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Neuromuscular Disorders 21 (2011) 223226

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Case report

Conduction block and tonic pupils in Charcot-Marie-Tooth

disease caused by a myelin protein zero p.Ile112Thr mutation
Sinead M. Murphy a,, Matilde Laura a, Julian Blake b,c, James Polke d, Fion Bremner e,
Mary M. Reilly a
a

MRC Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery and Department of Molecular Neuroscience,
UCL Institute of Neurology, London, UK
b
Department of Clinical Neurophysiology, The National Hospital for Neurology and Neurosurgery and Department of Molecular Neuroscience,
UCL Institute of Neurology, London, UK
c
Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK
d
Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery and Department of Molecular Neuroscience,
UCL Institute of Neurology, London, UK
e
The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Received 7 September 2010; received in revised form 26 November 2010; accepted 21 December 2010

Abstract
We report a patient with Charcot-Marie-Tooth disease (CMT) due to the p.Ile112Thr mutation in myelin protein zero (MPZ) who
presented with a patchy neuropathy with conduction block and tonic pupils. Conduction block is unusual in inherited neuropathies,
while pupil abnormalities are recognised to occur in CMT especially due to MPZ mutations. This case highlights that patchy demyelinating neuropathy with conduction block may occur in p.Ile112Thr MPZ mutations. Involvement of the pupils, as in this case, may be a
pointer towards a genetic rather than inammatory cause of neuropathy.
2010 Elsevier B.V. All rights reserved.
Keywords: Charcot-Marie-Tooth disease; CMT; Tonic pupils; Myelin protein zero; Conduction block

1. Introduction
Myelin protein zero (MPZ) mutations can cause both
demyelinating Charcot-Marie-Tooth disease (CMT1) and
axonal CMT (CMT2) [13]. In CMT1, conduction velocity
is usually uniform without temporal dispersion or conduction block [4] whereas in inammatory demyelinating
neuropathies, conduction block is commonly seen.
Occasionally, conduction block has been described in
genetically conrmed CMT [5,6].
Pupil involvement has been described in 17% of patients
with CMT [7]. The pupil abnormalities described include

Corresponding author. Address: MRC Centre for Neuromuscular

Disorders, 8-11 Queen Square, London, WC1N 3BG. Tel.: +44 (0) 845
1555000x3034.
E-mail address: sinead.murphy@uclh.nhs.uk (S.M. Murphy).
0960-8966/$ - see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.nmd.2010.12.010

tonic pupils [811], Argyll-Robertson pupils [12,13]

Horners syndrome [7] and anisocoria [7]. Patients with
MPZ mutations and a CMT2 phenotype, especially due
to the p.Thr124Met mutation, have been described to have
pupil involvement more frequently than in other forms of
CMT [1,9,1214]. There is no description in the literature
of a patient with conduction block and pupil involvement
due to a MPZ mutation.
Here, we describe a young man with genetically conrmed CMT due to a mutation in MPZ who had pupil
abnormalities and unusual neurophysiology consisting of
a patchy neuropathy with conduction block.
2. Case report
This 37-year-old man was adopted as an infant, thus no
family history is available. He walked late, subsequently

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S.M. Murphy et al. / Neuromuscular Disorders 21 (2011) 223226

toe-walked and required surgery to his feet at the age of

5 years. He had always been slow at running and developed
diculties with balance in his teens. He also noticed numbness to mid-calf and had some diculty doing buttons. He
noticed slow deterioration in his thirties, in particular nding balance worse in the dark and developing increasing
numbness in the feet. He described lifelong diculty with
night vision.
On examination, there was diculty with tandem walking, diculty standing on his heels and positive Rombergs
sign. He also had pes cavus and clawed toes with tight
Achilles tendons. There was distal wasting and weakness
to MRC grade 4 in the arms and legs with a glove and
stocking distribution of sensory loss. He was areexic
and plantar responses were mute. CMT Neuropathy Score
(CMTNS) [15] was 15/28 indicating moderate severity.
Visual acuity was 6/5 bilaterally with normal colour vision
and Humphrey visual elds, and fundoscopy was normal.
His pupils showed symmetrical abnormalities, being small
but regular in shape with no sector palsy apparent on slitlamp biomicroscopy. Both pupils showed almost no miotic
response to light but greater miosis on accommodative
eort (light-near dissociation) with cholinergic supersensitivity to 0.1% pilocarpine drops; however, the mydriatic
responses to sudden noise (the startle response) and 4%
cocaine drops were normal (Fig. 1).
Neurophysiology (Table 1) showed a patchy motor and
sensory neuropathy with some demyelinating features and
conduction block in the median nerves in both forearms.
This was unchanged over two years. Conduction block
was dened as a reduction of P30% in the area under
the CMAP curve or a reduction of P30% in CMAP

Table 1
Nerve conduction studies.
Right median nerve
DML ms (64)
CMAP wrist mV (P5)
CMAP elbow mV(P5)
MNCV m/s (P50)
f Latency ms (630)
SAP lv (>8)

4.9
5.4
1.6
20
84.8
NR

Left median nerve

DML ms (64)
CMAP wrist mV (P5)
CMAP elbow mV (P5)
MNCV m/s (P50)
f Latency ms (630)

4.7
6.2
1.1
21
NR

Right ulnar nerve

DML ms (63.5)
CMAP wrist mV (P8)
CMAP below elbow mV (P8)
CMAP above elbow mV (P8)
MNCV wrist-elbow m/s (P50)
MNCV elbow segment m/s (P50)
f Latency ms (630)

3.6
9.8
8.9
9.4
33
35
65.9

DML: distal motor latency; CMAP: compound motor

action potential; MNCV: motor nerve conduction velocity; SAP: sensory action potential; NR: not recordable.
Normal values in parentheses. Abnormal values
highlighted in bold.

amplitude as long as there was no signicant increase in

duration of the response.
He was negative for the chromosome 17 duplication and
for mutations in GJB1. Bi-directional sequence analysis of
the coding region of MPZ using standard reference primers
[16] revealed a mutation at c.335T > C (p.Ile112Thr).

Fig. 1. (A) At rest both pupils show symmetrical miosis. (B) Appearance of the pupils 30 min after topical administration of 4% cocaine in the right eye
and 0.1% pilocarpine in the left eye. Cocaine has produced a normal degree of mydriasis (and lid retraction) in the right eye conrming that the
sympathetic innervation of the iris dilator muscle is intact; however, dilute pilocarpine has caused an abnormal constriction of the left pupil indicating
interruption of the parasympathetic supply to the iris sphincter muscle.

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3. Discussion
We have described a patient with CMT due to a
p.Ile112Thr MPZ mutation with unusual neurophysiology
consisting of a patchy neuropathy with conduction block
as well as pupillary involvement.
The p.Ile112Thr mutation in MPZ has been previously
described as causing a severe CMT1 phenotype with no distinguishing features such as conduction block or pupil
involvement [1,17]. Our patient, however, diers as he
had a moderate, patchy neuropathy with conduction block
and pupil abnormalities.
The presence of conduction block is unusual in genetic
neuropathies but has been reported in association with
LITAF [6], GJB1 [5] and rarely with MPZ mutations
[1820]. Donaghy et al. described a family with a
p.Ile99Thr MPZ mutation, in whom neurophysiology in
the proband demonstrated conduction block; however,
neuropathic symptoms developed following a respiratory
tract infection, CSF protein was raised and he improved
with steroid treatment, therefore suggesting a superimposed inammatory neuropathy [18]. Street et al. reported
a family with a p.Ser140Thr MPZ mutation, one of whom
demonstrated a patchy neuropathy with conduction block
[19]. Souayah et al. more recently described a man with an
asymmetric demyelinating neuropathy and partial conduction block in the forearm segment of the median nerve
associated with an Arg98His MPZ mutation [20]. Another
MPZ mutation, p.Tyr145stop, has been reported to cause a
demyelinating neuropathy with additional lesions at compression sites, mimicking hereditary neuropathy with liability to pressure palsies (HNPP) [21].
Although conduction block in non-compressible sites
always raises the possibility of chronic inammatory demyelinating polyradiculoneuropathy (CIDP), there was nothing in our patient to suggest this. The p.Ile112Thr mutation
is located in exon 3, a region which codes for the extracellular domain of MPZ. It is dicult to hypothesize why a
mutation in MPZ should cause such patchy involvement
rather than the uniform velocities usually seen with
CMT. It is of interest, however, that heterozygous MPZ
knockout mice develop an age-dependant neuropathy that
resembles CIDP with patchy multifocal demyelination,
temporal dispersion and conduction block [22].
The loss of the miotic response of the pupils to a light
stimulus in a patient with normal vision indicates damage
either centrally (to the mesencephalic pretectum) or peripherally (to the parasympathetic pathway innervating the iris
sphincter muscles); that his damage was peripheral (i.e.
infranuclear) was conrmed by demonstrating denervation
supersensitivity to a weak muscarinic agonist. Such cholinergic supersensitivity has no localising value and may be
seen associated with pre- or post-ganglionic lesions [23];
however, there was no ophthalmoplegia or ptosis to suggest involvement of the pre-ganglionic (oculomotor)
nerves, and the pupils showed a slow but otherwise preserved miosis associated with accommodative eort

225

(light-near dissociation), suggesting a diagnosis of tonic

pupils and indicating damage to the post-ganglionic parasympathetic bres that run in the small posterior ciliary
nerves. Similar pupillary ndings of a lack of response to
light but retained response to accommodation, however,
without cholinergic supersensitivity, was reported in a
patient with two mutations in MPZ (p.His81Tyr and
p.Val113Phe [24]. In HolmesAdie syndrome the tonic
pupils are often initially large but progressively miose over
time, ending up much smaller than normal; however, in
some cases, and especially where the pupillotonia is associated with other conditions, the pupils are abnormally small
from the outset [25]. The lack of anisocoria and absence of
sector palsies in this patient are important clinical features
suggesting that his tonic pupils are caused by the identied
mutation in MPZ and are not due to a coincidental
HolmesAdie syndrome [26].
When associated with MPZ mutations, tonic pupils are
more often seen in axonal rather than demyelinating forms
of CMT [27]. Pupil abnormalities were not described in the
previous reports of patients with p.Ile112Thr MPZ mutations [1,17], neither were they reported in the patients with
MPZ mutations where conduction block was demonstrated [1821]. It is unclear why our patient should have
such specic involvement of the post-ganglionic parasympathetic pathway to the iris, as he did not have any other
features of parasympathetic dysfunction, and the short ciliary nerves are, as their name suggests, short and thus
should not be aected by a moderate severity length dependent neuropathy.
This report highlights that patchy demyelinating neuropathy with conduction block may occur in MPZ mutations. Involvement of the pupils, as in this case, may be a
pointer towards a genetic rather than inammatory cause
of neuropathy.
Acknowledgements
M.M.R. is grateful to the Medical Research Council
(MRC) and the Muscular Dystrophy Campaign and
S.M.M. and M.M.R. are grateful to the NINDS/ORD
(1U54NS065712-01) for their support. This work was
undertaken at University College London Hospitals/
University College London, which received a proportion
of funding from the Department of Healths National
Institute for Health Research Biomedical Research Centres
funding scheme.
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