease. CMTX1 presenting with Bell’s palsy
as an initial manifestation has not been previously described.
Episodes can begin suddenly or progress over days, and can
last for several weeks, often with a fluctuating course.
Attacks can be provoked by travel to high altitudes, fevers,
or intercurrent illnesses, or can be unprovoked.4,7,8 In case 1,
the recent travel to altitude possibly provoked his episode,
whereas the flight to cruise boat transition may have provoked the symptoms in case 2.
CNS events in patients with CMTX1 and CNS involvement
can be recurrent.4,5,7 On further history, the patient in case 1
had a transient episode of slurred speech and ataxia 4 years
prior. During that hospitalization, he was found to be influenza A positive, and his symptoms were attributed to the
viral infection after a head computed tomography (CT) and
lumbar puncture were unrevealing. His symptoms spontaneously resolved after 2 days. The patient in case 2 did not
have any prior episodes of transient neurologic dysfunction.
The MRI pattern of CMTX1 is unique and can assist with the
diagnosis. There are some similarities to methotrexate toxicity,
although this would be apparent on history. MRI changes in
CMTX1 classically show nonenhancing signal abnormalities in
the periventricular deep white matter, middle cerebral
peduncles, centrum semiovale, and the corpus callosum, often
with a posterior predominance. Additionally, T2 abnormalities
in CMTX1 typically spare the subcortical U-fibers distinguishing it from other white matter disorders such as acute
disseminated encephalomyelitis. MRI signal abnormalities
usually resolve within a few months.1 Interestingly, despite
bilateral MRI findings in both cases, neither patient demonstrated bilateral symptoms. Nerve conduction studies
commonly show “intermediate range” slowing of nerve conduction velocities ranging between 30 and 45 m/s, as well as
mildly prolonged distal motor and F wave latencies.1,2,6 The
CSF of these patients is typically normal, supporting the idea
that inflammation is not a primary etiology of this disorder.5
Various mutations in the GJB1 gene have been associated
with clinical and MRI evidence of CNS involvement. The exact
mechanism through which CNS damage occurs is unknown;
however, it is suspected to be secondary to disruption of gap
junction communication between oligodendrocytes and
astrocytes. Disruption of gap junction mediated coupling
between oligodendrocytes and astrocytes is thought to lead
to dysregulation of fluid exchange, resulting in the diffusion
restriction abnormalities that are often identified on MRI in
these patients.5 Additionally, it has been hypothesized that
physiologic stressors such as hypoxia and infections lead to
decreased gap junction coupling between oligodendrocytes

Downloaded by: Universitätsbibliothek. Copyrighted material.

X-Linked Charcot–Marie–Tooth Disease

Hardy et al.

Downloaded by: Universitätsbibliothek. Copyrighted material.

X-Linked Charcot–Marie–Tooth Disease

Fig. 1 Brain MRI images of X-linked Charcot–Marie–Tooth disease from patients in case 1 (A–C) and case 2 (D–F) demonstrating markedly
reduced diffusion on DWI (diffusion-weighted imaging) (A,D) and ADC (apparent diffusion coefficient) maps (B,E), with corresponding T2
hyperintensity on T2 FLAIR (fluid-attenuated inversion recovery) sequences (C,F). (G–I) Follow-up imaging for case 2 at 4 months postinitial
presentation showed near complete resolution of the signal abnormalities.

and astrocytes. Specifically, it has been shown that fluctuations in oxygen exposure lead to CSF acidosis, which is
believed to cause closure of gap junctions.8,9 Similarly,
proinflammatory cytokines released during infections inhibit glial gap junctions, which can also lead to decreased gap
junction coupling.9 Thus, patients with CMTX1 who have

fragile gap junction communication due to mutations in
connexin-32 may be more vulnerable to metabolic stressors
leading to transient neurologic deficits.
Treatment for CMTX1 is supportive and focuses on management of the peripheral neuropathy, which may include
physical therapy and the use of orthotics. Avoidance of
Neuropediatrics

Hardy et al.

known triggers is advised. In our patients, symptoms completely resolved within 1 to 2 days of hospitalization, and
neither patient has had a recurrence. Follow-up MRI for case
2 at 4 months shows near complete resolution of signal
abnormalities (►Fig. 1G–I). The patient in case 1 did not have
follow-up imaging performed.
As an X-linked recessive disorder, males with CMTX1 disease
have moderate-to-severe sensory/motor neuropathy, whereas
females have mild or no symptoms. In the cases presented here,
both of the patients’ mothers were asymptomatic, although
they both had a sensory neuropathy on examination.
Conflict of Interest
The authors have no conflicts of interest to disclose.

References
1 Wang Y, Yin F. A review of X-linked Charcot-Marie-Tooth disease.

J Child Neurol 2016;31(06):761–772
2 Scherer SS, Kleopa KA. X-linked Charcot-Marie-Tooth disease.

J Peripher Nerv Syst 2012;17(Suppl 3):9–13

Neuropediatrics

3 Bird TD. Charcot-Marie-Tooth Neuropathy X Type 1. In: GeneRe-

views [online]. Available at: https://www.ncbi.nlm.nih.gov/books/
NBK1374. Accessed October 24, 2018
4 Al-Mateen M, Craig AK, Chance PF. The central nervous system
phenotype of X-linked Charcot-Marie-Tooth disease: a transient
disorder of children and young adults. J Child Neurol 2014;29(03):
342–348
5 Taylor RA, Simon EM, Marks HG, Scherer SS. The CNS phenotype
of X-linked Charcot-Marie-Tooth disease: more than a peripheral
problem. Neurology 2003;61(11):1475–1478
6 Sagnelli A, Piscosquito G, Chiapparini L, et al. X-linked CharcotMarie-Tooth type 1: stroke-like presentation of a novel GJB1
mutation. J Peripher Nerv Syst 2014;19(02):183–186
7 Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD.
Transient, recurrent, white matter lesions in X-linked CharcotMarie-Tooth disease with novel connexin 32 mutation. Arch
Neurol 2003;60(04):605–609
8 Paulson HL, Garbern JY, Hoban TF, et al. Transient central nervous
system white matter abnormality in X-linked Charcot-Marie-Tooth
disease. Ann Neurol 2002;52(04):429–434
9 Abrams CK, Scherer SS. Gap junctions in inherited human disorders
of the central nervous system. Biochim Biophys Acta 2012;1818
(08):2030–2047

Downloaded by: Universitätsbibliothek. Copyrighted material.

X-Linked Charcot–Marie–Tooth Disease